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Yue X, Wang Y, Zheng R, Li L. The coping experiences in patients with hepatocellular carcinoma and their spouses following postoperative recurrence: A dyadic qualitative study. Asia Pac J Oncol Nurs 2025; 12:100665. [PMID: 40104041 PMCID: PMC11919323 DOI: 10.1016/j.apjon.2025.100665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 02/05/2025] [Indexed: 03/20/2025] Open
Abstract
Objective Dyadic coping practices can vary depending on cultural contexts, socioeconomic factors, and the stages of the cancer journey. This study aimed to explore the dyadic coping experiences of hepatocellular carcinoma (HCC) patients and their spouses following postoperative recurrence in the Chinese cultural context, where cancer recurrence is frequently seen as a death sentence, and family-centered care is prioritized. Methods A descriptive qualitative research design was used, involving face-to-face, in-depth semi-structured interviews with 13 pairs of hepatocellular carcinoma patients and their spouses at a tertiary cancer hospital from July to October 2023. The interview guide was designed based on the Actor-Partner Interdependence Model (APIM) framework. Data were analyzed using thematic analysis, and the study adhered to the COnsolidated criteria for REporting Qualitative research (COREQ) checklist. Results Three themes were identified: (1) active coping strategies, (2) negative coping tendencies, and (3) the need for systematic coping support. The majority of couples perceived hepatocellular carcinoma recurrence as a death sentence, which prompted them-especially the spouses-to adopt proactive strategies, such as striving to seek advanced treatments and concealing unfavorable information. In contrast, patients, particularly those with a hereditary hepatocellular carcinoma background, often exhibited passivity, withdrawal, and contemplation of treatment abandonment. Spouses frequently felt overwhelmed and unable to alleviate their partners' anxiety about recurrence and death, particularly in the absence of support from health care professionals. They expressed a strong need for professional guidance and targeted interventions to address end-of-life concerns, emphasizing the need for increased financial support, empowerment through knowledge, and access to peer support networks. Conclusions This research emphasizes the importance of recognizing the interdependent coping experiences of recurrent HCC patients and their spouses. Health care professionals are encouraged to implement culturally sensitive, dyadic interventions that foster collaborative coping, address death-related anxiety, and empower couples in managing recurrence together, thereby enhancing their coping strategies and confidence.
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Affiliation(s)
- Xian Yue
- Department of Nursing, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
- Department of Hepatobiliary, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yanhui Wang
- Department of Hepatobiliary, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Ruishuang Zheng
- Department of Hepatobiliary, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Laiyou Li
- Department of Nursing, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
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Fan HL, Chen JL, Liu ST, Lee JT, Huang SM, Wu ZF, Lai HC. Remimazolam induced cytotoxicity mediated through multiple stress pathways and acted synergistically with tyrosine kinase inhibitors in hepatocellular carcinoma. Redox Rep 2025; 30:2475696. [PMID: 40053437 PMCID: PMC11892054 DOI: 10.1080/13510002.2025.2475696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/09/2025] Open
Abstract
The primary treatment for hepatocellular carcinoma (HCC) involves surgical removal of the primary tumor, but this creates a favorable environment for the proliferation and spread of residual and circulating cancer cells. The development of remimazolam-based balanced anesthesia is crucial for future antitumor applications. It is important to understand the mechanisms of cytotoxicity for HCC in detail. We performed cell viability analysis, western blotting analysis, reverse transcription-polymerase chain reaction analysis, and flow cytometry analysis in two HCC cell lines, HepG2 and Hep3B cells. Our data demonstrated that remimazolam induced cytotoxicity by suppressing cell proliferation, inhibiting G1 phase progression, and affecting mitochondrial reactive oxygen species (ROS) levels, leading to apoptosis, DNA damage, cytosolic ROS elevation, lipid peroxidation, autophagy, mitochondrial depolarization, and endoplasmic reticulum stress. Inhibitors of apoptosis, autophagic cell death, and ferroptosis and a ROS scavenger failed to rescue cell death caused by remimazolam besylate. Our combination index revealed that remimazolam besylate has the potential to act as a sensitizer for targeted tyrosine kinase inhibitor therapy for HCC. Our findings open up new possibilities for combinatory HCC therapy using remimazolam, leveraging its dual functional roles in surgery and drug therapy for liver cancers.
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Affiliation(s)
- Hsiu-Lung Fan
- Division of General Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei City, Taiwan, Republic of China
| | - Jia-Lin Chen
- Department of Anesthesiology, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Shu-Ting Liu
- Department of Biochemistry, National Defense Medical Center, Taipei City, Taiwan, Republic of China
| | - Jia-Tong Lee
- Department of Biochemistry, National Defense Medical Center, Taipei City, Taiwan, Republic of China
| | - Shih-Ming Huang
- Department of Biochemistry, National Defense Medical Center, Taipei City, Taiwan, Republic of China
| | - Zhi-Fu Wu
- Department of Anesthesiology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan, Republic of China
- Department of Anesthesiology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan, Republic of China
- Center for Regional Anesthesia and Pain Medicine, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan, Republic of China
| | - Hou-Chuan Lai
- Department of Anesthesiology, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan, Republic of China
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Darbà J, Ascanio M. Hepatocellular carcinoma: what are the differential costs compared to the general population? J Med Econ 2025; 28:471-478. [PMID: 40126406 DOI: 10.1080/13696998.2025.2484073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 03/20/2025] [Accepted: 03/21/2025] [Indexed: 03/25/2025]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC), which accounts for about 90% of all primary liver cancer cases, is the fifth most common malignancy and the second leading cause of cancer-related mortality worldwide. This study aims to analyse the differential costs of HCC-related hospital admissions compared to the general population in Spain. METHODS A retrospective multicenter study analyzed inpatient admissions from a Spanish national discharge database, covering 90% of hospitals between 2010 and 2022. HCC-related admissions were identified using ICD-9 and ICD-10 codes, while control admissions were selected from the general population in the same database without an HCC diagnosis. The direct hospitalization cost was included, covering medical examinations, procedures, medications, surgeries, personnel and equipment. Statistical methods, including nearest-neighbor matching, propensity score matching, and a generalized linear model, were used to estimate differential costs and to ensure comparability based on age, gender, and Charlson Comorbidity Index (CCI). RESULTS A total of 199,670 HCC-related hospital admissions and 200,000 control admissions were analyzed. Most HCC-related admissions involved male patients (78%) aged 66-85 years, with an average CCI of 5.18. HCC-related admissions incurred significantly higher costs, with an estimated differential cost of €1,303.68 using GLM, €1,804.25 via propensity score matching, and €1,767.77 using nearest-neighbor matching. Total costs per HCC admission ranged between €1,000 and €31,000. CONCLUSIONS HCC-related hospital admissions impose a significantly higher economic burden due to the complexity of care. Given the high mortality and resource utilization, advancements in early detection, treatment, and cost-effective interventions are needed to improve patient outcomes and reduce healthcare costs.
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Affiliation(s)
- Josep Darbà
- Department of Economics, Universitat de Barcelona, Barcelona, Spain
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Li X, Cui Y, Gao S, Zhang Q, Dai Y, Wang S, Wu J, Li G, Song J. Development and validation of a score model for predicting the risk of first esophagogastric variceal hemorrhage and mortality in patients with hepatocellular carcinoma. Ann Med 2025; 57:2490210. [PMID: 40210586 PMCID: PMC11986866 DOI: 10.1080/07853890.2025.2490210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 02/14/2025] [Accepted: 04/02/2025] [Indexed: 04/12/2025] Open
Abstract
AIMS Esophagogastric variceal bleeding, especially first variceal hemorrhage, represents a challenging complication in the management of patients with hepatocellular carcinoma (HCC), and its presence significantly herald poor patient prognosis. The stratification system for the risk of first variceal hemorrhage and mortality has not been validated in patients with HCC. We aimed to develop and validate a simple score for the prediction of initial variceal bleeding and mortality in patients with HCC. METHODS This multicenter retrospective-prospective study included HCC patients at three tertiary hospitals in China from January 2016 to December 2023. The bleeding following endoscopy for hepatocellular carcinoma (BFE-HCC) score was constructed by the least absolute contraction and selection operator (LASSO) regression combined with multivariate logistic regression analysis. The performance of the score model was evaluated using the receiver operating characteristic (ROC) curve, the calibration curve, and the decision curve analysis (DCA). Finally, the of the results was further verified in an independent external cohort. RESULTS We recruited 351 patients from three centers (median age 56 years, 85.5% male and 83.5% with cirrhosis), 56.6% patients presented high-risk (HR) varices, and 35% patients experienced variceal bleeding. Multivariate logistic analysis revealed that the presence of cirrhosis, a history of acute variceal bleeding (AVB), Child-Pugh score, ALBI score, tumor size and portal vein tumor thrombosis (PVTT) Vp4 were independent predictors of HR varices. The BFE-HCC is composed of six variables: white blood cell count, HR varices, Child-Pugh score, HCC therapy modality, Vp4, and tumor stage. The area under the curve (AUC) of BFE-HCC was 0.82, and the calibration plots and decision curve analysis exhibited outstanding performance compared with the MELD, ALBI, and Child-Pugh scores. In addition, Patients with BFE-HCC ≥ 4 were at increased risk of mortality (P<0.01). CONCLUSIONS The BFE-HCC score is hopeful to predict initial variceal bleeding and mortality in patients with HCC, offering a promising tool for prognostic assessment and treatment decisions.
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Affiliation(s)
- Xueyan Li
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yajie Cui
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Shan Gao
- Department of Gastroenterology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, China
| | - Qingqing Zhang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yan Dai
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shaotong Wang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiandi Wu
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Gangping Li
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Song
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Zhao KF, Xie CB, Wu Y. Prediction of the efficacy of first transarterial chemoembolization for advanced hepatocellular carcinoma via a clinical-radiomics model. World J Clin Cases 2025; 13:101742. [DOI: 10.12998/wjcc.v13.i23.101742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 03/09/2025] [Accepted: 04/25/2025] [Indexed: 06/04/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a common tumor with a poor prognosis. Early intervention is essential; thus, good prognostic markers to identify patients who benefit from first transarterial chemoembolization (TACE) are needed.
AIM To investigate the efficacy of computed tomography (CT) radiomics in predicting the success of the first TACE in patients with advanced HCC and to develop an early prediction model based on clinical radiomics features.
METHODS Data from 122 patients with advanced HCC treated with TACE were analyzed. Intratumoral and peritumoral areas on arterial and venous CT images were selected to extract radiomic features, which were screened in the training cohort using the minimum redundancy maximum correlation. Then, support vector machines were used to construct the model. To construct a receiver operating characteristic curve, the predictive efficacy of each model was evaluated on the basis of the area under the curve (AUC).
RESULTS Among the 122 patients, 72 patients were effectively treated via TACE, and in 50 patients, this treatment was ineffective. In the radiomics model, the areas under the curve of the venous phase model were 0.867 (95%CI: 0.790-0.940) in the training cohort and 0.755 (0.600-0.910) in the validation cohort, indicating good predictive efficacy. The multivariate logistic regression results indicated that preoperative alpha-fetoprotein levels (P = 0.01) were a risk factor for TACE. The screened clinical features were combined with the radiomic features to construct a combined model. This combined model had an AUC of 0.92 (0.87-0.95) in the training cohort and 0.815 (0.67-0.95) in the validation cohort.
CONCLUSION CT radiomics has good value in predicting the efficacy of the first TACE treatment in patients with HCC. The combined model was a better tool for predicting the first TACE efficacy in patients with advanced HCC and could provide an efficient predictive tool to help with the selection of patients for TACE.
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Affiliation(s)
- Kai-Fei Zhao
- Department of Radiology, The Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Chao-Bang Xie
- Department of Radiology, The Affiliated Hospital of Guizhou Medical University, Guiyang 563000, Guizhou Province, China
| | - Yang Wu
- Department of Intervention, The Second Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
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Fang Z, Pan Y, Lu Z, Wang L, Hu X, Ma Y, Li S. LncRNA SNHG1: A novel biomarker and therapeutic target in hepatocellular carcinoma. Gene 2025; 958:149462. [PMID: 40187618 DOI: 10.1016/j.gene.2025.149462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 03/24/2025] [Accepted: 03/28/2025] [Indexed: 04/07/2025]
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality globally. Increasing evidence suggests that long non-coding RNAs play a critical role in cancer development, with the small nucleolar RNA host gene family being a key participant in multiple types of carcinogenesis, including HCC. Small nucleolar RNA host gene 1 (SNHG1) is a significant member of the SNHG family. SNHG1 expression consistently increases in various HCC-associated processes, such as cell proliferation, apoptosis, angiogenesis, migration, invasion, and treatment resistance. Higher SNHG1 expression levels predict worse prognosis by positively correlating with clinicopathological features, including larger tumour size, poor differentiation, and advanced stages in patients with HCC. Nevertheless, the precise role of SNHG1 in the initiation and progression of HCC remains unclear. Therefore, this review aims to summarise the current investigations on the pathogenesis of SNHG1 in HCC, highlighting its potential as a molecular marker for early prediction and prognostic assessment. As a multifunctional modulator, SNHG1 is extensively involved in molecular signalling pathways in HCC progression and is valuable for therapeutic targeting.
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Affiliation(s)
- Zhou Fang
- Department of Infectious Diseases, Zhoushan Hospital, Wenzhou Medical University, No.739 Dingshen Road, Zhoushan 316021 Zhejiang Province, China
| | - Yong Pan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of Zhejiang University, Hangzhou 31003, China
| | - Zhengmei Lu
- Department of Infectious Diseases, Zhoushan Hospital, Wenzhou Medical University, No.739 Dingshen Road, Zhoushan 316021 Zhejiang Province, China
| | - Lingyun Wang
- Department of Infectious Diseases, Zhoushan Hospital, Zhejiang University, No.739 Dingshen Road, Zhoushan 316021 Zhejiang Province, China
| | - Xiaodan Hu
- Department of Infectious Diseases, Zhoushan Hospital, Wenzhou Medical University, No.739 Dingshen Road, Zhoushan 316021 Zhejiang Province, China
| | - Yingqiu Ma
- Department of Infectious Diseases, Zhoushan Hospital, Wenzhou Medical University, No.739 Dingshen Road, Zhoushan 316021 Zhejiang Province, China
| | - Shibo Li
- Department of Infectious Diseases, Zhoushan Hospital, Wenzhou Medical University, No.739 Dingshen Road, Zhoushan 316021 Zhejiang Province, China.
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Shang LQ, Guo HX, Wang P, Sun XH, You JQ, Ma JT, Wang LK, Liu JX, Wang ZQ, Shao HB. Global scientific trends on hepatocellular carcinoma research from 2004 to 2023: A bibliometric and visualized analysis. World J Gastrointest Oncol 2025; 17:105781. [DOI: 10.4251/wjgo.v17.i6.105781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 03/22/2025] [Accepted: 04/17/2025] [Indexed: 06/13/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide, and the research landscape has rapidly evolved over the past two decades. Despite significant progress, an in-depth analysis of global research trends, collaborative networks, and emerging themes in HCC remains limited. This study aimed to fill this gap by conducting a bibliometric analysis to map the research output, identify key contributors, and highlight future directions in HCC research. We hypothesized that the analysis would reveal a growing focus on molecular mechanisms and immunotherapy, with increasing contributions from specific countries and institutions.
AIM To investigate global research trends, collaborative networks, and emerging themes in HCC from 2004 to 2023.
METHODS A bibliometric analysis was performed using 93987 publications from the Science Citation Index Expanded Database of the Web of Science Core Collection. Data were analyzed using the VOSviewer software to identify publication trends, leading contributors, and research themes. Key metrics included annual publication output, country and institutional contributions, journal impact, and thematic clusters. Statistical analysis was carried out to quantify trends and collaborations.
RESULTS The number of annual publications increased from 2341 in 2004 to 8756 in 2023, with 65583 papers (69.78%) published between 2014 and 2023. China, the United States, and Japan were the top contributors, constituting 58.3% of total publications. PLOS One published the most studies (n = 2145), while Gastroenterology had the highest average number of citations (78.4 citations per paper). Fudan University was the most prolific institution (n = 1872). Thematic analysis identified five main clusters, namely molecular mechanisms, therapeutic strategies, prognosis and immunology, risk factors, and diagnostic approaches.
CONCLUSION This study highlights the growing focus on HCC research, particularly in immunotherapy and molecular mechanisms, underscoring the significance of international collaboration to advance diagnosis and treatment strategies.
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Affiliation(s)
- Li-Qi Shang
- Department of Interventional Radiology, The First Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
| | - Hao-Xin Guo
- Department of Information Center, The First Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
| | - Peng Wang
- Department of Interventional Radiology, The First Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
| | - Xiao-Han Sun
- Department of Interventional Radiology, The First Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
| | - Jia-Qi You
- Department of Interventional Radiology, The First Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
| | - Jun-Ting Ma
- Department of Interventional Radiology, The First Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
| | - Lu-Ke Wang
- Department of Interventional Radiology, The First Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
| | - Jia-Xi Liu
- Department of Interventional Radiology, The First Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
| | - Zhong-Qing Wang
- Department of Information Center, The First Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
| | - Hai-Bo Shao
- Department of Interventional Radiology, The First Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
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Wang YT, Yong YL, Liu ZK, Shen YX, Yang XM, Chen ZN. Regulator of chromosome condensation 1 promotes hepatocellular carcinoma proliferation via cell-division-cycle-associated-8 dependent phosphoinositide 3-kinase/protein kinase B signaling. World J Gastrointest Oncol 2025; 17:106080. [DOI: 10.4251/wjgo.v17.i6.106080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2025] [Revised: 04/01/2025] [Accepted: 04/18/2025] [Indexed: 06/13/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) ranks among the most prevalent and deadly malignancies, characterized by a high recurrence rate. Regulator of chromosome condensation 1 (RCC1) serves as a principal guanine nucleotide exchange factor for ras-related nuclear protein guanosine triphosphatase (GTPase) and is implicated in various cancers. However, the role of RCC1 in HCC remains unexplored.
AIM To elucidate the functional significance and molecular mechanisms of RCC1 in HCC.
METHODS Bioinformatics were to examine the expression levels of RCC1 in HCC and to assess its impact on the prognosis of this malignancy. The cell counting kit-8 assay and flow cytometry were utilized to evaluate the cell viability and cell cycle of HCC cells. Furthermore, quantitative reverse transcription and immunoblotting were to investigate the influence of RCC1 on cyclin associated proteins.
RESULTS Bioinformatics analysis revealed that RCC1 was highly expressed in HCC and correlated with poor prognosis in HCC patients. Functional studies showed that RCC1 overexpression promoted the malignant phenotype of HCC cells, especially the proliferation of HCC cells, whereas RCC1 knockdown had the opposite effect. Mechanistically, we identified cell division cycle-associated (CDCA) 8 as a downstream target of RCC1 in HCC. RCC1 overexpression markedly increased CDCA8 levels, consequently enhancing cell proliferation and survival in HCC cells. Additionally, we discovered that RCC1 contributed to the development and progression of HCC by activating the phosphoinositide 3-kinase/protein kinase B/cyclin-dependent kinase inhibitor 1a pathway through CDCA8.
CONCLUSION Our study provides profound insights into the pivotal role of RCC1 in HCC and its potential as a therapeutic target.
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Affiliation(s)
- Ya-Tao Wang
- Department of Cell Biology, National Translational Science Center for Molecular Medicine, The Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China
| | - Yu-Le Yong
- Department of Cell Biology, National Translational Science Center for Molecular Medicine, The Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China
| | - Ze-Kun Liu
- Department of Cell Biology, National Translational Science Center for Molecular Medicine, The Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China
| | - Yi-Xuan Shen
- Department of Cell Biology, National Translational Science Center for Molecular Medicine, The Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China
| | - Xiang-Min Yang
- Department of Cell Biology, National Translational Science Center for Molecular Medicine, The Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China
| | - Zhi-Nan Chen
- Department of Cell Biology, National Translational Science Center for Molecular Medicine, The Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China
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Chen Y, Zou S, Xu L, Chen J, Wang L, Shen Y, Xu Y, Wei Y, Xu X. NSMCE2 promotes the occurrence and development of HCC by regulating the SUMOylation of PPARα. Int Immunopharmacol 2025; 157:114762. [PMID: 40318278 DOI: 10.1016/j.intimp.2025.114762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2025] [Revised: 04/17/2025] [Accepted: 04/27/2025] [Indexed: 05/07/2025]
Abstract
BACKGROUND Primary liver cancer is a malignant tumor of the digestive system and ranks as the sixth most commonly diagnosed cancer globally. It has also risen to become the third leading cause of cancer-related deaths globally, following lung and colorectal cancers. Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancer, approximately 75 to 85 %. Several studies suggest that NSMCE2 contributes to cancer through its SUMO E3 ligase activity, yet its specific role in HCC remains poorly understood. METHODS We gathered data from various databases and obtained 10 pairs of tissue samples from HCC patients to detect the NSMCE2 expression levels. Additionally, we conducted both in vivo and in vitro experiments to confirm the impact of NSMCE2 on the development and progression of HCC. We further analyzed the potential mechanism of NSMCE2 regulation on HCC by bioinformatics, and detected the specific mechanism of NSMCE2 regulating PPARα by co-immunoprecipitation. RESULTS Our study shows that NSMCE2 is an important tumor promoter in HCC and acts through the PPARα-CYP7A1 axis. Specifically, NSMCE2 affects the occurrence and progression of HCC by SUMOylating PPARα, reducing its ubiquitination degradation, and activating the PPARα-CYP7A1 axis. CONCLUSIONS Our study uncovered the role of NSMCE2 in the development and progression of HCC, providing new insights into the pathogenesis and potential therapeutic strategies of HCC.
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Affiliation(s)
- Yukai Chen
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China
| | - Shishi Zou
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China
| | - Le Xu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China
| | - Jiayu Chen
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China
| | - Ling Wang
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China
| | - Yang Shen
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China
| | - Yangtao Xu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China
| | - Yuxin Wei
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China
| | - Ximing Xu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China.
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10
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Peng W, Liang J, Qian X, Li M, Nie M, Chen B. IGF2BP1/AIFM2 axis regulates ferroptosis and glycolysis to drive hepatocellular carcinoma progression. Cell Signal 2025; 130:111660. [PMID: 39971223 DOI: 10.1016/j.cellsig.2025.111660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 02/12/2025] [Accepted: 02/13/2025] [Indexed: 02/21/2025]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is aggressive liver tumor that is the third leading cause of cancer death. Ferroptosis and glycolysis play key roles in HCC progression. Apoptosis-inducing factor mitochondria-associated 2 (AIFM2) in involved in regulating ferroptosis and glycolysis in cancers, but its role in HCC remains unclear. This research explored the function of AIFM2 in HCC. METHODS AIFM2 expression in HCC tissues was evaluated using the UALCAN and GEPIA databases, as well as RT-qPCR. Kaplan-Meier survival analysis analyzed the correlation between AIFM2 and the prognosis of HCC patients. EdU and transwell assays were utilized to examine HCC cell proliferation, migration, and invasion. Ferroptosis markers were analyzed by measuring iron levels, ROS production (DCFH-DA assay), and oxidative stress indicators (SOD, MDA, and GSH). Glycolytic activity was assessed through glucose uptake, lactate production, and ATP levels. m6A modification on AIFM2 mRNA was confirmed by MeRIP assay, and mRNA stability was evaluated with Actinomycin D treatment. Tumor growth and metastasis were studied in xenograft and lung metastasis models. RESULTS UALCAN analysis showed that AIFM2 was significantly upregulated in HCC tissues, which correlated with poor survival rates of HCC patients. IGF2BP1 was also highly expressed in HCC tissues and positively correlated with AIFM2 levels in HCC tissues. Functionally, AIFM2 knockdown suppressed glycolysis and enhanced ferroptosis, while its overexpression had opposite effects. IGF2BP1 was found to stabilize AIFM2 mRNA via m6A modification, promoting AIFM2 expression. IGF2BP1 knockdown reduced glycolysis, proliferation, and invasion while promoting ferroptosis, while AIFM2 overexpression could reverse this effect. In vivo, IGF2BP1 or AIFM2 silencing significantly suppressed tumor growth and metastasis. CONCLUSION IGF2BP1 stabilized AIFM2 mRNA to regulate ferroptosis and glycolysis and promoted HCC progression.
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Affiliation(s)
- Wei Peng
- Department of Gastrointestinal Surgery, Zhejiang Provincial People's Hospital Bijie Hospital, Bijie, Guizhou 551700, China
| | - Jie Liang
- Department of Gastrointestinal Surgery, Zhejiang Provincial People's Hospital Bijie Hospital, Bijie, Guizhou 551700, China
| | - Xuanlv Qian
- Department of Gastrointestinal Surgery, Zhejiang Provincial People's Hospital Bijie Hospital, Bijie, Guizhou 551700, China
| | - Mingwang Li
- Department of Gastrointestinal Surgery, Zhejiang Provincial People's Hospital Bijie Hospital, Bijie, Guizhou 551700, China
| | - Ming Nie
- Department of Gastrointestinal Surgery, Zhejiang Provincial People's Hospital Bijie Hospital, Bijie, Guizhou 551700, China
| | - Bin Chen
- Department of Gastrointestinal Surgery, Zhejiang Provincial People's Hospital Bijie Hospital, Bijie, Guizhou 551700, China.
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11
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Saleh RO, Hamad HA, Najim MA, Menon SV, Kaur M, Sivaprasad GV, Abohassan M, Juan WT, Husseen B, Mustafa YF. Exosome-mediated Transfer of lncRNA in Liver Associated Diseases; Uncovered Truths. Cell Biochem Biophys 2025; 83:1465-1481. [PMID: 39567423 DOI: 10.1007/s12013-024-01617-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/08/2024] [Indexed: 11/22/2024]
Abstract
Exosomes are extracellular vesicles with a diameter ranging from 40 to 160 nm. They are produced by hepatocytes, cholangiocytes, hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSECs) and Kupffer cells in liver tissue. The secretion of exosomes might vary in quantity and composition in reaction to multiple triggers and various stages of disease. They transport various payloads, such as proteins, DNAs, and RNAs, and enable cell interaction to regulate myriad physiological and pathological processes in liver tissue. Long non-coding RNAs (lncRNAs) are a crucial component of exosomes with an excellent capability to regulate multiple cellular activities such as differentiation, development, metabolism, proliferation, apoptosis, and activation. With the advancements in transcriptomic and genomic study methods and database management technology, the functions and mechanisms of exosomal lncRNAs in liver diseases have been well-studied. This article delves into the detailed role of exosomal lncRNAs in liver disease onset and progression, ranging from hepatocellular carcinoma (HCC) to liver fibrosis drug-induced liver damage (DILI) and steatotic liver diseases.
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Affiliation(s)
- Raed Obaid Saleh
- Medical Laboratory Techniques Department, College of Health and Medical Technology, University of Al Maarif, Anbar, Iraq.
| | - Hamad Ali Hamad
- Department of Pathological Analysis, Collage of Applied Sciences, University of Fallujah, Fallujah, Iraq
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University Putra Malaysia, Serdang, Malaysia
| | | | - Soumya V Menon
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Mandeep Kaur
- Department of Sciences, Vivekananda Global University, Jaipur, Rajasthan, India
| | - G V Sivaprasad
- Department of Basic Science & Humanities, Raghu Engineering College, Visakhapatnam, India
| | - Mohammad Abohassan
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Wen-Tau Juan
- Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Beneen Husseen
- Medical Laboratory Technique college, The Islamic University, Najaf, Iraq
- Medical Laboratory Technique college, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Medical Laboratory Technique college, The Islamic University of Babylon, Babylon, Iraq
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, Iraq
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12
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Collins AL, Kirkness K, Ramon-Gil E, Tzortzopoulou E, Geh D, Dishington J, Graham E, Muir R, Cameron R, Luli S, Khurram E, Storey D, Paish HL, Nelson G, McDonald D, Filby A, Borthwick LA, Oakley F, Mann DA, Leslie J. Precision-cut tumor slices for modeling hepatocellular carcinoma enable at-scale drug screening. Hepatol Commun 2025; 9:e0706. [PMID: 40377490 PMCID: PMC12088631 DOI: 10.1097/hc9.0000000000000706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 02/11/2025] [Indexed: 05/18/2025] Open
Abstract
BACKGROUND Disease modeling is vital for our understanding of disease mechanisms and for developing new therapeutic strategies. Accurately modeling the intact tumor microenvironment (TME) is increasingly recognized as essential for gaining insights into cancer biology and therapeutic response. Preclinical mouse models have provided utility for studying the evolving TME, but these models are costly and can lead to animal suffering and the discontinuation of drug investigations. To address these limitations, particularly in hepatocellular carcinoma (HCC), we have developed an ex vivo model using tumor precision-cut slices (TPCS) derived from orthotopic liver tumors. METHODS Murine HCC tumors were generated via intrahepatic injection of Hep-53.4 cells, providing a source of tumor tissue for TPCS generation. Subsequent scaling to a 96-well format and modification to include a secreted luciferase enabled longitudinal ex vivo screening of 26 drugs applied at 2 doses over an 8-day period, using just 5 tumors. One drug identified in the screen, salinomycin, was then validated in vivo via intraperitoneal injection of mice with orthotopic liver tumors. RESULTS Histological characterization determined that TPCS maintain the architecture, cellular complexity, and drug responsiveness of the original HCC-TME under simplified culture conditions that preserve viability and metabolic activity. In addition to typical HCC therapies, sorafenib and anti-PD1 immunotherapy, the screen identified 2 drugs as potent anticancer agents capable of impacting the viability of TPCS: salinomycin and rottlerin. Salinomycin was further validated in vivo, significantly reducing tumor burden without evidence of toxicity. CONCLUSIONS We present a 3Rs (Reduction, Refinement, Replacement) approach for studying HCC biology and performing 96-well-scale drug screening within an intact, metabolically active TME, offering a more ethical and effective platform for drug discovery.
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Affiliation(s)
- Amy L Collins
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- The Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
| | - Keara Kirkness
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- The Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
| | - Erik Ramon-Gil
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- The Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
| | - Eleni Tzortzopoulou
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Daniel Geh
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- The Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
| | - Jack Dishington
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- The Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
| | - Eleanor Graham
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- The Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
| | - Rhys Muir
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Rainie Cameron
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Saimir Luli
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Eman Khurram
- Newcastle University Medicine Malaysia, Iskandar Puteri, Malaysia
| | - Daniel Storey
- FibroFind Ltd, William Leech Building, Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - Hannah L. Paish
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- FibroFind Ltd, William Leech Building, Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - Glyn Nelson
- Bioimaging Unit, Newcastle University, Newcastle upon Tyne, UK
| | - David McDonald
- Flow Cytometry Core Facility, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Andrew Filby
- Flow Cytometry Core Facility, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Lee A. Borthwick
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- FibroFind Ltd, William Leech Building, Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - Fiona Oakley
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- The Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
- FibroFind Ltd, William Leech Building, Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - Derek A. Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- The Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
- FibroFind Ltd, William Leech Building, Medical School, Newcastle University, Newcastle upon Tyne, UK
- Department of Gastroenterology and Hepatology, School of Medicine, Koç University, Istanbul, Turkey
| | - Jack Leslie
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- The Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
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13
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Xu J, Pei Z, Wang Y, Jiang N, Gong Y, Gong F, Ni C, Cheng L. Bioactive microspheres to enhance sonodynamic-embolization-metalloimmune therapy for orthotopic liver cancer. Biomaterials 2025; 317:123063. [PMID: 39753085 DOI: 10.1016/j.biomaterials.2024.123063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 12/07/2024] [Accepted: 12/26/2024] [Indexed: 02/04/2025]
Abstract
The development of novel microspheres for the combination of sonodynamic therapy (SDT) with transarterial embolization (TAE) therapy to amplify their efficacy has received increasing attention. Herein, a novel strategy for encapsulating sonosensitizers (e.g., oxygen-deficient manganese tungstate (MnWOX) nanodots) with gelatin microspheres was proposed. The obtained MnWOX-encapsulated microspheres (abbr. Mn-GMSs) facilitated efficient sonodynamic-embolization-metalloimmune therapy via the immune effects of metal ions on orthotopic liver cancer tumor after transarterial embolization (TAE). Due to the strong cavitation effect caused by the porous structure, Mn-GMSs exhibited a greater reactive oxygen species (ROS) generation rate than the free MnWOX nanodots under US irradiation. Efficient SDT revealed robust cell-killing effects and triggered strong immunogenic cell death (ICD). Moreover, the Mn ions released from the bioactive Mn-GMSs further stimulated the dendritic cells (DCs) maturation and triggered the activation of the cGAS/STING pathway to enhance the immunological effect. Thus, Mn-GMSs achieved significant SDT therapeutic outcomes in H22 tumors in mice, and the combination of the Mn-GMSs triggered SDT with programmed cell death ligand 1 (PD-L1) antibodies could further enhance therapeutic outcomes. The Mn-GMSs exhibited high ROS generation efficacy under US irradiation, significant immune activation, good efficacy in combination with immune checkpoint inhibitor, and great potential for artery embolization-assisted drug delivery, thus enabling effective destruction of liver tumors in rats and rabbits. Therefore, this work provides a strategy for applying SDT in deep tumors and highlights a promising sonodynamic-embolization therapy for combating liver cancers.
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Affiliation(s)
- Jiachen Xu
- Department of Vascular Surgery and Interventional Radiology, The Forth Affiliated Hospital of Soochow University, Dushu Lake Hospital Affiliated to Soochow University, Suzhou, 215125, China; Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Zifan Pei
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon Based Functional Materials & Devices, Soochow University, Suzhou, 215123, China
| | - Yuanjie Wang
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon Based Functional Materials & Devices, Soochow University, Suzhou, 215123, China
| | - Nan Jiang
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Yuehan Gong
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon Based Functional Materials & Devices, Soochow University, Suzhou, 215123, China
| | - Fei Gong
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon Based Functional Materials & Devices, Soochow University, Suzhou, 215123, China.
| | - Caifang Ni
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
| | - Liang Cheng
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon Based Functional Materials & Devices, Soochow University, Suzhou, 215123, China.
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Liu S, Deng X, Lv X. Optimizing antiviral prophylaxis strategies: Insights and reflections on a real-world study. J Hepatol 2025; 82:e311-e312. [PMID: 39701296 DOI: 10.1016/j.jhep.2024.12.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 12/11/2024] [Indexed: 12/21/2024]
Affiliation(s)
- Shanshan Liu
- Sichuan Integrative Medicine Hospital, Chengdu, Chengdu 610041, Sichuan, China
| | - Xinmin Deng
- Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu 610075, Sichuan, China
| | - Xiaofeng Lv
- School of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China.
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15
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Sayilan Ozgun G, Ozgun E, Karabas T, Suer Gokmen S, Eskiocak S. Piperine induces cellular stresses, apoptosis, and cytotoxicity via JNK signaling and has concentration-dependently additive or synergistic effects with sorafenib in hepatocellular carcinoma: an in-vitro study. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:7017-7025. [PMID: 39708099 DOI: 10.1007/s00210-024-03725-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 12/10/2024] [Indexed: 12/23/2024]
Abstract
We aimed to determine the effects of piperine on cell viability, cellular stresses, and apoptosis first, then the relationship of piperine's effects with the c-Jun N-terminal kinase (JNK) signaling pathway, and also the interaction of piperine with sorafenib in hepatocellular carcinoma. Hepatocellular carcinoma (HepG2 and Hep3B) and non-cancerous hepatocyte (AML12) cell lines were used. The cell viability was determined by using MTT assay. Cellular stresses, apoptosis, and JNK signaling markers were measured by Western blotting. Cells were pre-treated with SP600125 as a JNK inhibitor. The inhibitory concentration 50% (IC50) values and interaction of piperine with sorafenib were calculated by using CompuSyn software. IC50 values of piperine were 97 µM for HepG2, 58 µM for Hep3B, and 184 µM for AML12 with incubation for 48 h. Piperine caused a significant concentration-dependent increase in cellular stresses, apoptosis, and activated JNK signaling in hepatocellular carcinoma cells. Pre-treatment with a JNK inhibitor significantly reduced piperine-induced cellular stresses, apoptosis, and cytotoxicity. Piperine had concentration-dependent additive or synergistic effects when combined with sorafenib in both HepG2 and Hep3B cells. We found that piperine induces cellular stresses, apoptosis, and cytotoxicity via JNK signaling and has concentration-dependently additive or synergistic effects with sorafenib in hepatocellular carcinoma.
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Affiliation(s)
- Gulben Sayilan Ozgun
- Department of Medical Biochemistry, Trakya University School of Medicine, Edirne, 22030, Turkey.
| | - Eray Ozgun
- Department of Medical Biochemistry, Trakya University School of Medicine, Edirne, 22030, Turkey
| | - Tugce Karabas
- Department of Medical Biochemistry, Trakya University School of Medicine, Edirne, 22030, Turkey
| | - Selma Suer Gokmen
- Department of Medical Biochemistry, Trakya University School of Medicine, Edirne, 22030, Turkey
| | - Sevgi Eskiocak
- Department of Medical Biochemistry, Trakya University School of Medicine, Edirne, 22030, Turkey
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16
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He J, Guo J, Liu S, Li H, Ma Y, Ma S, Hu Z, Zhao W, Tan M, Liu W, Liu B. Targeted degradation of GOLM1 by CC-885 via CRL4-CRBN E3 ligase inhibits hepatocellular carcinoma progression. Cell Signal 2025; 130:111665. [PMID: 39986359 DOI: 10.1016/j.cellsig.2025.111665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 12/04/2024] [Accepted: 02/14/2025] [Indexed: 02/24/2025]
Abstract
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, emphasizing the urgent need for novel therapeutic strategies. In this study, we investigate the anti-tumor potential of CC-885, a cereblon (CRBN) modulator known for its efficacy in targeting neoplastic cells through proteasomal degradation pathways. Our findings demonstrate that CC-885 exhibits potent anti-tumor activity against HCC. In vitro assays revealed that CC-885 significantly inhibits the proliferation, migration, and invasion of HCC cells. These effects were corroborated in vivo, where CC-885 markedly suppressed tumor growth and angiogenesis in chick embryos and impeded the progression of orthotopic liver tumors in murine models. Mechanistically, CC-885 selectively reduces GOLM1 protein levels via ubiquitin-mediated proteasomal degradation. Knockdown of GOLM1 recapitulated the anti-proliferative effects of CC-885, while overexpression of GOLM1 conferred resistance to CC-885-induced apoptosis and growth inhibition. Further investigation revealed that CC-885 facilitates the interaction between GOLM1 and the E3 ubiquitin ligase CRBN, promoting the ubiquitination and subsequent degradation of GOLM1. Transcriptomic analyses showed that both CC-885 treatment and GOLM1 knockdown modulate critical pathways involved in apoptosis. These findings position CC-885 as a promising therapeutic candidate for HCC, acting primarily through CRBN-dependent degradation of GOLM1, and support its further development for clinical application.
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Affiliation(s)
- Jingliang He
- Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China
| | - Jingli Guo
- Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Shunfang Liu
- Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China; Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road 1095, Wuhan 430030, China
| | - Hanxue Li
- Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China
| | - Yuanyuan Ma
- Cancer Center and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Shaojie Ma
- Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China
| | - Zhongke Hu
- Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China
| | - Wensi Zhao
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
| | - Minjia Tan
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Wei Liu
- Cancer Center and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
| | - Bin Liu
- Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China.
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17
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Shen M, He S, Yao N, Xie L, Zhang L, Chen T. Reply to: "Optimizing antiviral prophylaxis strategies: Insights and reflections on a real-world study" and "Optimal timing to initiate antiviral prophylaxis of MTCT: More needs to be done". J Hepatol 2025; 82:e315-e316. [PMID: 39929389 DOI: 10.1016/j.jhep.2025.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Accepted: 02/03/2025] [Indexed: 05/19/2025]
Affiliation(s)
- Mingwang Shen
- China-Australia Joint Research Center for Infectious Diseases, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, PR China; Key Laboratory for Disease Prevention and Control and Health Promotion of Shaanxi Province, Xi'an, Shaanxi, 710061, PR China; The Interdisciplinary Center for Mathematics and Life Sciences, School of Mathematics and Statistics, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, 710061, PR China.
| | - Shihao He
- China-Australia Joint Research Center for Infectious Diseases, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, PR China
| | - Naijuan Yao
- Department of Infectious Disease, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, Shaanxi, 710061, PR China; Department of Infectious Disease, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, 610072, PR China
| | - Li Xie
- China-Australia Joint Research Center for Infectious Diseases, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, PR China
| | - Lei Zhang
- China-Australia Joint Research Center for Infectious Diseases, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, PR China; Phase I Clinical Trial Research Ward, The Second Affiliated Hospital of Xi'an Jiaotong University, No.157 Xi Wu Road, Xi'an, Shaanxi, 710004, PR China; Melbourne Sexual Health Centre, Alfred Health, Melbourne, Australia; School of Translational Medicine, Faculty of Medicine, Monash University, Melbourne, Australia.
| | - Tianyan Chen
- Department of Infectious Disease, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, Shaanxi, 710061, PR China.
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Wang Q, Ruan Q, Ding H. XPD Regulates MIAT/miR-29a-3p/COL4A1 Axis to Impede Hepatocellular Carcinoma Development. FASEB J 2025; 39:e70611. [PMID: 40372289 DOI: 10.1096/fj.202402908r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 03/28/2025] [Accepted: 04/29/2025] [Indexed: 05/16/2025]
Abstract
Xeroderma pigmentosum group D (XPD) has been reported to inhibit cell growth of hepatocellular carcinoma (HCC). This work attempted to reveal the underlying mechanism of XPD in HCC. In this study, XPD and miR-29a-3p were down-regulated, and MIAT and COL4A1 were up-regulated in tumor tissues of HCC patients. The same phenomena were also observed in HCC cell lines. XPD overexpression enhanced E-cadherin expression, reduced N-cadherin and Vimentin expression, and repressed the migration and invasion of HepG2 and Hep3B cells. MIAT or COL4A1 overexpression reversed the effect of XPD on the invasion, migration, and epithelial-mesenchymal transition (EMT) of HCC cells. MIAT overexpression-mediated promotion of malignant phenotypes of HCC cells was reversed by COL4A1 deficiency. In terms of mechanics, MIAT enhanced COL4A1 expression by sponging miR-29a-3p. XPD interacted with P53. XPD overexpression repressed MIAT expression, which was abrogated by P53 silencing. Thus, XPD recruited P53 to repress MIAT expression. In vivo, XPD up-regulation inhibited tumor growth and reduced the metastatic lesions in intrahepatic, lung, and kidney tissues of mice. In conclusion, this study demonstrated that XPD recruited P53 to regulate the MIAT/miR-29a-3p/COL4A1 axis, which contributed to inhibiting migration, invasion, EMT, and metastasis of HCC. Thus, XPD may be a valuable target for HCC treatment.
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Affiliation(s)
- Qi Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Qichao Ruan
- Department of Gastroenterology, Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, China
| | - Hao Ding
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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19
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Chen Y, Wang Q, Bian S, Dong J, Xiong J, Le J. Exploration of the mechanism of Polyphyllin I against hepatocellular carcinoma based on network pharmacology, molecular docking and experimental validation. Discov Oncol 2025; 16:941. [PMID: 40434621 PMCID: PMC12120097 DOI: 10.1007/s12672-025-02341-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 04/08/2025] [Indexed: 05/29/2025] Open
Abstract
PURPOSE Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Targeted therapies hold promise for HCC treatment, and understanding the molecular mechanisms of action is crucial for developing novel therapeutic strategies. Polyphyllin I, a natural compound with known antitumor activity, represents a potential therapeutic candidate. METHODS This study employed a network pharmacology approach to investigate the anti-HCC effects of Polyphyllin I and its underlying mechanisms. Drug and disease related targets were identified and intersected to construct Components-Gene Symbols-Disease and Protein-Protein Interaction networks. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. Molecular docking simulations were conducted to explore the interactions between Polyphyllin I and key pathway proteins (VEGF-C and β-catenin). Finally, in vitro and in vivo experiments validated the anti-HCC effects and underlying mechanisms of Polyphyllin I. RESULTS Network pharmacology analysis revealed that Polyphyllin I targets multiple genes and pathways implicated in HCC development and progression. GO and KEGG analyses identified significant enrichment of pathways related to cell proliferation, apoptosis and angiogenesis, including VEGF and the Wnt/β-catenin signaling pathways. Molecular docking simulations demonstrated strong binding affinities between Polyphyllin I and VEGF-C and β-catenin. In vitro and in vivo experiments confirmed that Polyphyllin I effectively inhibits HCC cell proliferation, induces apoptosis, and suppresses angiogenesis, potentially by modulating the VEGF-C and Wnt/β-catenin signaling pathways. CONCLUSIONS The study provides compelling evidence for the antitumor activity of Polyphyllin I in HCC and elucidates its possible molecular mechanisms, suggesting that Polyphyllin I holds great potential as a therapeutic agent for HCC.
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Affiliation(s)
- Yilong Chen
- Shanghai Key Laboratory of Molecular Imaging, Zhoupu Hospital, Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, China
| | - Qiuying Wang
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China
| | - Shuixiu Bian
- Shanghai Key Laboratory of Molecular Imaging, Zhoupu Hospital, Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, China
| | - Jing Dong
- Shanghai Key Laboratory of Molecular Imaging, Zhoupu Hospital, Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China
| | - Jie Xiong
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
| | - Jiamei Le
- Shanghai Key Laboratory of Molecular Imaging, Zhoupu Hospital, Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China.
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, China.
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Yuan Y, Yu J, Li M, Zhou T, Deng Z, Yin C, Shi X, Tang D, Liu Y, Li Y. Paxilline derived from an endophytic fungus of Baphicacanthus cusia alleviates hepatocellular carcinoma through autophagy-mediated apoptosis. Sci Rep 2025; 15:18464. [PMID: 40425675 PMCID: PMC12117046 DOI: 10.1038/s41598-025-03044-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Accepted: 05/19/2025] [Indexed: 05/29/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignancy for which no effective drugs are available. Paxilline is derived from an endophytic fungus of the leaves of Baphicacanthus cusia (Nees) Bremek. In a previous study, we found that paxilline inhibited the proliferation of HepG2 cells; however, its mechanism remains unclear. In this study, ESI+ and NMR were used to characterize the paxilline structure. Network pharmacology analysis was performed with databases and software to obtain the core targets and signaling pathways associated with the anti-HCC effects of paxilline. Molecular docking was performed to validate the preliminary affinity of paxilline for the core targets. For further in vitro experiments, a CCK8 assay was performed to detect cell viability, a wound healing assay was performed to detect cell migration, an Annexin V-FITC assay was performed to detect the cell cycle and apoptosis rate in HepG2 cells, RT-qPCR analysis was performed to detect the expression of cell cycle-related genes and autophagy-related genes, Immunofluorescence staining was performed to detect the expression of LC3B, and Western blotting was performed to detect the expression of apoptosis-related proteins and autophagy-related proteins. As a result, we obtained a white powder, which was identified as paxilline. Network analysis and molecular docking results revealed that apoptosis-related and autophagy-relatted protein were key targets (mTOR and PI3K) for paxilline anti-HCC. Further examination revealed that paxilline promoted HepG2 cell apoptosis, inhibited HepG2 cell migration, and arrested HepG2 cell in the S phage. RT-qPCR analysis revealed that paxilline markedly downregulated the mRNA expression of Cyclin D1, CDK4, LC3B, mTOR, Parkin, and PINK1. Immunofluorescence staining demonstrated a significant upregulation of LC3B protein expression following paxilline treatment. Further validation by Western blotting showed that paxilline significantly increased the expression of LC3B II/I, bax, cleaved-PARP, and cleaved-caspase 3, while significantly decreased the expression of bcl-2. Additionally, a significant promotion of cellular apoptosis and expression of apoptotic proteins when treatment with chloroquine (CQ)/rapamycin (Rapa). Meanwhile, when combined with paxilline, it was found that paxilline may have a synergistic effects with Rapa, jointly promoting cellular apoptosis and the expression of proapoptotic proteins. In conclusion, these findings reveled paxilline alleviates HCC through autophagy-mediated apoptosis.
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Affiliation(s)
- Yin Yuan
- Yunnan Branch, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Xishuangbanna Dai Autonomous Prefecture, 666100, China
- Yunnan Key Laboratory of Southern Medicine Utilization, Xishuangbanna Dai Autonomous Prefecture, 666100, China
| | - Jing Yu
- Yunnan Branch, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Xishuangbanna Dai Autonomous Prefecture, 666100, China
- Yunnan Key Laboratory of Southern Medicine Utilization, Xishuangbanna Dai Autonomous Prefecture, 666100, China
| | - Meng Li
- College of Pharmacy, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Tian Zhou
- Heilongjiang University of Chinese Medicine, Harbin, 150040, China
- Xishuangbanna Jianlong Pharmaceutical Co., Ltd., Xishuangbanna Dai Autonomous Prefecture, 666100, China
| | - Zhaoyou Deng
- Yunnan Branch, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Xishuangbanna Dai Autonomous Prefecture, 666100, China
- Yunnan Key Laboratory of Southern Medicine Utilization, Xishuangbanna Dai Autonomous Prefecture, 666100, China
| | - Cuiyun Yin
- Yunnan Branch, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Xishuangbanna Dai Autonomous Prefecture, 666100, China
- Yunnan Key Laboratory of Southern Medicine Utilization, Xishuangbanna Dai Autonomous Prefecture, 666100, China
| | - Xuanchao Shi
- Yunnan Branch, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Xishuangbanna Dai Autonomous Prefecture, 666100, China
- Yunnan Key Laboratory of Southern Medicine Utilization, Xishuangbanna Dai Autonomous Prefecture, 666100, China
| | - Deying Tang
- Yunnan Branch, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Xishuangbanna Dai Autonomous Prefecture, 666100, China
- Yunnan Key Laboratory of Southern Medicine Utilization, Xishuangbanna Dai Autonomous Prefecture, 666100, China
| | - Yiran Liu
- Heilongjiang University of Chinese Medicine, Harbin, 150040, China
| | - Yihang Li
- Yunnan Branch, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Xishuangbanna Dai Autonomous Prefecture, 666100, China.
- Yunnan Key Laboratory of Southern Medicine Utilization, Xishuangbanna Dai Autonomous Prefecture, 666100, China.
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21
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Wei W, Gan Y, Zhang X, Chen Y, Huang Z, Wang S, Xie X, Li Y, Qin P, Jiang L. Exploring the level of metabolic reprogramming and the role of prognostic factor SF3A3 in hepatocellular carcinoma through integrated single-cell landscape analysis. PLoS One 2025; 20:e0323559. [PMID: 40424306 PMCID: PMC12111341 DOI: 10.1371/journal.pone.0323559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 04/09/2025] [Indexed: 05/29/2025] Open
Abstract
This study aims to investigate metabolic reprogramming heterogeneity in hepatocellular carcinoma (HCC) cells and identify novel therapeutic targets for HCC treatment. Single-cell RNA sequencing data from public databases were used to analyze the TME of HCC and reveal the characteristics of different cell subsets, including mononuclear phagocytes, epithelial cells, endothelial cells, NK/T cells, B cells, and unknown cells. The analysis revealed that these cell subsets play their own unique roles in tumor progression and immune escape. Analysis of copy number variations (CNVs) was performed on tumor-derived epithelial cells, with the epithelial cells in Cluster 3 subgroup showing the highest CNV levels. Gene Ontology (GO) enrichment analysis revealed that these cell subsets were involved in a variety of biological processes such as immune response, cell communication, and metabolic pathways, which were consistent with their functional roles. Pseudotemporal analysis further delineated the malignant trajectory of HCC cells, with Cluster 3 exhibiting enhanced phosphatidylinositol metabolism, suggesting a critical role for metabolic reprogramming in tumor invasion and proliferation. Furthermore, a diagnostic model incorporating metabolic reprogramming-associated gene signatures was established, which effectively distinguished HCC from normal tissues. Among these signatures, splicing factor 3a subunit 3 (SF3A3) was identified as both diagnostic and independent prognostic biomarker. Mechanistically, SF3A3 knockdown in HCC cell lines significantly suppressed proliferation, migration, PI3K/AKT signaling, and EMT marker expression, thereby demonstrating its role in driving HCC aggressiveness. In conclusion, these findings elucidate novel molecular characteristics of HCC based on metabolic reprogramming, while establishing SF3A3 as a promising multi-faceted target for HCC diagnosis, prognostic assessment, and therapeutic intervention.
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Affiliation(s)
- Wanshuo Wei
- Scool of Clinical Medicine, School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise, Guangxi Province, P.R. China
| | - Yuan Gan
- Scool of Clinical Medicine, School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise, Guangxi Province, P.R. China
| | - Xindan Zhang
- Scool of Clinical Medicine, School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise, Guangxi Province, P.R. China
| | - Yumo Chen
- The First Affiliated Hospital, School of Basic Medical Sciences, Guangxi Medical University, Nanning, Guangxi Province, P.R. China
| | - Zengfeng Huang
- The First Affiliated Hospital, School of Basic Medical Sciences, Guangxi Medical University, Nanning, Guangxi Province, P.R. China
| | - Shuhan Wang
- Scool of Clinical Medicine, School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise, Guangxi Province, P.R. China
| | - Xiaomei Xie
- Scool of Clinical Medicine, School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise, Guangxi Province, P.R. China
| | - Yongle Li
- Scool of Clinical Medicine, School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise, Guangxi Province, P.R. China
| | - Pengtao Qin
- Scool of Clinical Medicine, School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise, Guangxi Province, P.R. China
| | - Lihe Jiang
- Scool of Clinical Medicine, School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise, Guangxi Province, P.R. China
- The First Affiliated Hospital, School of Basic Medical Sciences, Guangxi Medical University, Nanning, Guangxi Province, P.R. China
- Fujian Key Laboratory of Medical Bioinformatics, School of Medical Technology and Engineering, Fujian Medical University, Fuzhou, Fujian Province, P.R. China
- Key Laboratory of Biomarkers and in Vitro Diagnosis Translation of Zhejiang province, Hangzhou, Zhejiang province, P.R. China.
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22
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Wei X, Zou L, Huang Y, Qiu C, Cheng G, Chen Y, Rao J. LDHA-mediated YAP lactylation promotes the tumor progression of hepatocellular carcinoma by inducing YAP dephosphorylation and activation. Biol Direct 2025; 20:64. [PMID: 40414964 DOI: 10.1186/s13062-025-00655-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 05/15/2025] [Indexed: 05/27/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is among the deadliest cancers globally. Yes-Associated Protein (YAP), a Hippo pathway effector, crucially regulates cell proliferation and apoptosis. Recent research has implicated YAP's role in HCC progression, but the mechanisms are unclear. This study aims to clarify YAP's function in HCC, emphasizing its regulation of key pathways and targets. RESULTS Gene knockout and overexpression models were established in nude mice and cell lines of HCC cells to investigate YAP's impact on tumorigenesis. Additionally, functional assays and molecular biology techniques were employed to identify YAP's regulatory networks. The study demonstrates that LDHA-regulated lactate production promotes YAP activation and malignant phenotypes in HCC. Overexpression of LDHA in HepG2 and Huh7 cells increased lactate levels and activated the YAP pathway, enhancing cell proliferation, migration, and invasion. Lactate treatment also promoted these malignant phenotypes by inhibiting YAP phosphorylation at Ser127. In a xenograft model, lactate accelerated tumor growth through YAP activation. YAP lactylation at K102 antagonized its Ser127 phosphorylation, further promoting malignant progression. CONCLUSIONS This study highlights the significance of YAP in HCC pathogenesis, providing insights into potential therapeutic targets for HCC management.
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Affiliation(s)
- Xiaoyong Wei
- Hepatobiliary Surgery, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Hospital, Jiangxi Clinical Research Center for Cancer, Nanchang, Jiangxi, 330029, China
| | - Long Zou
- Hepatobiliary Surgery, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Hospital, Jiangxi Clinical Research Center for Cancer, Nanchang, Jiangxi, 330029, China
| | - Yanqing Huang
- The Medical College of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Chuan Qiu
- The Medical College of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Guang Cheng
- Hepatobiliary Surgery, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Hospital, Jiangxi Clinical Research Center for Cancer, Nanchang, Jiangxi, 330029, China
| | - Ye Chen
- Hepatobiliary Surgery, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Hospital, Jiangxi Clinical Research Center for Cancer, Nanchang, Jiangxi, 330029, China
| | - Jun Rao
- Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Clinical Research Center for Cancer, Nanchang, Jiangxi, 330029, China.
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Ghorbani Vanan A, Nami MT, Ghorbaninezhad F, Eini P, Bagheri K, Mohammadlou M, Mohammadi F, Tahmasebi S, Safarzadeh E. Macrophage polarization in hepatocellular carcinoma: a lncRNA-centric perspective on tumor progression and metastasis. Clin Exp Med 2025; 25:173. [PMID: 40413657 DOI: 10.1007/s10238-025-01711-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2025] [Accepted: 05/01/2025] [Indexed: 05/27/2025]
Abstract
Hepatocellular carcinoma (HCC) represents a multifaceted and aggressive cancer frequently associated with chronic inflammation and immune cell activation. The pathogenesis of HCC is influenced by a variety of factors such as long non-coding RNAs (lncRNAs). LncRNAs, a significant class of non-coding RNAs, contribute to the intricate nature of the transcriptome and are extensively distributed across various tissues and cell types in mammals. In HCC, these transcripts are crucial not only for deepening our molecular understanding but also for advancing clinical outcomes, as they serve as both oncogenes and tumor suppressors by dysregulating essential genes and signaling pathways. Additionally, macrophage polarization is crucial in HCC tumor progression. The study explores the role of lncRNAs in hepatocellular carcinoma (HCC) and elucidates the specific molecular mechanisms by which key lncRNAs such as HULC and MALAT1 regulate macrophage polarization in the tumor microenvironment. These lncRNAs modulate cytokine profiles and influence immune regulators including IL-10 and TGF-β, steering macrophages toward an M2-like, pro-tumor phenotype that fosters aggressive tumor characteristics and progression. Mechanistically, these transcripts interact with epigenetic modifiers like EZH2 to alter histone modifications and chromatin accessibility, while also stabilizing mRNAs that encode inflammatory mediators, thereby reinforcing an immunosuppressive response. The clinical implications of these findings are substantial. The detection of such lncRNAs in patient samples offers a minimally invasive diagnostic avenue, while their pivotal role in complex immune cell behavior positions them as promising prognostic biomarkers. Moreover, targeting these lncRNAs may lead to innovative therapeutic strategies aimed at disrupting tumor-supportive inflammatory cascades and restoring an effective antitumor immune response. Understanding the intricate interplay between lncRNA-mediated epigenetic regulation and macrophage polarization not only refines our grasp of HCC progression but also opens new pathways for interventions designed to improve patient outcomes.
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Affiliation(s)
- Ahmad Ghorbani Vanan
- Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Mohammad Taha Nami
- Faculty of Life Science and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Farid Ghorbaninezhad
- Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Pooya Eini
- Toxicological Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kamyar Bagheri
- Student Research Committee, Abadan University of Medical Sciences, Abadan, Iran
| | - Maryam Mohammadlou
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | | | - Safa Tahmasebi
- Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Elham Safarzadeh
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran.
- Department of Microbiology, Parasitology, and Immunology, Ardabil University of Medical Sciences, Ardabil, Iran.
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24
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Zhou J, Shi Y, Jian Y, Li Y, Yu W, Mu W, Ge Y. Identification of key ferroptosis genes in hepatocellular carcinoma and type 2 diabetes mellitus through bioinformatics analysis. Discov Oncol 2025; 16:916. [PMID: 40413683 DOI: 10.1007/s12672-025-02758-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 05/19/2025] [Indexed: 05/27/2025] Open
Abstract
Ferroptosis is a programmed cell death mode associated with iron metabolism, with accumulation of intracellular lipid peroxides, which is closely related to the occurrence and development of multiple diseases, including type 2 diabetes mellitus (T2DM) and hepatocellular carcinoma (HCC). T2DM is a chronic metabolic disorder characterized by a combination of impaired insulin sensitivity and insufficient insulin production, frequently accompanied by obesity and fatty liver, which increases the risk of developing HCC. To explore the complex interactions between ferritin deposition, T2DM, and HCC, we performed bioinformatics analysis on publicly available gene expression data and identified 23 differentially expressed genes (DEGs) that are commonly expressed in both T2DM and HCC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that these DEGs are primarily enriched in fatty acid metabolism and ferroptosis pathways. The weighted gene co-expression network analysis (WGCNA) identified 6 key genes associated with the pathogenesis of both diseases. Taking the intersection of DEGs and iron deposition-related genes, we identified ACSL4 as a key ferroptosis gene involved in the co-morbidity of T2DM and HCC. To validate the bioinformatics findings, we assessed the expression of ACSL4 using Receiver operating characteristic (ROC) curve analysis, which revealed an Area Under the Curve (AUC) of 0.886 for HCC and 0.745 for T2DM. Additionally, an insulin resistance model was established in HepG2 cells by treatment with 350 µM palmitic acid (PA), resulting in significant changes in cell morphology. Oil Red O staining showed a marked increase in lipid accumulation. RT-PCR analysis further confirmed the significant alteration in ACSL4 gene expression. In conclusion, this study is the first to integrate bioinformatics tools to investigate the potential mechanistic links between iron metabolism and the comorbidity of T2DM and HCC, uncovering a novel pathogenic pathway. These findings provide new directions for drug development and therapeutic strategies in the future.
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Affiliation(s)
- Jinjin Zhou
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yage Shi
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yulun Jian
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yuhan Li
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Wenya Yu
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Wei Mu
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yang Ge
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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25
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Yang C, Zhang Y, Liu Y, Wu X, Sun F. Study on the molecular mechanism of UBA52 and BARD1 regulating hepatocellular carcinoma through the PI3 K/AKT signaling pathway. Discov Oncol 2025; 16:840. [PMID: 40397202 PMCID: PMC12095107 DOI: 10.1007/s12672-025-02600-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Accepted: 05/06/2025] [Indexed: 05/22/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally, with its development closely related to complex molecular mechanisms such as gene mutations and abnormal signaling pathways. However, the specific roles of many key genes remain unclear. UBA52 and BARD1 are important genes associated with protein degradation, DNA repair, and cell cycle regulation, but their mechanisms in liver cancer are not well understood. METHODS This study integrated HCC datasets (GSE135631, GSE184733, GSE202853) from the gene expression omnibus (GEO) database to screen for differentially expressed genes (DEGs), perform functional enrichment analysis, weighted gene co-expression network analysis (WGCNA), construct protein-protein interaction (PPI) networks, and conduct survival analysis. Western Blot (WB) and RT-qPCR experiments were used to verify the expression of UBA52 and BARD1 in liver cancer cells and their association with the PI3K/AKT signaling pathway. RESULTS Bioinformatics analysis identified UBA52 and BARD1 as core genes, showing high expression in HCC tissues and correlation with poor prognosis. Western Blot and RT-qPCR results further confirmed the high expression of UBA52 and BARD1 in HCC cell lines (HepG2 and Hep3b). PI3K inhibitors significantly downregulated the expression of UBA52 and BARD1, restored the levels of apoptosis-related factors (Fas, BAX, Caspase-3), and inhibited the expression of cell cycle-related proteins (Cyclin-D1, c-Myc). These findings suggest that UBA52 and BARD1 may regulate HCC cell proliferation, apoptosis, and metastasis through the PI3K/AKT signaling pathway. Furthermore, the molecular mechanism of hepatocellular carcinoma can be modulated by knocking out BARD1 or UBA52. CONCLUSION UBA52 and BARD1 are highly expressed in HCC, and their abnormal expression may promote the occurrence and development of liver cancer by regulating the PI3K/AKT signaling pathway and mechanisms related to apoptosis and cell cycle. The high expression of UBA52 and BARD1 is closely associated with poor prognosis, indicating their potential value as early diagnostic and targeted therapeutic biomarkers for HCC.
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Affiliation(s)
- Chenrui Yang
- Department of General Surgery, Danzhou People's Hospital (Danzhou People's Hospital Medical Group), 21-1 Datong Road, Nada Town, Danzhou City, 571700, Hainan, China
| | - Yanzhong Zhang
- Department of General Surgery, Danzhou People's Hospital (Danzhou People's Hospital Medical Group), 21-1 Datong Road, Nada Town, Danzhou City, 571700, Hainan, China.
| | - Yajuan Liu
- Department of Clinical Pharmacy, Danzhou People's Hospital (Danzhou People's Hospital Medical Group), 21-1 Datong Road, Nada Town, Danzhou City, 571700, Hainan, China
| | - Xiaoyong Wu
- Department of General Surgery, Danzhou People's Hospital (Danzhou People's Hospital Medical Group), 21-1 Datong Road, Nada Town, Danzhou City, 571700, Hainan, China
| | - Fangyuan Sun
- Department of General Surgery, Danzhou People's Hospital (Danzhou People's Hospital Medical Group), 21-1 Datong Road, Nada Town, Danzhou City, 571700, Hainan, China
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26
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Liu J, Xu T, Wang Y, Ji F, Zhang L. The spatio-temporal trends and determinants of liver cancer attributable to specific etiologies: a systematic analysis from the Global Burden of Disease Study 2021. Glob Health Res Policy 2025; 10:22. [PMID: 40394727 PMCID: PMC12090427 DOI: 10.1186/s41256-025-00416-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 03/17/2025] [Indexed: 05/22/2025] Open
Abstract
BACKGROUND Although liver cancer has varied causes, its evolving epidemiology and causal drivers remain underexplored. This study quantifies the trends and drivers of liver cancer burden attributable to specific causes from 1990 to 2021. METHODS Using data from the Global Burden of Disease Study, we extracted prevalence, mortality, and disability-adjusted life years (DALYs) associated with specific causes of liver cancer. We assessed spatio-temporal trends across the sociodemographic index (SDI) and quantified the contributions of epidemiological shifts, population growth, and ageing to DALYs. RESULTS In 2021, liver cancer accounted for 0.74 million cases, 0.48 million deaths, and 12.89 million DALYs globally. Average annual percentage changes (AAPCs) in prevalence, mortality, and DALY rates from 1990 to 2021 were 1.17%, 1.04%, and 0.48%, respectively. HBV, HCV, and alcohol use were major contributors to DALYs, accounting for 1.92 million (36.00%), 1.53 million (28.62%), and 1.27 million (23.88%) of the increase, respectively. High-income North America and Western Europe experienced rapid growth in liver cancer prevalence from 1990 to 2021, while High-income North America and Southern Latin America had rapid growth in mortality. Global DALY increases were mainly driven by population growth (3.91 million, 73.29%) and population ageing (3.03 million, 56.86%). CONCLUSIONS The study revealed that hepatitis B, hepatitis C, and alcohol consumption were the primary contributors to the increasing DALYs from liver cancer, with population growth and ageing as key drivers of these changes. These findings underscore the importance of considering the major factors and demographic dynamics in addressing the burden of liver cancer when formulating prevention and intervention strategies.
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Affiliation(s)
- Jinli Liu
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University,, Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, People's Republic of China.
- China-Australia Joint Research Center for Infectious Diseases, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, People's Republic of China.
- Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, 710061, People's Republic of China.
- Med-X Institute, Center for Immunological and Metabolic Diseases, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, People's Republic of China.
| | - Tingling Xu
- China-Australia Joint Research Center for Infectious Diseases, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, People's Republic of China
| | - Yanan Wang
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University,, Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, People's Republic of China
- Med-X Institute, Center for Immunological and Metabolic Diseases, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, People's Republic of China
| | - Fanpu Ji
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China.
| | - Lei Zhang
- China-Australia Joint Research Center for Infectious Diseases, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, People's Republic of China.
- Phase I Clinical Trial Research Ward, The Second Affiliated Hospital of Xi'an Jiaotong University, No.157 Xi Wu Road, Xi'an, 710004, Shaanxi Province, People's Republic of China.
- School of Translational Medicine, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia.
- Melbourne Sexual Health Centre, Alfred Health, Melbourne, Australia.
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27
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Qiu Y, Wu X, Luo Y, Shen L, Guo A, Jiang J, Zhu L, Zhang Y, Han F, Yu E. Identification and validation a novel kinase-related gene signature for predicting prognosis and responsiveness to immunotherapy in hepatocellular carcinoma. Clin Exp Med 2025; 25:170. [PMID: 40394340 PMCID: PMC12092527 DOI: 10.1007/s10238-025-01556-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 01/02/2025] [Indexed: 05/22/2025]
Abstract
Liver cancer research highlights the kinome's critical role in disease initiation and progression. However, comprehensive data analysis on the kinome's impact on hepatocellular carcinoma (HCC) prognosis is limited. We used the TCGA-LIHC mRNA expression profiles, analyzing them with various R packages. Key methods included univariate Cox regression for prognostic gene identification, consensus clustering for subtype classification, Gene Set Enrichment Analysis (GSEA), and immune landscape evaluation. A prognostic model was developed using LASSO Cox regression, and chemotherapy drug sensitivity was assessed using the pRRophetic package. We identified 45 kinases-related differentially expressed genes (DEGs), with 27 linked to HCC prognosis. Cluster analysis divided these genes into two subtypes, with distinct prognoses. We discovered 157 DEGs between kinase-related subtypes, 120 of which were prognostically relevant. A kinase-related gene signature (KRS) was developed for prognostic prediction. The high-KRS group showed poorer survival in TCGA-LIHC and validation cohorts, with notable differences in immune cell infiltration and checkpoint gene expression. This group also showed varying sensitivity to common drugs and anti-PD-L1 treatment. In contrast, the low-KRS group might respond better to anti-PD-1 immunotherapy. Our study introduces a kinase-related gene signature as a novel tool for predicting HCC prognosis. This signature aids in tailoring personalized treatment strategies, potentially improving clinical outcomes in HCC patients.
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Affiliation(s)
- Yaju Qiu
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China
| | - Xitian Wu
- Hepatobiliary and Pancreatic Surgery Department, The Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, China
| | - Yang Luo
- Hepatobiliary and Pancreatic Surgery Department, The Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, China
| | - Lianqiang Shen
- Department of General Surgery, The First People's Hospital of Linping District, Hangzhou, 311100, Zhejiang, China
| | - Anyang Guo
- Hepatobiliary and Pancreatic Surgery Department, The Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, China
| | - Jing Jiang
- Hepatobiliary and Pancreatic Surgery Department, The Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, China
| | - Lijuan Zhu
- Hepatobiliary and Pancreatic Surgery Department, The Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, China
| | - Yuhua Zhang
- Hepatobiliary and Pancreatic Surgery Department, The Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, China
| | - Fang Han
- Hepatobiliary and Pancreatic Surgery Department, The Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, China.
| | - Enyan Yu
- Department of Clinical Psychology, Zhejiang Cancer Hospital, Hangzhou, 310012, Zhejiang, China.
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Shen H, Li H, Tang H. CCDC110 promotes the progression of hepatocellular carcinoma by activating the TGF-β/SMAD signaling pathway through targeted regulation of TGFBR1. Cancer Cell Int 2025; 25:183. [PMID: 40394630 PMCID: PMC12093845 DOI: 10.1186/s12935-025-03803-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 05/01/2025] [Indexed: 05/22/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is recognized for its high growth rate, high degree of invasiveness, and tendency to spread, leading to a significant number of deaths. In the course of studying the transcriptome of HCC tissues, the protein coiled-coil domain-containing 110 (CCDC110) was identified. By employing tandem mass tag (TMT) quantitative proteomics, this research identified transforming growth factor beta receptor 1 (TGFBR1) as a potential target influenced by CCDC110. The purpose of this study was to examine the role of CCDC110 in the growth and invasion of HCC and to identify new potential targets for the treatment of HCC. METHODS In vitro and in vivo experiments were conducted to investigate the role and mechanism of CCDC110 in promoting the malignant behaviors of hepatocellular carcinoma through the regulation of TGFBR1. RESULTS We determined that the mRNA and protein levels of CCDC110 are elevated in hepatocellular carcinoma tissues and cell lines, which is correlated with a worse patient prognosis. CCDC110 enhances the proliferation of hepatocellular carcinoma cells, reduces their apoptosis, and increases their migration and invasion capabilities. In the cytoplasm, CCDC110 interacts with TGFBR1, enhancing stability of TGFBR1, promoting proliferation, and reducing the apoptosis, migration, and invasion of hepatocellular carcinoma cells through TGFBR1 both in vivo and in vitro. The CCDC110-TGFBR1 axis stimulates EMT, thereby enhancing the malignant biological behavior of hepatocellular carcinoma by activating the TGF-β/SMAD signaling pathway. The protein levels of CCDC110/TGFBR1 in hepatocellular carcinoma tissues are highly expressed and positively correlated. A combined analysis of CCDC110 and TGFBR1 provides improved guidance for the prognosis of patients with hepatocellular carcinoma. CONCLUSION CCDC110 is highly expressed in hepatocellular carcinoma tissues and cell lines, and the CCDC110-TGFBR1 axis facilitates EMT and the malignant biological behavior of hepatocellular carcinoma through the activation of the TGF-β/SMAD signaling pathway.
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Affiliation(s)
- Hao Shen
- Department of Thyroid Breast Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China.
| | - Haifeng Li
- Department of Hepatic-Biliary-Pancreatic Center, Zhongda Hospital, Medical School, Southeast University, Nanjing 210000, China
| | - Haodong Tang
- Department of Hepatic-Biliary-Pancreatic Center, Zhongda Hospital, Medical School, Southeast University, Nanjing 210000, China
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Shi Y, Han G, Zhou J, Shi X, Jia W, Cheng Y, Jin Y, Hua X, Wen T, Wu J, Gu S, Bai Y, Wang X, Zhang T, Chen Z, Zhang B, Huang M, Liu H, Mao Y, Zhou L, Wang R, Shan Y, Zhang W, Song T, Guo Y, Zhou F, Shao B, Zhang M, Liang B, Zheng J, Zhang G, Shen J, Su W, Zhang F, He Y, Hu S, Liu R, Zhang C, Shen S, Zeng H, Wang TE, Guo W, Shen Y, Chen Y, Li Y, Samol J, Hu H, Zhang W, Du C, Li E, Liu C, Pin CS, Li X, Xu H, Huang JF, Hao C, Lv J, Wang W, Xu Q, Bai A, Zhang X, Liu B, Jin C, Fan J. Toripalimab plus bevacizumab versus sorafenib as first-line treatment for advanced hepatocellular carcinoma (HEPATORCH): a randomised, open-label, phase 3 trial. Lancet Gastroenterol Hepatol 2025:S2468-1253(25)00059-7. [PMID: 40409323 DOI: 10.1016/s2468-1253(25)00059-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 02/14/2025] [Accepted: 02/14/2025] [Indexed: 05/25/2025]
Abstract
BACKGROUND Although several PD-1 or PD-L1 inhibitors combined with antiangiogenic agents have been approved as first-line treatment of advanced hepatocellular carcinoma, treatment needs remain unmet given the high incidence and mortality of hepatocellular carcinoma and due to factors such as regional approval status, medical insurance restrictions, and cost considerations. In this phase 3 HEPATORCH study, we aimed to compare the efficacy and safety of toripalimab plus bevacizumab versus sorafenib in patients with previously untreated advanced hepatocellular carcinoma. METHODS We did a randomised, open-label, phase 3 study in 57 hospitals across mainland China, Taiwan, and Singapore. Using a central interactive web response system, eligible patients aged 18-75 years with unresectable or metastatic hepatocellular carcinoma were randomly assigned (1:1) through a stratified block randomisation method to receive 240 mg toripalimab (intravenously, once every 3 weeks) plus 15 mg/kg bevacizumab (intravenously, once every 3 weeks) or 400 mg sorafenib (oral, twice daily). Randomisation was stratified by macrovascular invasion or extrahepatic spread (presence vs absence), ECOG performance status score (0 vs 1), and history of locoregional therapy (yes vs no). The co-primary endpoints were progression-free survival (assessed by the Independent Review Committee per Response Evaluation Criteria in Solid Tumors, version 1.1) and overall survival. Efficacy analysis was performed in the intention-to-treat population (ie, all patients randomly assigned to a treatment group). Safety was assessed in all patients who received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, NCT04723004, and is completed. FINDINGS Between Nov 23, 2020, and Jan 21, 2022, 545 patients were screened for study inclusion, of whom 219 did not meet the screening criteria. 326 patients were randomly assigned to receive an intervention: 162 patients were assigned to the toripalimab plus bevacizumab group and 164 were assigned to the sorafenib group, with median age 58·0 years (IQR 50·0-66·0) and 56·0 years (49·0-61·0) years, respectively. All 326 patients were included in the intention-to-treat population and the safety population. 282 (87%) patients were male and 44 (14%) were female. At the primary analysis of progression-free survival (data cutoff Aug 10, 2022), median follow-up was 9·4 months (IQR 7·0-12·0). Toripalimab plus bevacizumab significantly prolonged progression-free survival compared with sorafenib (median 5·8 months [95% CI 4·6-7·2] vs 4·0 months [2·8-4·2]; hazard ratio [HR] 0·69 [95% CI 0·53-0·91; p=0·0086). At the final analysis of overall survival (May 31, 2024), median follow-up was 16·4 months (IQR 7·1-29·5). Toripalimab plus bevacizumab significantly improved overall survival compared with sorafenib (median 20·0 months [95% CI 15·3-23·4] vs 14·5 months [11·4-18·8]; HR 0·76 [95% CI 0·58-0·99; p=0·039). Grade 3 or higher adverse events occurred in 102 (63%) patients in the toripalimab plus bevacizumab group compared with 100 (61%) in the sorafenib group, and led to discontinuation of treatment in 21 (13·0%) participants in the toripalimab plus bevacizumab group and 20 (12%) participants in the sorafenib group. The incidence of treatment-related fatal adverse events (two [1%] vs one [1%]) was similar between the toripalimab plus bevacizumab and sorafenib groups. The most common (incidence ≥5% in the toripalimab plus bevacizumab group) grade 3-4 adverse events were hypertension (26 [16%] in the toripalimab plus bevacizumab group vs 19 [12%] in the sorafenib group), thrombocytopenia (16 [10%] vs four [2%]), upper gastrointestinal haemorrhage (ten [6%] vs one [1%]), anaemia (nine [6%] vs seven [4%]), and abnormal hepatic function (nine [6%] vs five [3%]). The most common (incidence ≥2% in the toripalimab plus bevacizumab group) serious adverse events were upper gastrointestinal haemorrhage (12 [7%] vs one [1%]), abnormal hepatic function (eight [5%] vs five [3%]), ascites (six [4%] vs three [2%]), and gastrointestinal haemorrhage (four [2%] vs three [2%]). INTERPRETATION Among patients with previously untreated advanced hepatocellular carcinoma, toripalimab plus bevacizumab resulted in significantly longer progression-free survival and overall survival than did sorafenib, with an acceptable safety profile. Based on these results, the regimen has been approved for use in China by the National Medical Products Administration. FUNDING Shanghai Junshi Biosciences. TRANSLATION For the Chinese translation of the abstract see Supplementary Materials section.
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Affiliation(s)
- Yinghong Shi
- Zhongshan Hospital, Fudan University, Shanghai, China
| | - Guohong Han
- Xi'an International Medical Center Hospital of Digestive Diseases, Xi'an, China
| | - Jian Zhou
- Zhongshan Hospital, Fudan University, Shanghai, China
| | | | | | | | | | - Xiangdong Hua
- Liaoning Cancer Hospital and Institute, Shenyang, China
| | - Tianfu Wen
- West China Hospital, Sichuan University, Chengdu, China
| | - Jianbing Wu
- The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | | | - Yuxian Bai
- Harbin Medical University Cancer Hospital, Harbin, China
| | - Xiangcai Wang
- First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Tao Zhang
- Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhiyu Chen
- The Southwest Hospital of Army Medical University, Chongqing, China
| | - Bixiang Zhang
- Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | | | - Hongming Liu
- Daping Hospital, Army Medical University, Chongqing, China
| | - Yilei Mao
- Peking Union Medical College Hospital, Beijing, China
| | - Ledu Zhou
- Xiangya Hospital Central South University, Changsha, China
| | - Rui Wang
- The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Yunfeng Shan
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wu Zhang
- Shulan (Hangzhou) Hospital, Hangzhou, China
| | - Tianqiang Song
- Tianjin Medical University Cancer Institute & Hospital, Tianjin, China
| | - Yabing Guo
- Southern Medical University Nanfang Hospital, Guangzhou, China
| | - Fuxiang Zhou
- Zhongnan Hospital of Wuhan University, Wuhan, China
| | | | - Mingjun Zhang
- The Second Hospital of Anhui Medical University, Hefei, China
| | - Bo Liang
- Jilin Guowen Hospital, Changchun, China
| | | | | | - Jie Shen
- Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Weiwen Su
- Changhua Christian Hospital, Changhua, China
| | | | - Yifu He
- Anhui Provincial Cancer Hospital, Hefei, China
| | - Sheng Hu
- Hubei Cancer Hospital, Wuhan, China
| | - Rong Liu
- Chinese People's Liberation Army General Hospital, Beijing, China
| | - Chengwu Zhang
- Zhejiang Provincial People's Hospital, Hangzhou, China
| | - Shunli Shen
- The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hui Zeng
- Zhejiang Cancer Hospital, Hangzhou, China
| | | | - Wenzhi Guo
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yan Shen
- The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Yajin Chen
- Sun Yat-sen Memorial Hospital, Guangzhou, China
| | - Yong Li
- The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - J Samol
- Tan Tock Seng Hospital, Singapore
| | | | | | - Chengyou Du
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Enxiao Li
- The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Chao Liu
- Sun Yat-sen Memorial Hospital, Guangzhou, China
| | - Choo Su Pin
- National Cancer Center and Curie Oncology, Singapore
| | - Xun Li
- The First Hospital of Lanzhou University, Lanzhou, China
| | - Hao Xu
- The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Jee-Fu Huang
- Kaohsiung Medical University Chung Ho Memorial Hospital, Taiwan, China
| | | | - Jing Lv
- The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wei Wang
- The First People's Hospital of Foshan, Foshan, China
| | - Qian Xu
- Shanghai Junshi Biosciences, Shanghai, China
| | - Aobing Bai
- Shanghai Junshi Biosciences, Shanghai, China
| | - Xiao Zhang
- Shanghai Junshi Biosciences, Shanghai, China
| | - Bifeng Liu
- Shanghai Junshi Biosciences, Shanghai, China
| | - Chunlei Jin
- Shanghai Junshi Biosciences, Shanghai, China
| | - Jia Fan
- Zhongshan Hospital, Fudan University, Shanghai, China.
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Samra YA, Abd El Salam ASG, Abdelghany AM, El-Shishtawy MM. Safranal-loaded gold nanoparticles alleviate hepatocellular carcinoma via targeting the Wnt/β-catenin pathway. Discov Oncol 2025; 16:821. [PMID: 40389761 PMCID: PMC12089598 DOI: 10.1007/s12672-025-02447-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 04/21/2025] [Indexed: 05/21/2025] Open
Abstract
BACKGROUND The Wnt/β-catenin pathway is frequently activated in hepatocellular carcinoma (HCC); thus, it is considered a potential target for novel therapies. Safranal (SAF), a natural product, is reputed for its antitumor and antioxidant activities. Gold nanoparticles (AuNPs) exhibit unique physicochemical properties, they can carry and transport drugs to the tumor as they can passively accumulate within the tumor. The current study aims to evaluate SAF and SAF-AuNPs antitumor effect in HCC model via targeting the Wnt pathway and to evaluate the ability of SAF-AuNPs and Doxorubicin-gold nanoparticles (DOX-AuNPs) in ameliorating DOX chemo-resistance in HCC and enhancing its therapeutic index to reduce unwanted side effects. RESULTS SAF significantly attenuated the Wnt/β-catenin pathway, which down-regulated the proliferation and tumor angiogenesis. SAF decreased significantly Wnt-3a, β-catenin, Cyclin D1 VEGF and MMP-9. Developing SAF-AuNPs enhanced the antitumor activity of SAF against HCC. Furthermore, SAF-AuNPs enhanced DOX-AuNPs antitumor activity and lowered multi-drug resistance (MDR) protein level, which attenuates DOX chemo-resistance. CONCLUSIONS We conclude that SAF and SAF-AuNPs are promising treatments for HCC. They have promising antitumor activity in addition to the ability to attenuate DOX chemo-resistance, so, the desired therapeutic effect may be obtained with minor doses and lowering the side effects.
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Affiliation(s)
- Yara A Samra
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, 35516, Egypt
| | - Al Shaima G Abd El Salam
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, 35516, Egypt
| | - Amr M Abdelghany
- Department of Spectroscopy, Physics Division, National Research Center, Giza, 12311, Egypt
- Basic Science Department, Horus University, Coastal Road, New Damietta, Egypt
| | - Mamdouh M El-Shishtawy
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, 35516, Egypt.
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Liu Y, Peng J, Liang Y, Li Y, Zhen X, Li H. QuEChERS and UPLC-MS/MS-Based Quantification of Human Plasma of Eight Nucleoside Reverse Transcriptase Inhibitors and Platinum Anticancer Drugs for Hepatocellular Carcinoma. Molecules 2025; 30:2204. [PMID: 40430376 PMCID: PMC12114340 DOI: 10.3390/molecules30102204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Revised: 05/16/2025] [Accepted: 05/16/2025] [Indexed: 05/29/2025] Open
Abstract
Nucleoside reverse transcriptase inhibitors (NRTIs) and platinum-based chemotherapeutics are widely utilized in cancer treatment. Evidence suggests that drug plasma concentrations are closely linked to both therapeutic efficacy and the risk of adverse effects. Consequently, developing therapeutic drug monitoring (TDM) methods is essential. Here, an effective procedure utilizing QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) techniques for preparing samples and UPLC-MS/MS for simultaneously measuring eight NRTIs and platinum-based drugs in human plasma is described. Chromatographic separation was conducted with an Agilent Eclipse Plus C18 column (4.6 × 100 mm, 3.5 μm) with acetonitrile with 0.1% formic acid as Phase A and 0.1% formic acid in water as Phase B, achieving complete separation within 10 min. The target analytes-lamivudine, telbivudine, emtricitabine, entecavir, tenofovir, nedaplatin, oxaliplatin, and adefovir dipivoxil-exhibited strong linearity within the 10-1000 ng/mL and 1-100 ng/mL ranges, showing correlations (r2) ≥ 0.9962. The method demonstrated excellent accuracy (-6.72% to 7.82%) and selectivity (84.53%-110.49%), as well as satisfactory recovery and stability. Overall, this analytical approach can be used to detect the combination of eight NRTIs and platinum-based drugs in human plasma. This method enables plasma drug-level monitoring in real time, with applications for individualized treatment approaches.
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Affiliation(s)
- Yanan Liu
- College of Chemistry and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang 050000, China; (Y.L.); (Y.L.)
| | - Jiangning Peng
- College of Pharmacy, Hebei Medical University, Shijiazhuang 050000, China; (J.P.); (Y.L.)
| | - Yan Liang
- College of Pharmacy, Hebei Medical University, Shijiazhuang 050000, China; (J.P.); (Y.L.)
| | - Yilin Li
- College of Chemistry and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang 050000, China; (Y.L.); (Y.L.)
| | - Xiaolan Zhen
- Hebei Institute of Drug and Medical Device Inspection, Shijiazhuang 050000, China;
| | - Hui Li
- Hebei Institute of Drug and Medical Device Inspection, Shijiazhuang 050000, China;
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Lu H, Gao Y, Xia X, Fu Q, Xiang D. RALOX-HAIC (raltitrexed + oxaliplatin) combined with lenvatinib improves survival and safety in elderly patients with unresectable hepatocellular carcinoma. BMC Cancer 2025; 25:882. [PMID: 40380115 PMCID: PMC12083140 DOI: 10.1186/s12885-025-14274-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2025] [Accepted: 05/05/2025] [Indexed: 05/19/2025] Open
Abstract
OBJECTIVE To explore the efficacy and safety of RALOX-HAIC (raltitrexed plus oxaliplatin) combined with lenvatinib in the treatment of elderly patients with unresectable hepatocellular carcinoma (uHCC), aiming to provide a safer and more effective therapeutic strategy for this patient population. MATERIALS AND METHODS A retrospective analysis was conducted on the clinical data of 82 elderly patients with uHCC who received treatment in the Department of Interventional Radiology at Wuhan Union Hospital from January 2019 to December 2022. Patients were divided into two groups based on their treatment strategy: HAIC + Lenvatinib group (N = 39) and TACE group (N = 43). The primary endpoints were the objective response rate (ORR), disease control rate (DCR), overall survival (OS), and progression-free survival (PFS) in the two groups. The secondary endpoint was the incidence of treatment-related adverse events in both groups. RESULTS The ORR and DCR after treatment were higher in the HAIC + Lenvatinib group compared to the TACE group (61.5% vs. 37.2%, 82.1% vs. 58.1%, P < 0.05). The HAIC + Lenvatinib group had a longer median progression-free survival (mPFS,9.2 months vs. 4.6 months, P < 0.001) and median overall survival(mOS, 18.1 months vs. 10.6 months, P < 0.001) compared to the TACE group. The incidence of abdominal pain and fever was significantly higher in the TACE group than in the HAIC + Lenvatinib group (including all grades and grades 3/4, P < 0.05). The incidence of hand-foot syndrome (all grades) was higher in the HAIC + Lenvatinib group compared to the TACE group (15.4% vs. 0.0%, P = 0.009), but there was no significant difference in the incidence of grade 3/4 hand-foot syndrome between the two groups (2.6% vs. 0.0%, P = 0.476). CONCLUSION This study demonstrates that RALOX-HAIC combined with lenvatinib provides superior survival outcomes and tolerability compared to TACE alone in elderly patients (≥ 70 years) with unresectable HCC. This combination therapy may be a feasible and safe option for improving the prognosis of elderly patients with uHCC.
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Affiliation(s)
- Haohao Lu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, 430022, China
| | - Ya Gao
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430077, China
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, 430022, China
| | - Xiangwen Xia
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, 430022, China
| | - Qing Fu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, 430022, China.
| | - Dongqiao Xiang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, 430022, China.
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Paredes A, Villodre C, Melgar P, Pascual S, Ramia JM. Evaluation of the PreopScore® in liver transplantation for hepatocellular carcinoma patients. Cir Esp 2025:800104. [PMID: 40383441 DOI: 10.1016/j.cireng.2025.800104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 12/30/2024] [Indexed: 05/20/2025]
Affiliation(s)
- Adrian Paredes
- Servicio de Cirugía General y Aparato Digestivo, Hospital General Universitario Dr Balmis, Alicante, Spain; Universidad Miguel Hernández, Alicante, Spain
| | - Celia Villodre
- Servicio de Cirugía General y Aparato Digestivo, Hospital General Universitario Dr Balmis, Alicante, Spain; ISABIAL, Alicante, Spain; Universidad Miguel Hernández, Alicante, Spain
| | - Paola Melgar
- Servicio de Cirugía General y Aparato Digestivo, Hospital General Universitario Dr Balmis, Alicante, Spain; ISABIAL, Alicante, Spain; Universidad Miguel Hernández, Alicante, Spain
| | - Sonia Pascual
- Unidad de Hepatología, Servicio de Aparato Digestivo, Hospital General Universitario Dr Balmis, Alicante, Spain
| | - José M Ramia
- Servicio de Cirugía General y Aparato Digestivo, Hospital General Universitario Dr Balmis, Alicante, Spain; ISABIAL, Alicante, Spain; Universidad Miguel Hernández, Alicante, Spain.
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Ye Z, Yan B, Li H, Tang Q, Yuan K, Hou J, Xu L, Yuan J, Wang S, Jiao W, Fan H, Lyu Y, Wang B, Liu X. Dual-responsive magnetic vortex nanorings co-deliver lenvatinib and localized heat for synergistic activation of antitumor immunity. Acta Biomater 2025; 198:389-400. [PMID: 40204172 DOI: 10.1016/j.actbio.2025.04.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 03/27/2025] [Accepted: 04/07/2025] [Indexed: 04/11/2025]
Abstract
Hepatocellular carcinoma (HCC) presents significant treatment challenges, primarily due to its ability to suppress immune responses. Lenvatinib (LT), approved as a first-line therapy for HCC, modulates the immune microenvironment by reducing PD-L1 expression and decreasing the infiltration of regulatory T cells (Tregs) within the tumor. However, the low immunogenicity of HCC and high toxicity of LT often undermine its effectiveness. To address these challenges, polydopamine (PDA)-coated ferrimagnetic vortex-domain iron oxide nanorings (FVIO@PDA) were engineered to respond to both acidic conditions and magnetic fields, facilitating the simultaneous delivery of the drug (LT) and a physio-therapeutic heat modality. The dual-responsive nature of FVIO@PDA ensures a controlled and synergistic release of LT, activated by acidic tumor microenvironments and the heat produced by an alternating magnetic field (AMF). In a subcutaneous Hepa1-6 HCC model, LT-loaded FVIO@PDA-PEG (denoted as LT-loaded FPP)-mediated magnetic hyperthermia significantly increased the levels of cytotoxic T lymphocytes, showing an approximate 3.86-fold increase compared to the control groups. This combination of LT and magnetic hyperthermia also reduced Treg populations to 1.4 %, synergistically triggering a robust antitumor immune response. Additionally, it altered cytokine profiles, reducing the secretion of the immunosuppressive cytokine IL-10 to 0.41 times that of control levels, while increasing the secretion of pro-inflammatory cytokines IFN-γ and TNF-α by 3.25 and 4.34 times, respectively. Furthermore, LT-loaded FPP-mediated magnetic hyperthermia exhibits superior anti-tumor activity compared to either treatment alone. These results highlight the promise of combining LT with FPP-mediated immunogenic magnetic hyperthermia as a potent therapeutic strategy for HCC, offering a more effective approach to modulate the immune environment and enhance antitumor efficacy. STATEMENT OF SIGNIFICANCE: Lenvatinib (LT) is a selective multi-targeted tyrosine kinase inhibitor used for patients with unresectable HCC who have not previously undergone systemic therapy. LT's immunomodulatory effects alone are often insufficient to induce an effective immune response, and treatment outcomes continue to be unsatisfactory. We developed FVIO@PDA for the delivery of LT and localized heat. FVIO@PDA allowed for controlled release of LT, triggered by the acidic tumor microenvironment and the heat generated under an AMF. LT combined with magnetic hyperthermia increased CTLs, reduced Tregs, decreased immunosuppressive cytokines, and elevated pro-inflammatory ones, collectively initiating a strong antitumor immune response. LT combined with magnetic hyperthermia showed superior antitumor effect compared to either treatment alone.
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Affiliation(s)
- Zirui Ye
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Province Center for Regenerative Medicine and Surgery Engineering Research, Shaanxi Provincial Key Laboratory of Magnetic Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Institute of Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China
| | - Bin Yan
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Province Center for Regenerative Medicine and Surgery Engineering Research, Shaanxi Provincial Key Laboratory of Magnetic Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Institute of Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China
| | - Hugang Li
- School of Future Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China
| | - Qianqian Tang
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Province Center for Regenerative Medicine and Surgery Engineering Research, Shaanxi Provincial Key Laboratory of Magnetic Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Institute of Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China
| | - Kexin Yuan
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Province Center for Regenerative Medicine and Surgery Engineering Research, Shaanxi Provincial Key Laboratory of Magnetic Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Institute of Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China
| | - Jingjing Hou
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Province Center for Regenerative Medicine and Surgery Engineering Research, Shaanxi Provincial Key Laboratory of Magnetic Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Institute of Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China
| | - Lexuan Xu
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Province Center for Regenerative Medicine and Surgery Engineering Research, Shaanxi Provincial Key Laboratory of Magnetic Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Institute of Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China
| | - Jianlan Yuan
- Center for Nanomedicine and Engineering, Northwest University, Xi'an, 710127, China
| | - Siyao Wang
- Center for Nanomedicine and Engineering, Northwest University, Xi'an, 710127, China
| | - Wangbo Jiao
- Center for Nanomedicine and Engineering, Northwest University, Xi'an, 710127, China
| | - Haiming Fan
- Center for Nanomedicine and Engineering, Northwest University, Xi'an, 710127, China
| | - Yi Lyu
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Province Center for Regenerative Medicine and Surgery Engineering Research, Shaanxi Provincial Key Laboratory of Magnetic Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Institute of Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China
| | - Bo Wang
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Province Center for Regenerative Medicine and Surgery Engineering Research, Shaanxi Provincial Key Laboratory of Magnetic Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Institute of Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China.
| | - Xiaoli Liu
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Province Center for Regenerative Medicine and Surgery Engineering Research, Shaanxi Provincial Key Laboratory of Magnetic Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; School of Future Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China; Institute of Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China.
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Luo W, Li X, Shang Y, Chen Z, Cui Y. Study on the mechanism by which Xuanfu Hua Tang increases sensitivity of hepatocellular carcinoma cells to sorafenib by antagonizing the Notch1 pathway through HIF-2α. Front Oncol 2025; 15:1552480. [PMID: 40444091 PMCID: PMC12119620 DOI: 10.3389/fonc.2025.1552480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Accepted: 04/21/2025] [Indexed: 06/02/2025] Open
Abstract
Background It is crucial to explore ways to increase the sensitivity of hepatocellular carcinoma cells to sorafenib. Methods The HepG2 and Huh7 cell lines with overexpressed HIF-2α were constructed. The cells were treated with Xuanfu Hua Tang (Xuanfu HT) containing serum and sorafenib separately and by using both of them, the cell viability and other cell biology functions were detected by CCK-8 and other assays. The mechanism of quercetin was investigated by thermal stability assay and dual luciferase reporter gene assay, and the effects of Xuanfu HT on the transcript and protein levels of Notch1 pathway genes were evaluated by qPCR and Western Blot. The effects of Xuanfu HT in tumor growth was investigates by mice subcutaneous tumor implantation model. Results The Xuanfu HT increased sensitivity of HepG2 and Huh7 cell lines with overexpressed HIF-2αto sorafenib, and enhanced inhibition of cell proliferation, migration, invasion and angiogenesis by sorafenib. The component quercetin of Xuanfu HT containing serum could inhibit the binding between HIF-2α and the promoter of the transcription factor FOXP3 to inhibit the expression of FOXP3, so as to inhibit the activation of Notch1 pathway and angiogenesis. The expression of FOXP3 counteracted the decrease in Notch1 and VEGF expression, and angiogenic capacity induced by the combined treatment with Xuanfu HT and sorafenib. The tumor growth inhibitory effects of Xuanfu HT and sorafenib in mice were proved by constructing a subcutaneous tumor model. Conclusion Xuanfu HT can increase sorafenib sensitivity of hepatocellular carcinoma cells by antagonizing the Notch1 pathway through quercetin-binding HIF-2α.
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Affiliation(s)
- Wenzhao Luo
- Henan University of Chinese Medicine, School of Basic Medicine (Zhongjing School), Zhengzhou, Henan, China
- Henan Province Hospital of Traditional Chinese Medicine, Department of Hepatobiliary and Spleen Stomach, Zhengzhou, Henan, China
| | - Xian Li
- Henan Province Hospital of Traditional Chinese Medicine, Department of Hepatobiliary and Spleen Stomach, Zhengzhou, Henan, China
| | - Yiwan Shang
- Henan University of Chinese Medicine, School of Basic Medicine (Zhongjing School), Zhengzhou, Henan, China
- Henan University of Chinese Medicine, Academy of Chinese Medical Sciences, Zhengzhou, Henan, China
| | - Zhen Chen
- Henan University of Chinese Medicine, Academy of Chinese Medical Sciences, Zhengzhou, Henan, China
| | - Yinglin Cui
- Henan Province Hospital of Traditional Chinese Medicine, Department of Hepatobiliary and Spleen Stomach, Zhengzhou, Henan, China
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Rafaqat S, Noshair I, Shahid M, Bibi S, Hafeez R, Hamid H. Correlation between prognostic markers and clinical parameters in hepatocellular carcinoma: Pathophysiological aspects to therapeutic targets. World J Gastrointest Oncol 2025; 17:106278. [DOI: 10.4251/wjgo.v17.i5.106278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Revised: 03/08/2025] [Accepted: 03/17/2025] [Indexed: 05/15/2025] Open
Abstract
One of the main causes of cancer-related morbidity and mortality globally is hepatocellular carcinoma (HCC). At every stage of the disease, HCC may now be treated using a variety of therapy techniques. Nevertheless, despite the abundance of effective therapeutic choices, the prognosis for patients with HCC is still typically dismal. Prognostic indicators are crucial when assessing prognosis and tracking tumor metastases or recurrence. There are many prognostic markers in HCC. We mainly focused on newly reported prognostic markers such as MEX3A, apolipoprotein B, alpha-fetoprotein, circulating tumor cells, SAMD13, Agrin, and Glypican-3 in the pathogenesis of HCC. Further, we highlighted how these prognostic markers correlated to clinical parameters such as tumor node metastasis, tumor diameter, differentiation, hepatocirrhosis, vascular invasion, and others in HCC. Therefore, identifying specific prognostic biomarkers of HCC helps to provide a great opportunity to improve the prognosis in patients with HCC and provide therapeutic targets.
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Affiliation(s)
- Saira Rafaqat
- Department of Zoology, Lahore College for Women University, Lahore 54000, Pakistan
| | - Iqra Noshair
- Department of Zoology, Lahore College for Women University, Lahore 54000, Pakistan
| | - Momina Shahid
- Department of Zoology, University of Narowal, Narowal 54000, Pakistan
| | - Sadaf Bibi
- Department of Zoology, Government College University, Lahore 54000, Pakistan
| | - Ramsha Hafeez
- Department of Zoology, Lahore College for Women University, Lahore 54000, Pakistan
| | - Hafsa Hamid
- Department of Biotechnology, Lahore College for Women University, Lahore 54000, Pakistan
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Huang S, Sun J. A novel adenosine-to-inosine RNA editing-based nomogram for predicting prognosis of hepatocellular carcinoma. Front Pharmacol 2025; 16:1547320. [PMID: 40438593 PMCID: PMC12116476 DOI: 10.3389/fphar.2025.1547320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Accepted: 04/22/2025] [Indexed: 06/01/2025] Open
Abstract
Objective Although the role of adenosine-to-inosine RNA editing (ATIRE) has gained widespread attention in multiple cancers, its predictive role in hepatocellular carcinoma (HCC) remains little known. We aimed to establish a predicting signature based on ATIRE for the prognosis of HCC. Methods A total of 200 HCC patients with survival data and ATIRE profiles from The Cancer Genome Atlas (TCGA) database were divided into training (n = 140) and validation (n = 60) cohorts. Survival-related ATIRE sites were identified by the least absolute shrinkage and selection operator algorithm. ATIRE-based risk score was then generated with these ATIRE sites. Cox proportional hazards regression was employed to construct the ATIRE-based nomogram signature. The receiver operating characteristic (ROC) curve was used to evaluate the predictive efficacy of the signature. Harrell's C-index and calibration plot was utilized to evaluate the significant prognostic factors. Results Nine ATIRE sites were screened to establish the ATIRE risk score, and it was found to be associated with prognosis of HCC. Survival analysis revealed that higher ATIRE-based risk scores were significantly associated with worse overall survival (OS) in both the training dataset (p < 0.001) and the validation dataset (p = 0.011), as well as in the combined dataset (p < 0.001). The ROC curve displayed a good predictive efficiency of the risk score regarding 1-year, 2-year, and 3-year OS. Furthermore, ATIRE sites were significantly correlated with the expression of host genes and were likely to be involved in certain cancer-related pathways. Discussion Our findings provided a novel ATIRE-based nomogram, which could serve as a potential tool for predicting HCC prognosis.
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Affiliation(s)
| | - Ji Sun
- Department of Pharmacy, The First Hospital of Changsha, Changsha, China
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Burciu C, Miutescu B, Bende R, Burciu D, Moga TV, Popescu A, Popa A, Bende F, Gadour E, Burdan A, Iovanescu D, Danila M, Sirli R. Effects of the COVID-19 Pandemic and Post-Pandemic Changes on the Diagnosis, Treatment, and Mortality of Hepatocellular Carcinoma in a Tertiary Center in Western Romania. Cancers (Basel) 2025; 17:1660. [PMID: 40427157 PMCID: PMC12110651 DOI: 10.3390/cancers17101660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2025] [Revised: 05/08/2025] [Accepted: 05/13/2025] [Indexed: 05/29/2025] Open
Abstract
BACKGROUND/OBJECTIVES Access to healthcare services was significantly restricted during the COVID-19 pandemic, leading to changes in the management of hepatocellular carcinoma (HCC). However, limited research has examined how these changes evolved post-pandemic. This study evaluated the impact of the pandemic at a tertiary center in Romania, focusing on diagnosis rates, treatments, and survival outcomes. METHODS A retrospective study conducted at Timișoara County Hospital divided patients into three equal cohorts of 23 months each: the pre-pandemic period (PreP: 1 May 2018-31 March 2020), the pandemic period (PandP: 1 April 2020-28 February 2022), and the post-pandemic period (PostP: 1 March 2022-31 January 2024). Newly diagnosed HCC cases were evaluated for the tumor stage, biological markers, and treatment received during each period. A survival census was conducted nine months after the diagnosis. RESULTS During the PandP and PostP periods, the numbers of newly diagnosed HCC cases decreased to 58 cases (p < 0.001) and 64 cases (p < 0.005), respectively, representing reductions of 38.3% and 31.9% compared to the PreP period, which had 94 cases. The proportion of patients in the BCLC-B stage increased from 31.9% in the PreP period to 50% during the PandP period (p = 0.0401), with fewer BCLC-A-0 cases (17% vs 5.1%; p = 0.059) during PandP. The tumor characteristics, BCLC classification, and TNM staging showed no significant differences between the PreP and PostP periods. Systemic therapy was the most commonly used treatment (39.7-50%). No significant differences were observed across treatment types when comparing all three periods (p > 0.05). The median follow-up times in the PreP, PandP, and PostP periods were 157.5, 159.5, and 183.5 days, respectively, with no statistically significant differences. The survival curve showed no statistically significant differences in survival between the groups at the nine-month follow-up (p > 0.05). CONCLUSIONS The COVID-19 pandemic decreased HCC diagnoses, with only a partial rebound in the PostP period that did not reach PreP levels. While the PandP period showed worsening BCLC staging and an increase in tumor numbers, the tumor stage and treatment in the PostP period were similar to those in the PreP period. Similarly, the nine-month survival rates remained similar across all three periods.
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Affiliation(s)
- Calin Burciu
- Department of Gastroenterology, Faculty of Medicine, Pharmacy and Dental Medicine, “Vasile Goldis” West University of Arad, 310414 Arad, Romania; (C.B.); (D.I.)
- Center for Advanced Research in Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (R.B.); (D.B.); (T.V.M.); (A.P.); (A.P.); (F.B.); (A.B.); (M.D.); (R.S.)
- Department of Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania
| | - Bogdan Miutescu
- Center for Advanced Research in Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (R.B.); (D.B.); (T.V.M.); (A.P.); (A.P.); (F.B.); (A.B.); (M.D.); (R.S.)
- Department of Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania
- Department of Gastroenterology and Hepatology, “Pius Brinzeu” County Emergency Clinical Hospital, 300723 Timisoara, Romania
| | - Renata Bende
- Center for Advanced Research in Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (R.B.); (D.B.); (T.V.M.); (A.P.); (A.P.); (F.B.); (A.B.); (M.D.); (R.S.)
- Department of Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania
- Department of Gastroenterology and Hepatology, “Pius Brinzeu” County Emergency Clinical Hospital, 300723 Timisoara, Romania
| | - Deiana Burciu
- Center for Advanced Research in Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (R.B.); (D.B.); (T.V.M.); (A.P.); (A.P.); (F.B.); (A.B.); (M.D.); (R.S.)
- Department of Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania
- Department of Gastroenterology and Hepatology, “Pius Brinzeu” County Emergency Clinical Hospital, 300723 Timisoara, Romania
| | - Tudor Voicu Moga
- Center for Advanced Research in Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (R.B.); (D.B.); (T.V.M.); (A.P.); (A.P.); (F.B.); (A.B.); (M.D.); (R.S.)
- Department of Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania
- Department of Gastroenterology and Hepatology, “Pius Brinzeu” County Emergency Clinical Hospital, 300723 Timisoara, Romania
| | - Alina Popescu
- Center for Advanced Research in Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (R.B.); (D.B.); (T.V.M.); (A.P.); (A.P.); (F.B.); (A.B.); (M.D.); (R.S.)
- Department of Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania
- Department of Gastroenterology and Hepatology, “Pius Brinzeu” County Emergency Clinical Hospital, 300723 Timisoara, Romania
| | - Alexandru Popa
- Center for Advanced Research in Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (R.B.); (D.B.); (T.V.M.); (A.P.); (A.P.); (F.B.); (A.B.); (M.D.); (R.S.)
- Department of Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania
- Department of Gastroenterology and Hepatology, “Pius Brinzeu” County Emergency Clinical Hospital, 300723 Timisoara, Romania
| | - Felix Bende
- Center for Advanced Research in Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (R.B.); (D.B.); (T.V.M.); (A.P.); (A.P.); (F.B.); (A.B.); (M.D.); (R.S.)
- Department of Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania
- Department of Gastroenterology and Hepatology, “Pius Brinzeu” County Emergency Clinical Hospital, 300723 Timisoara, Romania
| | - Eyad Gadour
- Multi-Organ Transplant Centre of Excellence, Liver Transplantation Unit, King Fahad Specialist Hospital, Dammam 32253, Saudi Arabia;
- Department of Medicine, Faculty of Medicine, Zamzam University College, Khartoum 11113, Sudan
| | - Adrian Burdan
- Center for Advanced Research in Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (R.B.); (D.B.); (T.V.M.); (A.P.); (A.P.); (F.B.); (A.B.); (M.D.); (R.S.)
- Department of Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania
- Department of Gastroenterology and Hepatology, “Pius Brinzeu” County Emergency Clinical Hospital, 300723 Timisoara, Romania
| | - Dana Iovanescu
- Department of Gastroenterology, Faculty of Medicine, Pharmacy and Dental Medicine, “Vasile Goldis” West University of Arad, 310414 Arad, Romania; (C.B.); (D.I.)
| | - Mirela Danila
- Center for Advanced Research in Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (R.B.); (D.B.); (T.V.M.); (A.P.); (A.P.); (F.B.); (A.B.); (M.D.); (R.S.)
- Department of Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania
- Department of Gastroenterology and Hepatology, “Pius Brinzeu” County Emergency Clinical Hospital, 300723 Timisoara, Romania
| | - Roxana Sirli
- Center for Advanced Research in Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (R.B.); (D.B.); (T.V.M.); (A.P.); (A.P.); (F.B.); (A.B.); (M.D.); (R.S.)
- Department of Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania
- Department of Gastroenterology and Hepatology, “Pius Brinzeu” County Emergency Clinical Hospital, 300723 Timisoara, Romania
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Mittal G, A P, Dhali A, Prasad R, S Y, Nurani KM, Găman MA. Plant extracts with antioxidant and hepatoprotective benefits for liver health: A bibliometric analysis of drug delivery systems. World J Gastroenterol 2025; 31:105836. [DOI: 10.3748/wjg.v31.i18.105836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Revised: 03/07/2025] [Accepted: 04/21/2025] [Indexed: 05/13/2025] Open
Abstract
BACKGROUND The rising global burden of liver diseases, such as non-alcoholic fatty liver disease and liver fibrosis, has necessitated innovative therapeutic approaches. Plant-based therapies, recognized for their anti-inflammatory and antioxidant properties, have shown promising effects. However, poor bioavailability limits their clinical application.
AIM To map global research trends, key contributors, and emerging themes in plant-based therapies combined with advanced drug delivery systems for liver health.
METHODS Using the Scopus database, 645 documents were retrieved and analyzed using bibliometric tools Biblioshiny and VOSviewer. Analysis focused on publication trends, geographical contributions, and advancements in drug delivery technologies, including nanoparticles, liposomes, and polymeric micelles. Metrics such as publication growth rate, authorship collaboration, and thematic clustering were assessed.
RESULTS The dataset spans 43 years (1981-2024), with an annual growth rate of 11.09% in the number of publications. Research output is dominated by China (33%), followed by the United States (24%) and India (18%). Collaborative studies accounted for 24.34% of publications, with an average of 5.81 co-authors per document. Key innovations include nanoparticle encapsulation of curcumin and silymarin, improving bioavailability by up to 85%. Highly cited studies demonstrated the antioxidant, anti-inflammatory, and anti-fibrotic properties of these compounds. For instance, curcumin nanoparticles showed a 70% improvement in solubility, and silymarin liposomal formulations enhanced therapeutic efficiency by 62%. Thematic analysis revealed a transition from basic clinical observations to molecular and pharmacokinetic research, with a focus on oxidative stress mitigation and hepatoprotection.
CONCLUSION This study highlights the growing synergy between plant-based therapies and advanced drug delivery systems, with significant contributions from Asian and Western countries. Future efforts should prioritize clinical trials, standardization of plant extract formulations, and interdisciplinary approaches to maximize therapeutic outcomes. The findings provide a foundation for integrating plant-derived compounds into evidence-based hepatological therapies, addressing critical challenges in bioavailability and safety.
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Affiliation(s)
- Gaurav Mittal
- MBBS Final Year StudentMahatma Gandhi Institute of Medical Sciences, Maharashtra 442102, India
| | - Prashanth A
- Department of Physiology, Mahatma Gandhi Institute of Medical Sciences, Maharashtra 442102, India
| | - Arkadeep Dhali
- Academic Unit of Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield S5 7AU, United Kingdom
| | - Roshan Prasad
- Department of Medicine, Datta Meghe Institute of Higher Education and Research, Sawangi 442107, India
| | - Yogesh S
- Department of Medicine, Madras Medical College, Chennai 600003, India
| | | | - Mihnea-Alexandru Găman
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, Bucharest 050474, Romania
- Department of Hematology, Centre of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, Bucharest 022328, Romania
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Romanian Academy, Bucharest 010001, Romania
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Shen Y, Xu Y, Teng Y, Ding X, Chen J. First-line treatment of hepatocellular carcinoma: a propensity-matched analysis of tyrosine kinase inhibitors combined with TACE, with or without PD-1 inhibitors. Front Pharmacol 2025; 16:1533471. [PMID: 40432892 PMCID: PMC12106014 DOI: 10.3389/fphar.2025.1533471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Accepted: 04/24/2025] [Indexed: 05/29/2025] Open
Abstract
Objective This study attempted to comprehensively assess the clinical outcomes of cases with progressive HCC (pHCC) undergoing treatment with TKI and ICI in conjunction with TACE, as compared to the combination of TKI with TACE alone. Methods From March 2019 to January 2022, this cohort comprised 82 cases who received TACE in conjunction with TKI and 52 cases who were treated with TACE plus TKI alone. The propensity scores was used to mitigate selection bias. Results The multivariate analysis further reinforced that liver cirrhosis (HR = 1.233, 95% CI: 1.024-1.484, P = 0.027), tumor diameter (HR = 1.283, 95% CI: 1.086-1.515, P = 0.003), and the treatment strategy (HR = 0.495, 95% CI: 0.264-0.793, P = 0.000) were independently linked to OS, underscoring their prognostic relevance. Conclusion Incorporating TACE, TKI, and ICI remarkably enhanced both PFS and OS relative to TACE with TKI alone, positioning it as a more efficacious first-line therapeutic strategy for unresectable HCC, while maintaining an acceptable safety profile in clinical settings.
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Affiliation(s)
| | | | | | | | - Jinglong Chen
- Department of Oncology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
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Lu P, Su X, Leong S, Xiu X, Song P, Peng J, Si Y. Analysis of Colorectal Cancer Gene Mutations and Application of Long Blocker Displacement Amplification Technology for High-Throughput Mutation Detection. BIOSENSORS 2025; 15:308. [PMID: 40422048 DOI: 10.3390/bios15050308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2025] [Revised: 05/01/2025] [Accepted: 05/09/2025] [Indexed: 05/28/2025]
Abstract
Genetic mutation detection for colorectal cancer (CRC) is crucial for precision diagnosis and treatment, yet current methods often suffer from challenges such as low sensitivity, time consumption, and high costs. In our preliminary bioinformatic analysis of 751 CRC cases from The Cancer Genome Atlas and 131 Chinese patient samples, APC, TP53, and KRAS were identified as the most frequently mutated genes. Among them, KRAS missense mutations emerged as key diagnostic biomarkers. In this study, we applied a fluorescence-based long block displacement amplification (LBDA) sensing method for the rapid, high-throughput, and cost-effective detection of KRAS genetic mutations. In the LBDA system, SYBR Green dye binds to the amplified double-stranded DNA, generating a fluorescence signal that directly reflects the abundance of mutant types (MTs). This real-time signal output enables the enrichment and sensitive detection of MTs, establishing LBDA as an efficient biosensing platform for KRAS genotyping. Using this technique, a detection limit of 0.08% variant allele frequency was achieved with 20 ng of synthetic DNA input. To evaluate clinical performance, the LBDA method was applied to 118 tissue samples from 59 CRC patients, including tumor and matched peritumoral tissues. For 59 CRC tumor samples, LBDA successfully identified KRAS mutations in 37.29% of cases, closely matching results (42.37%) obtained by next-generation sequencing and achieving 88% sensitivity and 100% specificity. In conclusion, this study presents a rapid and cost-effective mutation detection method based on optical biosensing, offering strong potential for advancing personalized CRC diagnosis and treatment.
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Affiliation(s)
- Ping Lu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Xinglei Su
- School of Biomedical Engineering, Zhangjiang Institute for Advanced Study and National Center for Translational Medicine, Shanghai Jiao Tong University, Shanghai 200240, China
- Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine Institute of Molecular Medicine Renji Hospital School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
- School of Life Sciences, Shanghai University, Shanghai 200444, China
| | - Sirui Leong
- School of Biomedical Engineering, Zhangjiang Institute for Advanced Study and National Center for Translational Medicine, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Xuehao Xiu
- School of Biomedical Engineering, Zhangjiang Institute for Advanced Study and National Center for Translational Medicine, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Ping Song
- School of Biomedical Engineering, Zhangjiang Institute for Advanced Study and National Center for Translational Medicine, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Junjie Peng
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Yunpei Si
- School of Biomedical Engineering, Zhangjiang Institute for Advanced Study and National Center for Translational Medicine, Shanghai Jiao Tong University, Shanghai 200240, China
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Wang MD, Lv SD, Diao YK, Xu JH, Chen FJ, Li YC, Gu WM, Wang H, Yang YZ, Zeng YY, Zhou YH, Wang XM, Li J, Chen TH, Liang YJ, Yao LQ, Gu LH, Wu H, Xu XF, Li C, Shen F, Yang T. Risk stratification model for predicting distant metastasis after hepatectomy for hepatocellular carcinoma: A multi-institutional analysis. Biosci Trends 2025; 19:211-220. [PMID: 40044158 DOI: 10.5582/bst.2024.01387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/13/2025]
Abstract
Distant metastasis after hepatectomy for hepatocellular carcinoma (HCC) significantly impairs long-term outcome. This study aimed to identify patterns, risk factors, and develop a prediction model for distant metastasis at first recurrence following HCC resection. This multi-center retrospective study included patients undergoing curative hepatectomy for HCC. Risk factors for distant metastasis were identified using Cox regression. A nomogram was constructed and validated using the concordance index (C-index) and calibration curves. Among 2,705 patients, 1,507 experienced recurrence, with 342 (22.7 per cent) developing distant metastasis. Common metastatic sites included extrahepatic vessels (36.2 per cent), lungs (26.0 per cent), and lymph nodes (20.8 per cent). Patients with distant metastasis had significantly worse 5-year overall survival compared to those with intrahepatic recurrence (9.1 versus 41.1 per cent, p < 0.001). Independent risk factors included preoperative tumor rupture, tumor size over 5.0 cm, multiple tumors, satellite nodules, macro- and microvascular invasion, narrow resection margin, and intraoperative blood transfusion. The nomogram demonstrated excellent discrimination (C-index > 0.85) and accurately stratified patients into three risk categories. In conclusion, distant metastasis at first recurrence following HCC resection was associated with poor prognosis. The proposed nomogram facilitates accurate prediction of distant metastasis, potentially informing personalized postoperative monitoring and interventions for high-risk patients.
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Affiliation(s)
- Ming-Da Wang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
- Eastern Hepatobiliary Clinical Research Institute, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Shao-Dong Lv
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Yong-Kang Diao
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
- Eastern Hepatobiliary Clinical Research Institute, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Jia-Hao Xu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
- Eastern Hepatobiliary Clinical Research Institute, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Fu-Jie Chen
- Department of Graduate, Bengbu Medical College, Bengbu, China
| | - Yu-Chen Li
- Department of Graduate, Bengbu Medical College, Bengbu, China
| | - Wei-Min Gu
- The First Department of General Surgery, the Fourth Hospital of Harbin, Heilongjiang, China
| | - Hong Wang
- Department of General Surgery, Liuyang People's Hospital, Hunan, China
| | - Yu-Ze Yang
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Centre, First Hospital of Jilin University, Changchun, China
| | - Yong-Yi Zeng
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital, Fujian Medical University, Fujian, China
| | - Ya-Hao Zhou
- Department of Hepatobiliary Surgery, Pu'er People's Hospital, Yunnan, China
| | - Xian-Ming Wang
- Department of General Surgery, First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong, China
| | - Jie Li
- Department of Hepatobiliary Surgery, Fuyang People's Hospital, Anhui, China
| | - Ting-Hao Chen
- Department of General Surgery, Ziyang First People's Hospital, Sichuan, China
| | - Ying-Jian Liang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Harbin Medical University, Heilongjiang, China
| | - Lan-Qing Yao
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
- Eastern Hepatobiliary Clinical Research Institute, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Li-Hui Gu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
- Eastern Hepatobiliary Clinical Research Institute, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Han Wu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
- Eastern Hepatobiliary Clinical Research Institute, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Xin-Fei Xu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
- Eastern Hepatobiliary Clinical Research Institute, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Chao Li
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
- Eastern Hepatobiliary Clinical Research Institute, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Feng Shen
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
- Eastern Hepatobiliary Clinical Research Institute, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Tian Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
- Eastern Hepatobiliary Clinical Research Institute, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
- Department of Graduate, Bengbu Medical College, Bengbu, China
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Xie C, Qiu N, Wang C, Chen J, Zhang H, Lu X, Chen S, Sun Y, Lian Z, Hu H, Zhu H, Xu X. G-LERP/miR-374i-b Attenuates IRI and Suppresses Hepatocellular Carcinoma Progression. Transplantation 2025:00007890-990000000-01080. [PMID: 40336158 DOI: 10.1097/tp.0000000000005412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/09/2025]
Abstract
BACKGROUND Liver transplantation (LT) is the most effective therapeutic strategy for late-stage hepatocellular carcinoma (HCC), but it is prone to ischemia-reperfusion injury (IRI), leading to poor prognosis. Previous articles have reported that miR-374b-5p expression is increased in HCC tissues, and its relationship with IRI and HCC carcinoma progression is unclear. METHODS Previous reports have shown that miR-374b-5p expression is significantly upregulated in HCC tissues. The effect of miR-374b-5p on patient symptoms and prognosis were analyzed from The Cancer Genome Atlas database and liver specimens from LT patients. To further explore its therapeutic potential, a liver-targeted esterase-responsive gene delivery system (G-LERP/miR-374i-b) was developed to downregulate miR-374b-5p expression in the mouse hepatic IRI (HIRI) model. An orthotopic HCC model was further established to mimic the postoperative recurrence of HCC. RESULTS In this study, we found that miR-374b-5p expression correlates with tumor size and microvascular invasion based on patients' clinical information. Patients with low miR-374b-5p expression had a higher Milan criteria score and a lower Model for End-stage Liver Disease score. We verified the positive correlation between miR-374b-5p expression and the proliferation and invasion of HCC cells. Effective downregulation of miR-374b-5p simultaneously alleviated HIRI and reduced tumor burden by 56%, whereas miR-374b-5p upregulation promoted HCC progression. Furthermore, we found G-LERP/miR-374i-b attenuated hepatic inflammation by downregulating the nuclear factor kappa-B pathway, thereby reducing HIRI and the risk of HCC recurrence. CONCLUSIONS This research is the first to demonstrate miR-374b-5p as a dual therapeutic target during LT and postoperative recurrence of HCC. Preintervention of miR-374b-5p using an esterase-responsive gene delivery system during the preoperative period simultaneously alleviates IRI and suppresses HCC progression.
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Affiliation(s)
- Chang Xie
- School of Clinical Medicine, Hangzhou Normal University, Zhejiang Province, Hangzhou, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Zhejiang Province, Hangzhou, China
| | - Nasha Qiu
- School of Clinical Medicine, Hangzhou Normal University, Zhejiang Province, Hangzhou, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Zhejiang Province, Hangzhou, China
| | - Chao Wang
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Zhejiang Province, Hangzhou, China
| | - Jun Chen
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Zhejiang Province, Hangzhou, China
| | - Hui Zhang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Zhejiang Province, Hangzhou, China
| | - Xinfeng Lu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Zhejiang Province, Hangzhou, China
| | - Siyu Chen
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Zhejiang Province, Hangzhou, China
| | - Yiyang Sun
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Zhejiang Province, Hangzhou, China
| | - Zhengxing Lian
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Zhejiang Province, Hangzhou, China
| | - Haitao Hu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Zhejiang Province, Hangzhou, China
| | - Hengkai Zhu
- Department of Hepatobiliary Pancreatic Surgery, Shulan Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Zhejiang Province, Hangzhou, China
| | - Xiao Xu
- School of Clinical Medicine, Hangzhou Medical College, Zhejiang Province, Hangzhou, China
- Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang Province, Hangzhou, China
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Muthusamy G, Liu CC, Johnston AN. LFHP-1c Attenuates Hepatocellular Carcinoma Viability In Vitro Independent of PGAM5. Cancers (Basel) 2025; 17:1573. [PMID: 40361499 PMCID: PMC12071907 DOI: 10.3390/cancers17091573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2025] [Revised: 04/12/2025] [Accepted: 04/29/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND/OBJECTIVES Upregulation of phosphoglycerate mutase 5 (PGAM5) is correlated with reduced survival outcomes in hepatocellular carcinoma (HCC). PGAM5 knockdown or knockout attenuates HCC growth in in vitro and in vivo models. A novel small molecule inhibitor of PGAM5, LFHP-1c, has recently been characterized. The objective of this study was to determine if LFHP-1c effectively reduces HCC viability in cell models. METHODS The hepatoma and HCC cell lines, HepG2 and HuH7, respectively, were treated with LFHP-1c. Label-free imaging was used to quantify growth. Cellular viability and reactive oxygen species (ROS) production were measured using luminescent or fluorescent assays. Expression of antioxidant and metabolic proteins was measured by immunoblot. HepG2 and HuH7 PGAM5 knockout cell lines were used as negative controls. RESULTS Treatment with LFHP-1c reduced cell growth and viability in HepG2 and HuH7 cell lines. Reactive oxygen species production was upregulated in both wild-type and PGAM5 knockout cell lines following LFHP-1c exposure. Cell viability was reduced following LFHP-1c treatment in PGAM5 knockout cell lines. CONCLUSIONS LFHP-1c reduces hepatoma and HCC viability and enhances ROS production, but these effects are independent of PGAM5.
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Affiliation(s)
- Ganesan Muthusamy
- School of Veterinary Medicine, Veterinary Clinical Sciences, Louisiana State University, Baton Rouge, LA 70802, USA
| | - Chin-Chi Liu
- School of Veterinary Medicine, Office of Research and Graduate Education, Louisiana State University, Baton Rouge, LA 70802, USA;
| | - Andrea N. Johnston
- School of Veterinary Medicine, Veterinary Clinical Sciences, Louisiana State University, Baton Rouge, LA 70802, USA
- College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA
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45
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An Y, Liu W, Deng Y, Huang W, Huang J. SLC7A11-HSPB1 Axis: A Novel Mechanism for Hepatocellular Carcinoma Progression and Ferroptosis Regulation. Biomed J 2025:100869. [PMID: 40339903 DOI: 10.1016/j.bj.2025.100869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 03/27/2025] [Accepted: 05/02/2025] [Indexed: 05/10/2025] Open
Abstract
BACKGROUND SLC7A11, a plasma membrane protein, has been implicated as an oncogene in various cancers, including hepatocellular carcinoma (HCC). Its role in HCC pathogenesis, particularly in relation to ferroptosis, is not well understood. This study aims to investigate the function of SLC7A11 with ferroptosis and its interaction in development of HCC. METHODS AND MATERIAL Clinical HCC tissue samples were used to analyze the expression of SLC7A11 by RT-PCR. The impact of SLC7A11 on HCC cell viability, proliferation, and migration was assessed by CCK-8, AlamarBlue and Transwell. Protein-protein interactions were explored using co-immunoprecipitation and immunofluorescence. The effect of SLC7A11 on ferroptosis was evaluated by iron levels, ROS, and GSH. The impact of sorafenib and doxorubicin (DOX) on HCC cells was analyzed using cell viability assay. RESULTS SLC7A11 was found to be highly expressed in HCC tissues and was correlated with tumor size and poor prognosis. Overexpression of SLC7A11 in HCC cells promoted cell viability, proliferation, and migration. Additionally, SLC7A11 overexpression mitigated erastin-induced ferroptosis, as evidenced by decreased ROS levels and increased GSH levels. We also discovered that SLC7A11 interacted with HSPB1. HSPB1 inhibited erastin-induced ferroptosis. Furthermore, a portion of the cell death induced by sorafenib and DOX is attributed to ferroptosis, with HSPB1 and SLC7A11 inhibiting the death induced by the two drugs, respectively. CONCLUSIONS SLC7A11 plays a significant role in HCC progression by inhibiting ferroptosis, and its interaction with HSPB1 is a critical pathway in this process. Targeting the SLC7A11-HSPB1 axis may provide a novel therapeutic strategy for HCC treatment, highlighting the importance of understanding the mechanisms of ferroptosis in cancer cells.
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Affiliation(s)
- Yan An
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China; Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200050, China
| | - Weilong Liu
- Institute of Hepatology, National clinical research center for infectious diseases, Guangdong Key Lab for Diagnosis &Treatment of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, 518112, China
| | - Yuliang Deng
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Wanqiu Huang
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China.
| | - Jian Huang
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China.
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46
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Han X, He L, Li S, Zhu Y. Trends in liver cancer rehabilitation needs, disease burden, and attributable risk factors in China, 1990-2021. Sci Rep 2025; 15:15682. [PMID: 40325048 PMCID: PMC12053601 DOI: 10.1038/s41598-025-00317-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Accepted: 04/28/2025] [Indexed: 05/07/2025] Open
Abstract
This study investigates trends in liver cancer rehabilitation needs, disease burden, and attributable risk factors in China from 1990 to 2021 using data from the Global Burden of Disease Study 2021. Key metrics included age-standardized prevalence (ASPR), years lived with disability (YLDs), and risk factor attribution. Between 1990 and 2021, the number of liver cancer patients requiring rehabilitation surged by 100.1% (132,779 to 265,539 cases), with YLDs rising by 102.8% (22,981 to 46,602). While ASPR and age-standardized YLD rates (ASYR) showed modest declines (ASPR: - 0.1% annual change; ASYR: - 0.23%), males exhibited a disproportionately higher burden, with 2021 cases and YLDs 2.98- and 2.74-fold greater than females, respectively. Risk factor analysis revealed smoking (14.0%), drug use (11.5%), and alcohol consumption (11.4%) as primary contributors, while metabolic factors like high BMI (7.5%) and fasting plasma glucose (1.9%) demonstrated accelerating impacts (YLDs EAPC: + 4.47% and + 1.31%, respectively). Aging populations and shifting etiologies drove increased rehabilitation demands, particularly among those ≥ 80 years. These findings underscore urgent needs for gender-specific interventions targeting modifiable risks and integrated nursing rehabilitation strategies to mitigate China's growing liver cancer burden.
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Affiliation(s)
- Xiangping Han
- Department of Oncology II, Zhumadian Central Hospital, No. 747, West Section of Zhonghua Road, Yicheng District, Zhumadian City, 463000, Henan, China.
| | - Lei He
- Third Department of Psychological Medicine, Zhumadian Second People's Hospital, No. 51 Xuesong Road, Zhumadian City, 463000, Henan Province, China
- Department of Nursing, Zhumadian Second People's Hospital, No. 51 Xuesong Road, Zhumadian City, Henan Province, China
| | - Shaoying Li
- Department of Oncology II, Zhumadian Central Hospital, No. 747, West Section of Zhonghua Road, Yicheng District, Zhumadian City, 463000, Henan, China
| | - Yuxing Zhu
- Third Department of Psychological Medicine, Zhumadian Second People's Hospital, No. 51 Xuesong Road, Zhumadian City, 463000, Henan Province, China
- Department of Nursing, Zhumadian Second People's Hospital, No. 51 Xuesong Road, Zhumadian City, Henan Province, China
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Li LY, Li RS, Zhou J, Fan J, Wang ZL, Hu B, Mu Q. Synthesis and bioactivity of cyclic peptide GG-8-6 analogues as anti-hepatocellular carcinoma agents. Eur J Med Chem 2025; 289:117473. [PMID: 40054296 DOI: 10.1016/j.ejmech.2025.117473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 02/20/2025] [Accepted: 02/28/2025] [Indexed: 03/29/2025]
Abstract
GG-8-6, a cyclic peptide with effective anti-hepatocellular carcinoma activity in vitro and in vivo, was synthesized based on the lead compound Grifficyclocin B, which was isolated from the plants of Goniothalamus species (Annonaceae family). Based on the previous study, we synthesized 17 analogues of GG-8-6 to find better potential and higher-yield cyclopeptides. Among these analogues, nine increased their yield compared to GG-8-6, and compound 1 reached a high yield of 14.7 %. In addition, the bioassay results showed that ten analogues exhibited significant anti-hepatocellular carcinoma activities in vitro, which promoted cell apoptosis and reduced intracellular ATP levels. Among them, the activity of compounds 1, 2 and 3 was significantly better than GG-8-6, while the yield of compounds 1 and 3 reached nearly five times that of GG-8-6. Compound 17 was obtained by deprotection from compound 1, which preserved antitumor activity, and more new derivatives could be synthesized based on the hydroxyl group in its structure. A subcutaneous xenografted mice model confirmed the in vivo antitumor activity of compounds 1 and 17. The results indicated that both compounds significantly inhibited the growth of tumours. At 10 mg/kg and 15 mg/kg doses for compounds 1 and 17, the inhibition rates reached 84.3 % and 58.39 %, respectively. Furthermore, the potential mechanism of compounds 1 and 17 was analyzed by transcriptomic analysis. Our results indicated that GG-8-6 analogues as new cyclic peptides might be potential candidates for developing new drugs treating hepatocellular carcinoma.
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MESH Headings
- Peptides, Cyclic/pharmacology
- Peptides, Cyclic/chemistry
- Peptides, Cyclic/chemical synthesis
- Humans
- Animals
- Liver Neoplasms/drug therapy
- Liver Neoplasms/pathology
- Liver Neoplasms/metabolism
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/metabolism
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/chemical synthesis
- Antineoplastic Agents/chemistry
- Mice
- Structure-Activity Relationship
- Apoptosis/drug effects
- Cell Proliferation/drug effects
- Drug Screening Assays, Antitumor
- Molecular Structure
- Dose-Response Relationship, Drug
- Mice, Nude
- Mice, Inbred BALB C
- Hep G2 Cells
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Affiliation(s)
- Ling-Yun Li
- School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Rong-Sheng Li
- School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Jian Zhou
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, And Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, China
| | - Jia Fan
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, And Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, China
| | - Zheng-Lin Wang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Bo Hu
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, And Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, China.
| | - Qing Mu
- School of Pharmacy, Fudan University, Shanghai, 201203, China.
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Li J, Feng T, Cui C, Wang H, Su T, Jin L, Zhao X, Xiao W. Post-TACE ALBI-Score Trajectory in Intermediate and Advanced Hepatocellular Carcinoma: Prognostic Implications and Influencing Factors Analysis. J Hepatocell Carcinoma 2025; 12:865-878. [PMID: 40352961 PMCID: PMC12063622 DOI: 10.2147/jhc.s503581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Accepted: 04/23/2025] [Indexed: 05/14/2025] Open
Abstract
Objective The long-term effects of transarterial chemoembolization (TACE) on liver function and their prognostic implications in hepatocellular carcinoma (HCC) have not been fully explored. The Albumin-Bilirubin (ALBI) score, an objective measure of liver function, is a validated prognostic tool in HCC. This study aims to characterize the longitudinal trajectories of ALBI-scores after TACE, evaluate their impact on clinical outcomes, and identify factors influencing these trajectories. Materials and Methods This retrospective study included patients with BCLC stage B/C HCC who underwent TACE, with baseline and at least two post-TACE ALBI-score measurements. Group-Based Trajectory Modeling (GBTM) was used to identify distinct ALBI-score trajectories. Clinical outcomes and patient characteristics were compared across trajectory groups. A CatBoost-based clinical prediction model was developed to identify factors influencing ALBI-score trajectories, with Shapley Additive Explanations (SHAP) values providing feature importance interpretation. Results Among 501 patients, three ALBI-score trajectories were identified: improve, stable, and decline. The improve group had better overall survival (OS) and progression-free survival (PFS) compared to the stable and decline groups. Multivariate analysis confirmed that ALBI-score trajectories were independent risk factors for OS. Subgroup analysis suggested that TACE plus systemic therapy reduced mortality risk in the stable and decline groups. The CatBoost model effectively distinguished distinct trajectory groups, with SHAP analysis highlighting ALBI-grade, Child-Pugh class, and tumor number as key predictors. Conclusion Post-TACE ALBI-score trajectories are closely linked to clinical outcomes, with improved liver function associated with better prognosis. Monitoring these trajectories could guide personalized treatment strategies for HCC patients undergoing TACE.
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Affiliation(s)
- Jian Li
- The Department of Interventional Radiology of Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People’s Republic of China
| | - Tianyuyi Feng
- The Department of Radiology of the Fifth People’s Hospital of Shanghai, Fudan University, Shanghai, 200240, People’s Republic of China
| | - Chi Cui
- Center of Vascular and Interventional Surgery, Department of General Surgery, The Third People’s Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University & The Second Affiliated Hospital of Chengdu, Chongqing Medical University, Chengdu, 610031, People’s Republic of China
| | - Haochen Wang
- The Department of Interventional Radiology of Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People’s Republic of China
| | - Tianhao Su
- The Department of Interventional Radiology of Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People’s Republic of China
| | - Long Jin
- The Department of Interventional Radiology of Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People’s Republic of China
| | - Xiaohu Zhao
- The Department of Radiology of the Fifth People’s Hospital of Shanghai, Fudan University, Shanghai, 200240, People’s Republic of China
| | - Weizhong Xiao
- Center of Vascular and Interventional Surgery, Department of General Surgery, The Third People’s Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University & The Second Affiliated Hospital of Chengdu, Chongqing Medical University, Chengdu, 610031, People’s Republic of China
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Mohammadzadeh S, Mohebbi A, Abdi A, Mohammadi A. Inter-reader agreement of RECIST and mRECIST criteria for assessing response to transarterial chemoembolization in hepatocellular carcinoma. BMC Med Imaging 2025; 25:148. [PMID: 40319244 PMCID: PMC12049784 DOI: 10.1186/s12880-025-01688-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Accepted: 04/23/2025] [Indexed: 05/07/2025] Open
Abstract
OBJECTIVES To evaluate the reproducibilities of Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST (mRECIST) for hepatocellular carcinoma (HCC) patients treated with transarterial chemoembolization (TACE) using contrast-enhanced computed tomography (CT). METHODS This retrospective study included 105 consecutive patients with confirmed HCC recruited from November 2002 to June 2012. The study protocol has been pre-registered at ( https://osf.io/nxg4q/ ) on the Open Science Framework (OSF) platform. Patients with pre-procedural and follow-up CT scans who had solely received TACE were included. The tumor response evaluation to TACE was conducted using RECIST 1.1 and mRECIST guidelines. Three experienced board-certified abdominal radiologists interpreted CT scans. RESULTS For pre-procedure CT, the agreement was more excellent when using RECIST guidelines with a "marginally significant" p-value of 0.056. This trend continued for post-procedural CT scans, with RECIST again showing significantly higher agreement with a p-value of 0.001. When evaluating the four categories of response, Gwet's coefficient was 0.90 (CI = 0.83 to 0.97) for RECIST and 0.80 (CI = 0.63 to 0.90) for mRECIST. Conversely, the Fleiss Kappa analysis demonstrated a higher agreement for the mRECIST guideline. There was an insignificant difference in RECIST and mRECIST guidelines inter-reader agreement when categorizing the tumor response with a p-value of 0.101. CONCLUSION Both guidelines' inter-reader reproducibility in assessing tumor response through CT after the TACE procedure was excellent, with RECIST's reproducibility being very slightly better.
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Affiliation(s)
- Saeed Mohammadzadeh
- Universal Scientific Education and Research Network (USERN), Tehran, Iran
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Alisa Mohebbi
- Universal Scientific Education and Research Network (USERN), Tehran, Iran
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Abdi
- Universal Scientific Education and Research Network (USERN), Tehran, Iran
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Afshin Mohammadi
- Department of Radiology, Faculty of Medicine, Urmia University of Medical Science, Urmia, Iran.
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Lei W, Zhou K, Lei Y, Li Q, Zhu H. Pathogenesis and Systemic Treatment of Hepatocellular Carcinoma: Current Status and Prospects. Mol Cancer Ther 2025; 24:692-708. [PMID: 39417575 DOI: 10.1158/1535-7163.mct-24-0403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 08/14/2024] [Accepted: 10/08/2024] [Indexed: 10/19/2024]
Abstract
Hepatocellular carcinoma (HCC) remains one of the major threats to human health worldwide. The emergence of systemic therapeutic options has greatly improved the prognosis of patients with HCC, particularly those with advanced stages of the disease. In this review, we discussed the pathogenesis of HCC, genetic alterations associated with the development of HCC, and alterations in the tumor immune microenvironment. Then, important indicators and emerging technologies related to the diagnosis of HCC are summarized. Also, we reviewed the major advances in treatments for HCC, offering insights into future prospects for next-generation managements.
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Affiliation(s)
- Wanting Lei
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Kexun Zhou
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Ye Lei
- College of Liberal Arts, Neijiang Normal University, Neijiang, China
| | - Qiu Li
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Zhu
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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