1
|
Zhang X, Zhang L, Ji L, Liangpunsakul S, Zhang J, Hong F, Lyu H, Hwang S, Gou C, Jiang Y, Chen X, Li Q, Tong G, Zhang A, Wang J, Li X, Zhang M, Sun X, Li M, Gao Y. Pien Tze Huang plus entecavir improves hepatic fibrosis in Chinese patients with chronic hepatitis B. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 142:156741. [PMID: 40318534 DOI: 10.1016/j.phymed.2025.156741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 03/04/2025] [Accepted: 04/07/2025] [Indexed: 05/07/2025]
Abstract
BACKGROUND Pien Tze Huang (PTH), a well-established traditional Chinese medicine compound, has exhibited anti-hepatic fibrosis properties both in vitro and in vivo animal models, but the randomized clinical trials to evaluate anti-hepatic fibrosis efficacy of PTH are deficient. Chronic hepatitis B (CHB) is a leading cause of hepatic fibrosis in China. Although antiviral therapies have demonstrated significant effectiveness in arresting the progression of fibrotic disease, complete regression of established fibrosis is limited to only a subset of treated patients. PURPOSE To assess the efficacy of PTH in improving hepatic fibrosis in CHB patients. STUDY DESIGN We conducted a randomized, double-blind, placebo-controlled clinical trial involving 144 CHB patients with hepatic fibrosis. This study was carried out from September 2020 to April 2023. (Clinical Trials Registration: ChiCTR2000035128) METHODS: CHB patients with an Ishak score of 2-5 points were recruited from ten hospitals across China. Participants were randomized in 1:1 ratio to receive either oral PTH (0.6 g per dose, three times/day) or placebo for 48 weeks, in addition to the standard treatment of entecavir (0.5 mg/day). The primary endpoint was the change in Ishak score. Secondary outcomes included changes in Knodell HAI score, liver stiffness measurement, AST- to -platelet ratio index, Fibrosis-4 index and hepatic function indices. RESULTS Of the 144 randomized patients, 142 patients (71 in the PTH group and 71 in the placebo group) were included in the primary analysis. The PTH group exhibited lower Ishak score compared to the control group (2.37 ± 0.94 vs. 2.87 ± 1.04, F = 6.072, p = 0.015). Notably, in treatment-naive patients, the PTH group showed significant improvement in Ishak score post-treatment compared with the control group (2.13 ± 0.72 vs. 2.74 ± 1.07, F = 6.336, p = 0.014). However, no significant changes were observed in these parameters among patients already receiving antiviral therapy. CONCLUSIONS The combination of PTH and entecavir demonstrates significant improvement in hepatic fibrosis among CHB patients, especially those who are treatment-naive patients.
Collapse
Affiliation(s)
- Xin Zhang
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China; Institute of Infectious Diseases, Shanghai Institute of Traditional Chinese Medicine, Shanghai, China; Laboratory of Cellular Immunity, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine; Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education, Shanghai, China
| | - Liwen Zhang
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China; Institute of Infectious Diseases, Shanghai Institute of Traditional Chinese Medicine, Shanghai, China; Laboratory of Cellular Immunity, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine; Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education, Shanghai, China
| | - Longshan Ji
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China; Institute of Infectious Diseases, Shanghai Institute of Traditional Chinese Medicine, Shanghai, China; Laboratory of Cellular Immunity, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine; Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education, Shanghai, China
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, USA
| | - Jinghao Zhang
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Fei Hong
- Fujian Pien Tze Huang Enterprise Key Laboratory of Natural Medicine Research and Development, Zhangzhou Pien Tze Huang Pharmaceutical Co., Ltd, Zhangzhou, China
| | - Hua Lyu
- National Monitoring Center for Medical Services Quality of TCM Hospital, Shanghai, China
| | - Seonghwan Hwang
- College of Pharmacy, Pusan National University, Busan, South Korea
| | - Chunyan Gou
- Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Yuyong Jiang
- Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaorong Chen
- Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Qin Li
- Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Guangdong Tong
- Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
| | - Anna Zhang
- Henan Infectious Disease Hospital, Zhengzhou, China
| | - Jing Wang
- The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Xiaodong Li
- Hubei province Hospital of Traditional Chinese Medicine, Wuhan, China
| | - Mingxin Zhang
- The First Affiliated Hospital of Xi'an Medical University, Xi'an, China
| | - Xuehua Sun
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China; Institute of Infectious Diseases, Shanghai Institute of Traditional Chinese Medicine, Shanghai, China; Laboratory of Cellular Immunity, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine; Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education, Shanghai, China.
| | - Man Li
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China; Institute of Infectious Diseases, Shanghai Institute of Traditional Chinese Medicine, Shanghai, China; Laboratory of Cellular Immunity, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine; Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education, Shanghai, China.
| | - Yueqiu Gao
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China; Institute of Infectious Diseases, Shanghai Institute of Traditional Chinese Medicine, Shanghai, China; Laboratory of Cellular Immunity, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine; Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education, Shanghai, China.
| |
Collapse
|
2
|
Mohamed NM, Mohamed RH, Kennedy JF, Elhefnawi MM, Hamdy NM. A comprehensive review and in silico analysis of the role of survivin (BIRC5) in hepatocellular carcinoma hallmarks: A step toward precision. Int J Biol Macromol 2025; 311:143616. [PMID: 40306500 DOI: 10.1016/j.ijbiomac.2025.143616] [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: 02/13/2025] [Revised: 04/25/2025] [Accepted: 04/27/2025] [Indexed: 05/02/2025]
Abstract
Hepatocellular carcinoma (HCC) is a complex malignancy driven by the dysregulation of multiple cellular pathways. Survivin, a key member of the inhibitor of apoptosis (IAP) family, plays a central role in HCC tumorigenesis and progression. Despite significant research, a comprehensive understanding of the contributions of survivin to the hallmarks of cancer, its molecular network, and its potential as a therapeutic target remains incomplete. In this review, we integrated bioinformatics analysis with an extensive literature review to provide deeper insights into the role of survivin in HCC. Using bioinformatics tools such as the Human Protein Atlas, GEPIA, STRING, TIMER, and Metascape, we analyzed survivin expression and its functional associations and identified the top 20 coexpressed genes in HCC. These include TK1, SPC25, SGO2, PTTG1, PRR11, PLK1, NCAPH, KPNA2, KIF2C, KIF11, HJURP, GTSE1, FOXM1, CEP55, CENPA, CDCA3, CDC45, CCNB2, CCNB1 and CTD-2510F5.4. Our findings also revealed significant protein-protein interactions among these genes, which were enriched in pathways associated with the FOXM1 oncogenic signaling cascade, and biological processes such as cell cycle regulation, mitotic checkpoints, and diseases such as liver neoplasms. We also discussed the involvement of survivin in key oncogenic pathways, including the PI3K/AKT, WNT/β-catenin, Hippo, and JAK/STAT3 pathways, and its role in modulating cell cycle checkpoints, apoptosis, and autophagy. Furthermore, we explored its interactions with the tumor microenvironment, particularly its impact on immune modulation through myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, and natural killer cell function in HCC. Additionally, we highlighted its involvement in alkylglycerone phosphate synthase (AGPS)-mediated lipid reprogramming and identified important gaps in the survivin network that warrant further investigation. This review also examined the role of survivin in cancer stemness, inflammation, and virally mediated hepatocarcinogenesis. We evaluated its potential as a diagnostic, prognostic, predictive, and pharmacodynamic biomarker in HCC, emphasizing its relevance in precision medicine. Finally, we summarized emerging survivin-targeted therapeutics and ongoing clinical trials, underscoring the need for novel strategies to effectively target survivin in HCC.
Collapse
Affiliation(s)
- Nermin M Mohamed
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Abassia, 11566 Cairo, Egypt
| | - Rania Hassan Mohamed
- Department of Biochemistry, Faculty of Science, Ain Shams University, Abassia, 11566 Cairo, Egypt
| | - John F Kennedy
- Chembiotech Laboratories, Kyrewood House, Tenbury Wells, Worcestershire, United Kingdom
| | - Mahmoud M Elhefnawi
- Biomedical Informatics and Chemoinformatics Group, Informatics and Systems Department, National Research Centre, Cairo, Egypt.
| | - Nadia M Hamdy
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Abassia, 11566 Cairo, Egypt.
| |
Collapse
|
3
|
Mori Y, Tamburini K, Novruzov E, Schmitt D, Mavriopoulou E, Loosen SH, Roderburg C, Watabe T, Kratochwil C, Röhrich M, Alavi A, Haberkorn U, Giesel FL. Efficacy of [ 68Ga]Ga-FAPI-PET as a non-invasive evaluation method of liver fibrosis. Ann Nucl Med 2025; 39:631-639. [PMID: 40048016 PMCID: PMC12095406 DOI: 10.1007/s12149-025-02027-6] [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: 10/27/2024] [Accepted: 02/12/2025] [Indexed: 05/22/2025]
Abstract
INTRODUCTION Liver fibrosis is a chronic fibrosing hepatic disorder following recurrent injury, characterized by the excessive accumulation of extracellular matrix. Early detection has a great clinical impact because 80-90% of hepatocellular carcinomas are known to develop in fibrotic or cirrhotic (end-stage fibrotic) livers. PET imaging with FAP ligands exhibited highly promising results in recent years to visualize fibrosis in various organs due to the crucial role of activated fibroblasts in fibrosing processes. However, still little is known about the efficacy of FAP imaging in liver fibrosis. Thus, we sought to investigate the potential of FAPI-PET in a cohort of oncological and non-oncological patients. METHODS 199 patients who underwent FAPI-PET/CT at the University Hospital of Heidelberg between July 2017 and July 2020 were retrospectively analyzed. The tracer uptake of the liver was analyzed and correlated with radiological and clinical parameters. RESULTS We observed a weak but significant negative correlation between the hepatic FAPI uptake and CT density (r = - 0.273, P < 0.001***). A positive correlation was observed between hepatic FAPI uptake and the aspartate aminotransferase (AST)-to-platelet ratio index (APRI) (r = 0.183, P = 0.009**), an established surrogate for liver fibrosis. The liver SUV (standardized uptake value) mean and SUVmax of FAPI showed significant differences between groups of patients with low (< 0.5), middle (0.5-1.0) and higher (> 1.0) levels of APRI (both P < 0.001***). CONCLUSION These preliminary observational results suggest that FAPI-PET may be a viable non-invasive method to asses liver fibrosis.
Collapse
Affiliation(s)
- Yuriko Mori
- Department of Nuclear Medicine, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstrasse 5, 40225, Duesseldorf, Germany.
| | - Katharina Tamburini
- Department of Nuclear Medicine, Heidelberg University Hospital, INF 400, 69120, Heidelberg, Germany
| | - Emil Novruzov
- Department of Nuclear Medicine, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstrasse 5, 40225, Duesseldorf, Germany
| | - Dominik Schmitt
- Department of Nuclear Medicine, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstrasse 5, 40225, Duesseldorf, Germany
| | - Eleni Mavriopoulou
- Department of Nuclear Medicine, Heidelberg University Hospital, INF 400, 69120, Heidelberg, Germany
| | - Sven H Loosen
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstrasse 5, 40225, Duesseldorf, Germany
| | - Christoph Roderburg
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstrasse 5, 40225, Duesseldorf, Germany
| | - Tadashi Watabe
- Institute for Radiation Sciences, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Clemens Kratochwil
- Department of Nuclear Medicine, Heidelberg University Hospital, INF 400, 69120, Heidelberg, Germany
| | - Manuel Röhrich
- Department of Nuclear Medicine, Mainz University Hospital, Langenbeckstraße 1, 55131, Mainz, Germany
| | - Abass Alavi
- Department of Radiology, Hospital of University of Pennsylvania, Philadelphia, PA, USA
| | - Uwe Haberkorn
- Department of Nuclear Medicine, Heidelberg University Hospital, INF 400, 69120, Heidelberg, Germany
| | - Frederik L Giesel
- Department of Nuclear Medicine, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstrasse 5, 40225, Duesseldorf, Germany
- Institute for Radiation Sciences, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| |
Collapse
|
4
|
Królikowska K, Kurman N, Błaszczak K, Ławicki S, Gudowska-Sawczuk M, Zajkowska M. The Significance of Neuropilins in Gastrointestinal Cancers. Int J Mol Sci 2025; 26:4937. [PMID: 40430075 PMCID: PMC12112013 DOI: 10.3390/ijms26104937] [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: 03/26/2025] [Revised: 05/19/2025] [Accepted: 05/20/2025] [Indexed: 05/29/2025] Open
Abstract
Cancers represent a significant global health concern, being among the most prevalent malignancies and contributing substantially to morbidity and mortality rates. Notably, colorectal, gastric, pancreatic, and liver cancers are the most frequently diagnosed among these malignancies. The pathogenesis of gastrointestinal (GI) cancers is multifactorial, encompassing a complex interplay of genetic predispositions, environmental exposures, and lifestyle choices. Despite advances in diagnostic approaches and therapeutic strategies, existing treatment modalities, particularly in the advanced stages of these cancers, remain ineffective. Recent research efforts have increasingly focused on the identification and characterization of novel biomarkers that could enhance both the detection and treatment of gastrointestinal cancers. One particularly promising area of investigation involves neuropilins (NRPs). NRPs are involved in essential biological processes such as angiogenesis, cellular migration, and tumor cell-microenvironment interactions, all of which promote tumor progression and contribute to the development of treatment resistance. Overexpression of neuropilins has been linked to poor prognosis in patients, implying that they could be useful in diagnosis and serve as targets for molecular treatment. Recent research also suggests that inhibiting neuropilin activity may slow tumor growth and inhibit angiogenic processes, opening up new possibilities for targeted therapeutic techniques in the treatment of gastrointestinal malignancies.
Collapse
Affiliation(s)
- Kinga Królikowska
- Department of Population Medicine and Lifestyle Diseases Prevention, The Faculty of Medicine, Medical University of Bialystok, 15-269 Bialystok, Poland (S.Ł.)
| | - Natalia Kurman
- Department of Population Medicine and Lifestyle Diseases Prevention, The Faculty of Medicine, Medical University of Bialystok, 15-269 Bialystok, Poland (S.Ł.)
| | - Katarzyna Błaszczak
- Department of Population Medicine and Lifestyle Diseases Prevention, The Faculty of Medicine, Medical University of Bialystok, 15-269 Bialystok, Poland (S.Ł.)
| | - Sławomir Ławicki
- Department of Population Medicine and Lifestyle Diseases Prevention, The Faculty of Medicine, Medical University of Bialystok, 15-269 Bialystok, Poland (S.Ł.)
| | - Monika Gudowska-Sawczuk
- Department of Biochemical Diagnostics, Medical University of Bialystok, Waszyngtona 15A St., 15-269 Bialystok, Poland;
| | - Monika Zajkowska
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, Waszyngtona 15A St., 15-269 Bialystok, Poland
| |
Collapse
|
5
|
Tu DY, Peng R, Jin SJ, Su BB, Fan SS, Zhang JH, Wang SY, Miao YY, Jiang GQ, Zhang C, Cao J, Bai DS. MARCH8 suppresses hepatocellular carcinoma by promoting SREBP1 degradation and modulating fatty acid de novo synthesis. Cell Death Dis 2025; 16:391. [PMID: 40379644 DOI: 10.1038/s41419-025-07707-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 04/16/2025] [Accepted: 05/01/2025] [Indexed: 05/19/2025]
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors of the digestive system, and its prevalence is currently increasing. The current study aims to elucidate the mechanism by which membrane-associated RING-CH8 (MARCH8) impedes the progression of HCC. MARCH8 was identified as a distinct prognostic marker for recurrence-free survival (RFS) and overall survival (OS) in patients with HCC. This study shows that MARCH8 hinders lipid deposition by suppressing the expression of key enzymes for the de novo synthesis of fatty acids (FAs) via RNA sequencing, untargeted metabolomics, and a series of in vivo and in vitro experiments. Further experimental validation demonstrated that MARCH8 was a novel E3 ligase of sterol regulatory element binding protein 1 (SREBP1). And, it primarily promoted the degradation of SREBP1, thereby suppressing the expression of key enzymes involved in the de novo synthesis of FAs. In conclusion, this study has identified MARCH8 as a key "switch" that can be targeted to prevent de novo FA synthesis in HCC cells. This finding may have substantial implications for discovering innovative therapeutic strategies for HCC.
Collapse
Affiliation(s)
- Dao-Yuan Tu
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China
| | - Rui Peng
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China
| | - Sheng-Jie Jin
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China
- General Surgery Institute of Northern Jiangsu People's Hospital, Yangzhou, China
| | - Bing-Bing Su
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China
| | - Song-Song Fan
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China
| | - Jia-Hao Zhang
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China
| | - Shun-Yi Wang
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China
| | - Yang-Yang Miao
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China
| | - Guo-Qing Jiang
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China
- General Surgery Institute of Northern Jiangsu People's Hospital, Yangzhou, China
| | - Chi Zhang
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China.
- General Surgery Institute of Northern Jiangsu People's Hospital, Yangzhou, China.
| | - Jun Cao
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China.
- General Surgery Institute of Northern Jiangsu People's Hospital, Yangzhou, China.
| | - Dou-Sheng Bai
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China.
- General Surgery Institute of Northern Jiangsu People's Hospital, Yangzhou, China.
| |
Collapse
|
6
|
Fu L, Li S, Mei J, Li Z, Yang X, Zheng C, Li N, Lin Y, Cao C, Liu L, Huang L, Shen X, Huang Y, Yun J. BIRC2 blockade facilitates immunotherapy of hepatocellular carcinoma. Mol Cancer 2025; 24:113. [PMID: 40223121 PMCID: PMC11995630 DOI: 10.1186/s12943-025-02319-5] [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: 09/14/2024] [Accepted: 04/01/2025] [Indexed: 04/15/2025] Open
Abstract
BACKGROUND The effectiveness of immunotherapy in hepatocellular carcinoma (HCC) is limited, however, the molecular mechanism remains unclear. In this study, we identified baculoviral IAP repeat-containing protein 2 (BIRC2) as a key regulator involved in immune evasion of HCC. METHODS Genome-wide CRISPR/Cas9 screening was conducted to identify tumor-intrinsic genes pivotal for immune escape. In vitro and in vivo models demonstrated the role of BIRC2 in protecting HCC cells from immune killing. Then the function and relevant signaling pathways of BIRC2 were explored. The therapeutic efficacy of BIRC2 inhibitor was examined in different in situ and xenograft HCC models. RESULTS Elevated expression of BIRC2 correlated with adverse prognosis and resistance to immunotherapy in HCC patients. Mechanistically, BIRC2 interacted with and promoted the ubiquitination-dependent degradation of NFκB-inducing kinase (NIK), leading to the inactivation of the non-canonical NFκB signaling pathway. This resulted in the decrease of major histocompatibility complex class I (MHC-I) expression, thereby protecting HCC cells from T cell-mediated cytotoxicity. Silencing BIRC2 using shRNA or inhibiting it with small molecules increased the sensitivity of HCC cells to immune killing. Meanwhile, BIRC2 blockade improved the function of T cells both in vitro and in vivo. Targeting BIRC2 significantly inhibited tumor growth, and enhanced the efficacy of anti-programmed death protein 1 (PD-1) therapy. CONCLUSIONS Our findings suggested that BIRC2 blockade facilitated immunotherapy of HCC by simultaneously sensitizing tumor cells to immune attack and boosting the anti-tumor immune response of T cells.
Collapse
Affiliation(s)
- Lingyi Fu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Shuo Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Jie Mei
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Ziteng Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Xia Yang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Chengyou Zheng
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Nai Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Yansong Lin
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Chao Cao
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Lixuan Liu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Liyun Huang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Xiujiao Shen
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Yuhua Huang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Jingping Yun
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China.
| |
Collapse
|
7
|
Zhao Y, Wang X, Yang X, Li J, Han B. Insights into the history and trends of nanotechnology for the treatment of hepatocellular carcinoma: a bibliometric-based visual analysis. Discov Oncol 2025; 16:484. [PMID: 40192866 PMCID: PMC11977073 DOI: 10.1007/s12672-025-02145-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 03/13/2025] [Indexed: 04/10/2025] Open
Abstract
BACKGROUND Nanotechnology has great potential and advantages in the treatment of hepatocellular carcinoma (HCC), but the research trends and future directions are not yet clear. OBJECTIVES Analyze the development trajectory, research hotspots, and future trends of nanotechnology and HCC research globally in the past 20 years, providing a more comprehensive and intuitive reference for researchers in this field. METHODS Retrieve relevant literature on nanotechnology and HCC research in the Web of Science (WOS) Core Collection database, and conduct bibliometric analysis using software such as CiteSpace, VOSviewer, and SCImago Graphica. RESULTS A total of 852 English publications meeting the criteria were retrieved from the WOS database, with an overall increasing trend in the number of publications and citation frequency over the years. China leads in the number of publications and international collaborations, followed by the USA and India. The most influential research institution is the Chinese Academy of Sciences, the most influential scholar/team is the Rahman, Mahfoozur team, and the journal with the most publications is the International Journal of Nanomedicine. A comprehensive analysis reveals that the current main research directions include new types of nanoparticles, targeted drug delivery systems, photothermal/photodynamic therapy, gene delivery systems, diagnostics, and imaging. It is anticipated that further collaboration among scholars, institutions, and countries will accelerate the development of nanotechnology in the field of HCC research. CONCLUSION This study provides an in-depth analysis of the research status and development trends of nanotechnology in treating HCC from a bibliometric perspective, offering possible guidance for researchers to explore hot topics and frontiers, select suitable journals, and partners in this field.
Collapse
Affiliation(s)
- Yulei Zhao
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250355, Shandong, China
| | - Xingxin Wang
- College of Acupuncture and Tuina, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Xiaoman Yang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250355, Shandong, China
| | - Jiaheng Li
- College of Health, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Bingbing Han
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250355, Shandong, China.
| |
Collapse
|
8
|
Basile L, Cannarella R, Magni P, Condorelli RA, Calogero AE, La Vignera S. Role of gliflozins on hepatocellular carcinoma progression: a systematic synthesis of preclinical and clinical evidence. Expert Opin Drug Saf 2025; 24:413-426. [PMID: 39714931 DOI: 10.1080/14740338.2024.2447057] [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: 09/28/2024] [Revised: 11/02/2024] [Accepted: 12/22/2024] [Indexed: 12/24/2024]
Abstract
INTRODUCTION The risk of HCC is twice as high in diabetic patients compared to non-diabetic ones, suggesting that diabetes advances carcinogenesis in the liver through a variety of mechanisms. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to improve liver outcomes, emerging as promising agents to treat hepatocellular carcinoma (HCC) in patients with type 2 diabetes mellitus (T2DM). METHODS We searched PubMed and Scopus databases for articles presenting an association between SGLT2is and HCC to explore the putative mechanisms of action underlying the anti-proliferative activity of SGLT2is. RESULTS A total of 24 articles were selected for inclusion, of which 14 were preclinical and 10 were clinical. Preclinical studies were mainly focused on canagliflozin, used alone or in combination with other drugs. CONCLUSIONS Overall, canagliflozin had a negative effect on HCC cell proliferation by interfering with glucose-dependent and independent metabolic pathways, negatively impacting angiogenesis, and inducing apoptosis in in-vitro cell models. In-vivo, a protective effect on hepatic steatosis and fibrosis and HCC development has been reported. Human studies showed a lower risk of developing HCC in patients on SGLT2is. However, this is supported by retrospective cohort studies. Clinical trials are needed to confirm the causal relationship between SGLT2i administration and HCC development.
Collapse
Affiliation(s)
- Livia Basile
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Rossella Cannarella
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
- Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Paolo Magni
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
- IRCCS MultiMedica, Sesto S. Giovanni, Milan, Italy
| | - Rosita A Condorelli
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Aldo E Calogero
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Sandro La Vignera
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| |
Collapse
|
9
|
Corey KE, Dudzinski DM, Guimaraes AR, Mino-Kenudson M. Case 9-2025: A 59-Year-Old Man with Hepatocellular Carcinoma. N Engl J Med 2025; 392:1216-1227. [PMID: 40138556 DOI: 10.1056/nejmcpc1909622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/29/2025]
Affiliation(s)
- Kathleen E Corey
- Department of Medicine, Massachusetts General Hospital, Boston
- Department of Medicine, Harvard Medical School, Boston
| | - David M Dudzinski
- Department of Medicine, Massachusetts General Hospital, Boston
- Department of Medicine, Harvard Medical School, Boston
| | - Alexander R Guimaraes
- Department of Radiology, Massachusetts General Hospital, Boston
- Department of Radiology, Harvard Medical School, Boston
| | - Mari Mino-Kenudson
- Department of Pathology, Massachusetts General Hospital, Boston
- Department of Pathology, Harvard Medical School, Boston
| |
Collapse
|
10
|
Chen JN, Wang L, He YX, Sun XW, Cheng LJ, Li YN, Yoshida S, Shen ZY. SEL1L-mediated endoplasmic reticulum associated degradation inhibition suppresses proliferation and migration in Huh7 hepatocellular carcinoma cells. World J Gastroenterol 2025; 31:103133. [PMID: 40093667 PMCID: PMC11886529 DOI: 10.3748/wjg.v31.i10.103133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 01/04/2025] [Accepted: 02/05/2025] [Indexed: 02/26/2025] Open
Abstract
BACKGROUND Proteins play a central role in regulating biological functions, and various pathways regulate their synthesis and secretion. Endoplasmic reticulum-associated protein degradation (ERAD) is crucial for monitoring protein synthesis and processing unfolded or misfolded proteins in actively growing tumor cells. However, the role of the multiple ERAD complexes in liver cancer remains unclear. AIM To elucidate the effects of SEL1L-mediated ERAD on Huh7 and explore the underlying mechanisms in vivo and in vitro. METHODS Huh7 cells were treated with ERAD inhibitor to identify ERAD's role. Cell counting kit-8, 5-ethynyl-2'-deoxyuridine and colony formation experiments were performed. Apoptosis level and migration ability were assessed using fluorescence activated cell sorting and Transwell assay, respectively. Huh7 SEL1L knockout cell line was established via clustered regularly interspaced short palindromic repeats, proliferation, apoptosis, and migration were assessed through previous experiments. The role of SEL1L in vivo and the downstream target of SEL1L were identified using Xenograft and mass spectrometry, respectively. RESULTS The ERAD inhibitor suppressed cell proliferation and migration and promoted apoptosis. SEL1L-HRD1 significantly influenced Huh7 cell growth. SEL1L knockout suppressed tumor cell proliferation and migration and enhanced apoptosis. Mass spectrometry revealed EXT2 is a primary substrate of ERAD. SEL1L knockout significantly increased the protein expression of EXT2. Furthermore, EXT2 knockdown partially restored the effect of SEL1L knockout. CONCLUSION ERAD inhibition suppressed the proliferation and migration of Huh7 and promoted its apoptosis. EXT2 plays an important role and ERAD might be a potential treatment for Huh7 hepatocellular carcinoma.
Collapse
Affiliation(s)
- Jia-Nan Chen
- School of Medicine, Nankai University, Tianjin 300071, China
- Department of Organ Transplant, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300192, China
| | - Li Wang
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Frontiers Science Center for Cell Responses, Nankai University, Tianjin 300071, China
| | - Yu-Xin He
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Frontiers Science Center for Cell Responses, Nankai University, Tianjin 300071, China
| | - Xiao-Wei Sun
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Frontiers Science Center for Cell Responses, Nankai University, Tianjin 300071, China
| | - Long-Jiao Cheng
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Frontiers Science Center for Cell Responses, Nankai University, Tianjin 300071, China
| | - Ya-Nan Li
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Frontiers Science Center for Cell Responses, Nankai University, Tianjin 300071, China
| | - Sei Yoshida
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Frontiers Science Center for Cell Responses, Nankai University, Tianjin 300071, China
- Research Institute of Transplant Medicine, Nankai University, Tianjin 300192, China
- Nankai International Advanced Research Institute, Shenzhen 518045, Guangdong Province, China
| | - Zhong-Yang Shen
- School of Medicine, Nankai University, Tianjin 300071, China
- Department of Organ Transplant, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300192, China
- Research Institute of Transplant Medicine, Nankai University, Tianjin 300192, China
- Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300192, China
| |
Collapse
|
11
|
Giron-Michel J, Padelli M, Oberlin E, Guenou H, Duclos-Vallée JC. State-of-the-Art Liver Cancer Organoids: Modeling Cancer Stem Cell Heterogeneity for Personalized Treatment. BioDrugs 2025; 39:237-260. [PMID: 39826071 PMCID: PMC11906529 DOI: 10.1007/s40259-024-00702-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/21/2024] [Indexed: 01/20/2025]
Abstract
Liver cancer poses a global health challenge with limited therapeutic options. Notably, the limited success of current therapies in patients with primary liver cancers (PLCs) may be attributed to the high heterogeneity of both hepatocellular carcinoma (HCCs) and intrahepatic cholangiocarcinoma (iCCAs). This heterogeneity evolves over time as tumor-initiating stem cells, or cancer stem cells (CSCs), undergo (epi)genetic alterations or encounter microenvironmental changes within the tumor microenvironment. These modifications enable CSCs to exhibit plasticity, differentiating into various resistant tumor cell types. Addressing this challenge requires urgent efforts to develop personalized treatments guided by biomarkers, with a specific focus on targeting CSCs. The lack of effective precision treatments for PLCs is partly due to the scarcity of ex vivo preclinical models that accurately capture the complexity of CSC-related tumors and can predict therapeutic responses. Fortunately, recent advancements in the establishment of patient-derived liver cancer cell lines and organoids have opened new avenues for precision medicine research. Notably, patient-derived organoid (PDO) cultures have demonstrated self-assembly and self-renewal capabilities, retaining essential characteristics of their respective in vivo tissues, including both inter- and intratumoral heterogeneities. The emergence of PDOs derived from PLCs serves as patient avatars, enabling preclinical investigations for patient stratification, screening of anticancer drugs, efficacy testing, and thereby advancing the field of precision medicine. This review offers a comprehensive summary of the advancements in constructing PLC-derived PDO models. Emphasis is placed on the role of CSCs, which not only contribute significantly to the establishment of PDO cultures but also faithfully capture tumor heterogeneity and the ensuing development of therapy resistance. The exploration of PDOs' benefits in personalized medicine research is undertaken, including a discussion of their limitations, particularly in terms of culture conditions, reproducibility, and scalability.
Collapse
Affiliation(s)
- Julien Giron-Michel
- INSERM UMR-S-MD 1197, Paul-Brousse Hospital, Villejuif, France.
- Orsay-Vallée Campus, Paris-Saclay University, Gif-sur-Yvette, France.
| | - Maël Padelli
- INSERM UMR-S-MD 1197, Paul-Brousse Hospital, Villejuif, France
- Orsay-Vallée Campus, Paris-Saclay University, Gif-sur-Yvette, France
- Department of Biochemistry and Oncogenetics, Paul Brousse Hospital, AP-HP, Villejuif, France
| | - Estelle Oberlin
- INSERM UMR-S-MD 1197, Paul-Brousse Hospital, Villejuif, France
- Orsay-Vallée Campus, Paris-Saclay University, Gif-sur-Yvette, France
| | - Hind Guenou
- INSERM UMR-S-MD 1197, Paul-Brousse Hospital, Villejuif, France
- Orsay-Vallée Campus, Paris-Saclay University, Gif-sur-Yvette, France
| | - Jean-Charles Duclos-Vallée
- Orsay-Vallée Campus, Paris-Saclay University, Gif-sur-Yvette, France
- INSERM UMR-S 1193, Paul Brousse Hospital, Villejuif, France
- Hepato-Biliary Department, Paul Brousse Hospital, APHP, Villejuif, France
- Fédération Hospitalo-Universitaire (FHU) Hepatinov, Villejuif, France
| |
Collapse
|
12
|
Li J, Liu X, Tran TT, Lee M, Tsai RYL. DNA Methylation and Target Gene Expression in Fatty Liver Progression From Simple Steatosis to Advanced Fibrosis. Liver Int 2025; 45:e70040. [PMID: 39982030 DOI: 10.1111/liv.70040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 02/07/2025] [Accepted: 02/12/2025] [Indexed: 02/22/2025]
Abstract
BACKGROUND AND AIM Metabolic dysfunction-associated steatotic liver diseases (MASLD), also known as non-alcoholic fatty liver diseases (NAFLD), have become a leading risk factor for hepatocellular carcinoma (HCC) in Western countries. NAFLD progresses from simple steatosis to HCC, with advanced liver fibrosis (ALF) and metabolic dysfunction-associated steatohepatitis (MASH) or non-alcoholic steatohepatitis (NASH) representing the two preceding high-risk stages. METHODS We analysed changes in the DNA methylation landscape from simple steatosis to ALF or NASH and determined their relevance in gene regulation and HCC survival. Methylomic datasets generated from applying the Illumina 450K BeadChip on human MASLD/NAFLD liver samples were analysed using integrative data analyses to identify differentially methylated regions (DMRs) associated with ALF (F3/4 vs. F0/1) or non-fibrotic NASH (NASH-F0/1 vs. NAFLD-F0/1). RESULTS Gene Set Enrichment Analysis (GSEA) of genes associated with fibrosis-DMRs showed enrichment in xenobiotic metabolism, UV response and hypoxia pathways. Expression of 25 DMR-associated genes showed significant associations with HCC survival outcomes, including 16 genes with fibrosis-DMRs and 2 with NASH-DMRs mapped to their promoter regions. Binding motifs of seven transcription factors (TFs) were enriched in fibrosis-DMRs. Four DMR-associated genes (ESR1, TYW3, CLGN and TUBB) displayed an inverse relationship between promoter methylation and gene expression during human MASLD progression, which was further validated in a mouse MASLD model. CONCLUSIONS We propose a model in which changes in promoter DNA methylation during NAFLD progression regulate gene expression, impacting HCC survival outcomes.
Collapse
Affiliation(s)
- Jin Li
- Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas, USA
| | - Xiaoqin Liu
- Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas, USA
- Department of Translational Medical Sciences, School of Medicine, Texas A&M University Health Science Center, Houston, Texas, USA
| | - Tran T Tran
- Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas, USA
| | - Miryoung Lee
- Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Brownsville, Texas, USA
| | - Robert Y L Tsai
- Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas, USA
- Department of Translational Medical Sciences, School of Medicine, Texas A&M University Health Science Center, Houston, Texas, USA
| |
Collapse
|
13
|
Christodoulidis G, Bartzi D, Koumarelas KE. Anticipation for hepatic arterial infusion chemotherapy in the treatment of hepatocellular carcinoma. World J Gastrointest Oncol 2025; 17:100505. [PMID: 39958551 PMCID: PMC11755988 DOI: 10.4251/wjgo.v17.i2.100505] [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: 08/18/2024] [Revised: 10/16/2024] [Accepted: 11/12/2024] [Indexed: 01/18/2025] Open
Abstract
Hepatic arterial infusion chemotherapy (HAIC) is an advanced targeted therapeutic approach for hepatocellular carcinoma (HCC), the most common type of primary liver cancer. HAIC has demonstrated significant potential in managing advanced HCC, particularly in regions with high prevalence rates. Despite its promise, several challenges and areas for future research remain. Clinical studies have substantiated the efficacy of HAIC in enhancing survival outcomes for patients with advanced hepatic carcinoma. Notably, combination therapies involving immune checkpoint inhibitors, such as lenvatinib and programmed death-1 inhibitors, have shown substantial improvements in median overall survival and progression-free survival compared to systemic chemotherapy. These combination therapies have also exhibited superior response rates and disease control, with manageable and often less severe adverse events relative to systemic treatments. This article is based on the review by Zhou et al and aims to discuss the current status and future directions in the treatment of HCC, emphasizing the role of HAIC and its integration with novel therapeutic agents.
Collapse
Affiliation(s)
| | - Dimitra Bartzi
- Department of Oncology, The 251 Airforce General Hospital, Athens 11525, Greece
| | | |
Collapse
|
14
|
Jin Y, Sun G, Chen B, Feng S, Tang M, Wang H, Zhang Y, Wang Y, An Y, Xiao Y, Liu Z, Liu P, Tian Z, Yin H, Zhang S, Luan X. Delivering miR-23b-3p by small extracellular vesicles to promote cell senescence and aberrant lipid metabolism. BMC Biol 2025; 23:41. [PMID: 39934790 PMCID: PMC11817603 DOI: 10.1186/s12915-025-02143-9] [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: 03/30/2024] [Accepted: 01/23/2025] [Indexed: 02/13/2025] Open
Abstract
BACKGROUND Aging is a natural process that affects the majority of organs within the organism. The liver, however, plays a pivotal role in maintaining the organism's homeostasis due to its robust regenerative and metabolic capabilities. Nevertheless, the liver also undergoes the effects of aging, which can result in a range of metabolic disorders. The function of extracellular vesicles and the signals they convey represent a significant area of interest within the field of ageing research. However, research on liver ageing from the perspective of EVs remains relatively limited. RESULTS In the present study, we extracted liver tissue small extracellular vesicles (sEVs) of mice at different ages and performed transcriptome and proteome analyses to investigate the senescence-associated secretory phenotype (SASP) and mechanisms. sEVs in the older group were rich in miR-23b-3p, which was abundant in the sEVs of induced aging cells and promoted cell senescence by targeting TNF alpha induced protein 3 (Tnfaip3). After injecting adeno-associated virus (AAV) expressing miR-23b-3p into mice, the liver of mice in the experimental group displayed a more evident inflammatory response than that in the control group. Additionally, we found elevated miR-23b-3p in blood-derived-sEVs from patients with familial hypercholesterolemia. CONCLUSIONS Our findings suggest that miR-23b-3p plays a pivotal role in liver aging and is associated with abnormal lipid metabolism. The upregulation of miR-23b-3p in liver EVs may serve as a potential biomarker for aging and metabolic disorders. Targeting miR-23b-3p could provide new therapeutic strategies for ameliorating age-related liver dysfunction and associated metabolic abnormalities.
Collapse
Affiliation(s)
- Ye Jin
- Rare Disease Medical Center, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China
- Center for Digital Medicine and Artificial Intelligence, National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China
| | - Gaoge Sun
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China
| | - Binxian Chen
- Rare Disease Medical Center, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China
- School of Medicine, Tsinghua University, Beijing, 100084, China
| | - Siqin Feng
- Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China
| | - Muyun Tang
- Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China
| | - Hui Wang
- Department of Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China
| | - Ying Zhang
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China
| | - Yuan Wang
- Echo Biotech Co., Ltd, Beijing, 102627, China
| | - Yang An
- GemPharmatech Co., Ltd, Nanjing, 210000, China
| | - Yu Xiao
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China
- Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, 100084, China
- Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing, 100084, China
- Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510260, China
| | - Zihan Liu
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China
| | - Peng Liu
- Medical Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China
| | - Zhuang Tian
- Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China.
| | - Hang Yin
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China.
- Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, 100084, China.
- Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing, 100084, China.
| | - Shuyang Zhang
- Rare Disease Medical Center, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China.
- School of Medicine, Tsinghua University, Beijing, 100084, China.
- Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China.
| | - Xiaodong Luan
- Rare Disease Medical Center, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China.
- Center for Drug Research and Evaluation, National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China.
| |
Collapse
|
15
|
Khalid M, Likhitsup A, Parikh ND. Embolic and Ablative Therapy for Hepatocellular Carcinoma. Clin Liver Dis 2025; 29:87-103. [PMID: 39608960 DOI: 10.1016/j.cld.2024.08.003] [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: 11/30/2024]
Abstract
Embolic and ablative locoregional therapies (LRTs) for hepatocellular carcinoma are widely used to cure, bridge, or downstage patients for more definitive therapies. Common ablative therapies include microwave ablation and radiofrequency ablation, while embolic options include transarterial chemoembolization and 90Y transarterial radioembolization. While these therapies can be highly effective for the appropriate stage of disease, LRTs can suffer from a high rate of posttreatment recurrences. Considerations for administration of specific therapies include disease burden and underlying liver function. Recent data on concomitant or adjuvant systemic therapy, with LRT, have the potential to improve disease control and improve outcomes in this high-risk patient population.
Collapse
Affiliation(s)
- Mian Khalid
- Division of Gastroenterology, University of Maryland Medical Center, Baltimore, MD, USA
| | - Alisa Likhitsup
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA
| | - Neehar D Parikh
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA.
| |
Collapse
|
16
|
Fu J, Wu S, Bao N, Wu L, Qu H, Wang Z, Dong H, Wu J, Jin Y. A Universal Strategy of Anti-Tumor mRNA Vaccine by Harnessing "Off-the-Shelf" Immunity. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2401287. [PMID: 39761175 PMCID: PMC11848573 DOI: 10.1002/advs.202401287] [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: 02/03/2024] [Revised: 11/01/2024] [Indexed: 02/25/2025]
Abstract
Personalized neoantigen cancer mRNA vaccines are promising candidates for precision medicine. However, the difficulty of identifying neoantigens heavily hinders their broad applicability. This study developed a universal strategy of anti-tumor mRNA vaccine by harnessing "off-the-shelf" immunity to known antigens. First, the model antigen ovalbumin (OVA) is used for mRNA vaccine design. In vitro test indicated that this mRNA vaccine reprogrammed tumor cells that can be recognized and killed by OVA-specific cytotoxic T lymphocytes (CTLs). In situ mRNA vaccine notably inhibited tumor growth across three subcutaneous solid tumor models in mice. Further single-cell sequencing analyses revealed that mRNA vaccination act to reshape the immunosuppressive tumor microenvironment (TME) toward more proinflammatory characteristics. Strikingly, this framework of mRNA-based strategy can be applied to two clinical pathogen antigens, hepatitis B surface antigen (HBsAg), and SARS-CoV-2 spike receptor-binding domain (SRBD). Interestingly, the mRNA-based strategy largely recapitulated the scenario of spontaneous cancer regression following pathogen infection or vaccination. Collectively, this study provides not only proof of concept for universal anti-tumor mRNA therapy, but also mechanistic insights in echoing the long-standing puzzle of spontaneous cancer regression.
Collapse
Affiliation(s)
- Jiayan Fu
- National Key Laboratory of Advanced Drug Delivery and Release SystemsZhejiang UniversityHangzhouZhejiang310058China
- MOE Laboratory of Biosystems Homeostasis & ProtectionInnovation Center for Cell Signaling NetworkCollege of Life SciencesZhejiang UniversityHangzhouZhejiang310058China
| | - Shuangqi Wu
- National Key Laboratory of Advanced Drug Delivery and Release SystemsZhejiang UniversityHangzhouZhejiang310058China
- MOE Laboratory of Biosystems Homeostasis & ProtectionInnovation Center for Cell Signaling NetworkCollege of Life SciencesZhejiang UniversityHangzhouZhejiang310058China
| | - Nengcheng Bao
- National Key Laboratory of Advanced Drug Delivery and Release SystemsZhejiang UniversityHangzhouZhejiang310058China
- MOE Laboratory of Biosystems Homeostasis & ProtectionInnovation Center for Cell Signaling NetworkCollege of Life SciencesZhejiang UniversityHangzhouZhejiang310058China
| | - Lili Wu
- National Key Laboratory of Advanced Drug Delivery and Release SystemsZhejiang UniversityHangzhouZhejiang310058China
- MOE Laboratory of Biosystems Homeostasis & ProtectionInnovation Center for Cell Signaling NetworkCollege of Life SciencesZhejiang UniversityHangzhouZhejiang310058China
| | - Huiru Qu
- National Key Laboratory of Advanced Drug Delivery and Release SystemsZhejiang UniversityHangzhouZhejiang310058China
- MOE Laboratory of Biosystems Homeostasis & ProtectionInnovation Center for Cell Signaling NetworkCollege of Life SciencesZhejiang UniversityHangzhouZhejiang310058China
| | - Zhechao Wang
- National Key Laboratory of Advanced Drug Delivery and Release SystemsZhejiang UniversityHangzhouZhejiang310058China
- MOE Laboratory of Biosystems Homeostasis & ProtectionInnovation Center for Cell Signaling NetworkCollege of Life SciencesZhejiang UniversityHangzhouZhejiang310058China
| | - Haiyang Dong
- National Key Laboratory of Advanced Drug Delivery and Release SystemsZhejiang UniversityHangzhouZhejiang310058China
- MOE Laboratory of Biosystems Homeostasis & ProtectionInnovation Center for Cell Signaling NetworkCollege of Life SciencesZhejiang UniversityHangzhouZhejiang310058China
| | - Jian Wu
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang310006China
| | - Yongfeng Jin
- National Key Laboratory of Advanced Drug Delivery and Release SystemsZhejiang UniversityHangzhouZhejiang310058China
- MOE Laboratory of Biosystems Homeostasis & ProtectionInnovation Center for Cell Signaling NetworkCollege of Life SciencesZhejiang UniversityHangzhouZhejiang310058China
| |
Collapse
|
17
|
Damian D. The Role of Viruses in Cellular Transformation and Cancer. Cancer Rep (Hoboken) 2025; 8:e70150. [PMID: 39930651 PMCID: PMC11810984 DOI: 10.1002/cnr2.70150] [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: 10/16/2024] [Revised: 01/21/2025] [Accepted: 01/31/2025] [Indexed: 02/13/2025] Open
Abstract
BACKGROUND Viral infections are established contributors to oncogenesis, leading to significant public health challenges. This systematic review aims to synthesize current knowledge on the mechanisms of viral cellular transformation and their association with various cancers. RECENT FINDINGS Studies reveal key mechanisms of oncogenesis, including direct viral integration into the host genome, expression of viral oncogenes, and indirect pathways such as chronic inflammation and immune evasion. Notably, Human Papillomavirus (HPV) was linked predominantly to cervical and oropharyngeal cancers, while Epstein-Barr Virus (EBV) was associated with lymphomas. Hepatitis B and C viruses were linked to liver cancer, highlighting the diverse impacts of viral infections on oncogenic processes. CONCLUSIONS This review underscores the complexity of viral interactions with host cells and their implications for cancer development. Findings suggest that targeted interventions, such as vaccination and antiviral therapies, may play a crucial role in reducing the incidence of virus-related cancers. Further research is needed to explore novel therapeutic strategies and the role of co-factors in viral oncogenesis.
Collapse
Affiliation(s)
- Donath Damian
- Department of BiochemistryUniversity of Dar es Salaam – Mbeya College of Health and Allied SciencesMbeyaTanzania
| |
Collapse
|
18
|
Bhange M, Telange D. Convergence of nanotechnology and artificial intelligence in the fight against liver cancer: a comprehensive review. Discov Oncol 2025; 16:77. [PMID: 39841330 PMCID: PMC11754566 DOI: 10.1007/s12672-025-01821-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 01/15/2025] [Indexed: 01/23/2025] Open
Abstract
Liver cancer is one of the most challenging malignancies, often associated with poor prognosis and limited treatment options. Recent advancements in nanotechnology and artificial intelligence (AI) have opened new frontiers in the fight against this disease. Nanotechnology enables precise, targeted drug delivery, enhancing the efficacy of therapeutics while minimizing off-target effects. Simultaneously, AI contributes to improved diagnostic accuracy, predictive modeling, and the development of personalized treatment strategies. This review explores the convergence of nanotechnology and AI in liver cancer treatment, evaluating current progress, identifying existing research gaps, and discussing future directions. We highlight how AI-powered algorithms can optimize nanocarrier design, facilitate real-time monitoring of treatment efficacy, and enhance clinical decision-making. By integrating AI with nanotechnology, clinicians can achieve more accurate patient stratification and treatment personalization, ultimately improving patient outcomes. This convergence holds significant promise for transforming liver cancer therapy into a more precise, individualized, and efficient process. However, data privacy, regulatory hurdles, and the need for large-scale clinical validation remain. Addressing these issues will be essential to fully realizing the potential of these technologies in oncology.
Collapse
Affiliation(s)
- Manjusha Bhange
- Department of Pharmaceutics, Datta Meghe College of Pharmacy, Datta Meghe Institute of Higher Education and Research (DU), Sawangi Meghe, Wardha, Maharashtra, 442001, India.
| | - Darshan Telange
- Department of Pharmaceutics, Datta Meghe College of Pharmacy, Datta Meghe Institute of Higher Education and Research (DU), Sawangi Meghe, Wardha, Maharashtra, 442001, India
| |
Collapse
|
19
|
Kehm RD, Vilfranc CL, McDonald JA, Wu HC. County-Level Food Insecurity and Hepatocellular Carcinoma Risk: A Cross-Sectional Analysis. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2025; 22:120. [PMID: 39857573 PMCID: PMC11765400 DOI: 10.3390/ijerph22010120] [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: 11/01/2024] [Revised: 01/15/2025] [Accepted: 01/17/2025] [Indexed: 01/27/2025]
Abstract
Food insecurity (FI) is associated with several known hepatocellular carcinoma (HCC) risk factors, but few studies have directly examined FI in association with HCC risk. We aimed to investigate whether county-level FI is associated with HCC risk. We used data from 21 registries in the Surveillance Epidemiology and End Results database to obtain county-level counts of HCC cases from 2018 to 2021. We obtained the county-level FI rates for 2018-2021 from Feeding America's Map the Meal Gap. We used multi-level Poisson regression models with robust standard errors to calculate incidence rate ratios (IRRs) and 95% confidence intervals (CIs). Overall, a one-standard-deviation (SD) increase in county-level FI was associated with an 8% increase in HCC risk in the fully adjusted model (IRR = 1.08, 95% CI = 1.06, 1.10). When stratified by age at diagnosis, a one-SD increase in county-level FI was associated with a 2% higher risk of HCC in the ≥65 age group (IRR = 1.02, 95% CI = 1.00, 1.05) and a 15% higher risk in the <65 age group (IRR = 1.15, 95% CI = 1.11, 1.19; interaction p-value < 0.001). If confirmed in other studies, these findings support the need for interventions and policies addressing FI in populations at increased risk for HCC.
Collapse
Affiliation(s)
- Rebecca D. Kehm
- Department of Epidemiology, Mailman School of Public Health of Columbia University, New York, NY 10032, USA; (R.D.K.); (J.A.M.)
- Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA;
| | - Chrystelle L. Vilfranc
- Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA;
| | - Jasmine A. McDonald
- Department of Epidemiology, Mailman School of Public Health of Columbia University, New York, NY 10032, USA; (R.D.K.); (J.A.M.)
- Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA;
| | - Hui-Chen Wu
- Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA;
- Department of Environmental Health Sciences, Mailman School of Public Health of Columbia University, New York, NY 10032, USA
| |
Collapse
|
20
|
Sun L, Ma Y, Geng C, Gao X, Li X, Ru Q, Zhu S, Zhang P. DPP4, a potential tumor biomarker, and tumor therapeutic target: review. Mol Biol Rep 2025; 52:126. [PMID: 39821530 DOI: 10.1007/s11033-025-10235-6] [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: 11/14/2024] [Accepted: 01/07/2025] [Indexed: 01/19/2025]
Abstract
Dipeptidyl peptidase 4 (DPP4) is a serine protease widely distributed in membrane-bound and soluble forms in various tissues and organs throughout the body. DPP4 plays a role in inflammation, immune regulation, cell growth, migration and differentiation. The role of DPP4 in tumors has garnered increasing attention. Previous research has demonstrated that DPP4 contributes to the promotion of cancer in most cancers, and it may play a specific biological function through the variation in tumor cell types and expression forms. However, the expression of DDP4 in different tumor types and its specific mechanism remains unclear. In this review, we describe the structure of DPP4, summarize the recent research progress of its expression and potential mechanisms in common tumors, and discuss the development prospects of DPP4 inhibitors in tumor therapy. Although current research emphasizes the potential of DPP4 as a drug target, the incomplete understanding of its regulatory mechanisms impedes the discovery and development of new therapies against it. Further research on DPP4-related tumors is anticipated to promote its clinical application as a potential therapeutic target.
Collapse
Affiliation(s)
- Lu Sun
- Department of Ultrasound, Qilu Hospital of Shandong University (Qingdao), Qingdao, 266035, China
| | - Yuhui Ma
- Department of Ultrasound, Qilu Hospital of Shandong University (Qingdao), Qingdao, 266035, China
| | - Chenchen Geng
- Department of Ultrasound, Qilu Hospital of Shandong University (Qingdao), Qingdao, 266035, China
| | - Xiaoqian Gao
- Department of Ultrasound, Qilu Hospital of Shandong University (Qingdao), Qingdao, 266035, China
| | - Xinbing Li
- Department of Ultrasound, Qilu Hospital of Shandong University (Qingdao), Qingdao, 266035, China
| | - Qi Ru
- Department of Ultrasound, Qilu Hospital of Shandong University (Qingdao), Qingdao, 266035, China
| | - Shuzhen Zhu
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China.
- Department of Clinical Laboratory, Qilu Hospital of Shandong University (Qingdao), Qingdao, Shandong, 266035, China.
| | - Ping Zhang
- Department of Ultrasound, Qilu Hospital of Shandong University (Qingdao), Qingdao, 266035, China.
- Health Management Center, Qilu Hospital of Shandong University (Qingdao), Qingdao, 266035, China.
| |
Collapse
|
21
|
Huang S, Yang Y, Ji B, Ullah U, Chaulagain RP, Tian Y, Qiu J, Gao F, Deng P, Chen H, Qi J, Cang X, Liu L, Jin S. Exploring extrahepatic metastasis of hepatocellular carcinoma based on methylation driver genes and establishing a prognostic model for hepatocellular carcinoma. Gene 2025; 933:148937. [PMID: 39265845 DOI: 10.1016/j.gene.2024.148937] [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: 05/04/2024] [Revised: 09/07/2024] [Accepted: 09/09/2024] [Indexed: 09/14/2024]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC), theseventh most common cancer worldwide, is characterized by a high mortality rate, advanced diagnosis, and susceptibility to extrahepatic metastasis. Numerous studies have shown that DNA methylation is a crucial factor in epigenetic modifications and regulation of carcinogenesis. METHODS HCC patient data were sourced from the TCGA dataset as a training set, while GSE116174 was used as an external validation set for verification. Differential methylation and expression analyses were performed on HCC samples with and without extrahepatic metastasis. In the intersecting genes, the relationship between methylation and expression levels of the intersecting genes was analyzed. Genes with a correlation coefficient≥|0.30| and P<0.05 were identified as methylation driver genes. Cox regression analysis was conducted to identify genes associated with HCC prognosis and establish a risk score. Subsequently, a prognostic model was established and validated using Cox regression analysis incorporating the risk score and other clinical factors. Using immunohistochemistry to evaluate the expression of DHX58 and EIF5A2 in HCC tissues with and without extrahepatic metastasis. Immunoinfiltration analysis was performed on the HCC samples using CIBERSORT. RESULTS Our research identified eight methylation driver genes for HCC extrahepatic metastasis, of which two genes (DHX58 and EIF5A2) were associated with HCC patient prognosis. And the study further constructed and validated the risk score and prognostic model. Immunoinfiltration analysis showed that M0 macrophage abundance was correlated with the prognosis of HCC patients. Immunohistochemistry revealed differences in DHX58 and EIF5A2 expression between HCC tissues with and without extrahepatic metastasis, consistent with our bioinformatics findings.
Collapse
Affiliation(s)
- ShiLing Huang
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - Yang Yang
- Department of Graduation, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - BoShu Ji
- Department of Pathology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - Ubaid Ullah
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - Ram Prasad Chaulagain
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - YingYing Tian
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - JiaWei Qiu
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - FeiYang Gao
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - PengChao Deng
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - HongLiang Chen
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - JiHan Qi
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - XueYu Cang
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - LiNa Liu
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - ShiZhu Jin
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150086, China.
| |
Collapse
|
22
|
Yamaguchi M. Extracellular Regucalcin: A Potent Suppressor in the Cancer Cell Microenvironment. Cancers (Basel) 2025; 17:240. [PMID: 39858022 PMCID: PMC11763602 DOI: 10.3390/cancers17020240] [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: 11/26/2024] [Revised: 01/03/2025] [Accepted: 01/07/2025] [Indexed: 01/27/2025] Open
Abstract
The regucalcin gene is located on the X chromosome, comprising seven exons and six introns. This gene and protein are expressed in various tissues and cells and is predominantly expressed in human liver, kidney, and adrenal tissues. Regucalcin gene expression is enhanced via a mechanism mediated by several signaling molecules and transcription factors. Regucalcin plays a multifunctional role in cellular regulation in maintaining cell homeostasis. In addition, regucalcin has been implicated in several metabolic disorders and diseases. In particular, regucalcin plays a role as a novel suppressor in several types of cancer patients. Increased expression of regucalcin suppresses the growth of human cancer cells, suggesting its pivotal role in suppressing tumor development. The survival time of cancer patients is prolonged with increased expression of regucalcin in the tumor tissues. The adhesion, migration, invasion, and bone metastatic activity of cancer cells are blocked by the overexpression of regucalcin, promoting dormancy in cancer patients. Interestingly, regucalcin is also found in human serum, suggesting its character as a novel biomarker in various diseases. This extracellular regucalcin has been shown to suppress human cancer cells' growth and bone metastatic activity. Thus, extracellular regucalcin may play a vital role as a suppressor of human cancer activity. Alteration of the serum regucalcin levels in physiological and pathophysiological conditions may influence the activity of cancer cells in the microenvironment. This review will discuss the potential role of extracellular regucalcin in cancer cell activity as a critical suppressor in the cancer microenvironment.
Collapse
Affiliation(s)
- Masayoshi Yamaguchi
- Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, 701 Ilalo Street, Honolulu, HI 96813, USA
| |
Collapse
|
23
|
Qian J, Jiang B, Qin Z, Tan Y. Knockdown of hsa_circ_0102231 Impedes the Progression of Liver Cancer through the miR-873-SOX4 Axis. Curr Gene Ther 2025; 25:317-326. [PMID: 38963113 DOI: 10.2174/0115665232301878240627051455] [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: 01/28/2024] [Revised: 05/17/2024] [Accepted: 05/29/2024] [Indexed: 07/05/2024]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most intractable tumors in the world due to its high rate of recurrence and heterogeneity. AIMS The objective of this study was to investigate the role of circular RNA 0102231 (hsa_circ_ 0102231) in the progression of liver cancer. METHODS In this study, quantitative polymerase chain reaction experiments were performed to quantify the hsa_circ_0102231 level in different liver cancer cell lines. Bioinformatics analysis, as well as a dual-luciferase reporter and RNA pull-down assay, were used to identify putative hsa_circ_ 0102231 downstream targets. Colony formation and CCK8 assays were utilized to examine cell proliferation, whereas Transwell assays were employed to monitor cell migration. Lastly, the role of hsa_circ_0102231 in liver cancer was assessed in a subcutaneous xenograft model. RESULTS The expression of hsa_circ_0102231 increased significantly in HepG2 and Huh-7 cells compared with controls, and hsa_circ_0102231 knockdown inhibited cell proliferation and migration in vitro and in vivo. Bioinformatics analysis, as well as a dual-luciferase reporter and RNA pulldown assay, revealed that miR-873 and SOX4 were hsa_circ_0102231 downstream targets. miR-873 inhibition or SOX4 overexpression rescued the proliferation and migration of HepG2 and Huh-7 cells after hsa_circ_0102231 knockdown. Furthermore, SOX4 overexpression reversed the miR-873-induced inhibition of cell migration and proliferation in vitro. CONCLUSION These results show that hsa_circ_0102231 knockdown impedes the progression of liver cancer by regulating the miR-873/SOX4 axis. However, further studies are needed to determine whether hsa_circ_0102231 may be a therapeutic target in liver cancer.
Collapse
Affiliation(s)
- Jingyu Qian
- Department of Interventional Radiology, The First Affiliated Hospital of Bengbu Medical University, Anhui, Bengbu, 233004, People's Republic of China
| | - Banghong Jiang
- Department of Plastic Surgery, The First Affiliated Hospital of Bengbu Medical University, Anhui, Bengbu, 233004, People's Republic of China
| | - Zhongqiang Qin
- Department of Interventional Radiology, The First Affiliated Hospital of Bengbu Medical University, Anhui, Bengbu, 233004, People's Republic of China
| | - Yulin Tan
- Department of Interventional Radiology, The First Affiliated Hospital of Bengbu Medical University, Anhui, Bengbu, 233004, People's Republic of China
| |
Collapse
|
24
|
Jackson JW, Kaldhone PR, Stewart C, Anderson J, MacGregor S, Maclean M, Major M, Atreya CD. 405 nm violet-blue light inactivates hepatitis C cell culture virus (HCVcc) in ex vivo human platelet concentrates and plasma. Sci Rep 2024; 14:31540. [PMID: 39733162 PMCID: PMC11682286 DOI: 10.1038/s41598-024-83171-3] [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: 06/20/2024] [Accepted: 12/12/2024] [Indexed: 12/30/2024] Open
Abstract
Added safety measures coupled with the development and use of pathogen reduction technologies (PRT) significantly reduces the risk of transfusion-transmitted infections (TTIs) from blood products. Current approved PRTs utilize chemical and/or UV-light based inactivation methods. While the effectiveness of these PRTs in reducing pathogens are well documented, these can cause tolerable yet unintended consequences on the quality and efficacy of the transfusion products. As an alternative to UV-based approaches, we have previously demonstrated that 405 nm violet-blue light exposure successfully inactivates a variety of pathogens, including bacteria, parasites, and viruses, in both platelet concentrates (PCs) and plasma. Herein, we show that 405 nm light treatment effectively inactivates hepatitis C cell culture virus (HCVcc) by up to ~ 3.8 log10 in small volumes of a variety of matrices, such as cell culture media, PBS, plasma, and PCs with 27 J/cm2 of light exposure, and total inactivation of HCVcc after 162 J/cm2 light exposure. Furthermore, we demonstrate that carry-over of media supplemented with fetal bovine serum enhances the production of reactive oxygen species (ROS), providing mechanistic insights to 405 nm light-mediated viral inactivation. Overall, 405 nm light successfully inactivates HCVcc, further strengthening this method as a novel PRT for platelets and plasma.
Collapse
Affiliation(s)
- Joseph W Jackson
- Division of Blood Components and Devices, Center for Biologics Evaluation and Research, FDA, Silver Spring, MD, 20993, USA
| | - Pravin R Kaldhone
- Division of Blood Components and Devices, Center for Biologics Evaluation and Research, FDA, Silver Spring, MD, 20993, USA
- Congressional Research Service, Library of Congress, Washington, DC, 20540, USA
| | - Caitlin Stewart
- Department of Electronic and Electrical Engineering, The Robertson Trust Laboratory for Electronic Sterilization Technologies (ROLEST), University of Strathclyde, Glasgow, UK
| | - John Anderson
- Department of Electronic and Electrical Engineering, The Robertson Trust Laboratory for Electronic Sterilization Technologies (ROLEST), University of Strathclyde, Glasgow, UK
| | - Scott MacGregor
- Department of Electronic and Electrical Engineering, The Robertson Trust Laboratory for Electronic Sterilization Technologies (ROLEST), University of Strathclyde, Glasgow, UK
| | - Michelle Maclean
- Department of Electronic and Electrical Engineering, The Robertson Trust Laboratory for Electronic Sterilization Technologies (ROLEST), University of Strathclyde, Glasgow, UK
- Department of Biomedical Engineering, University of Strathclyde, Glasgow, UK
| | - Marian Major
- Division of Viral Products, Center for Biologics Evaluation and Research, FDA, Silver Spring, MD, 20993, USA.
| | - Chintamani D Atreya
- Division of Blood Components and Devices, Center for Biologics Evaluation and Research, FDA, Silver Spring, MD, 20993, USA.
| |
Collapse
|
25
|
Zhao H, Liu J, Zhang X, Xu J, Zhai X. Bioinformatics and experimental verification to explore the potential mechanism of ginsenoside Rg3 suppresses hepatocellular carcinoma progression. Int Immunopharmacol 2024; 143:113543. [PMID: 39549544 DOI: 10.1016/j.intimp.2024.113543] [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: 03/27/2024] [Revised: 09/12/2024] [Accepted: 10/28/2024] [Indexed: 11/18/2024]
Abstract
Ginsenoside Rg3 is an extract from ginseng and has the activities of antitumor in a variety of carcinomas, making it a promising monomer of Chinese herbal medicine for tumor treatment. This study aimed to investigate the targets and mechanisms of action of Rg3 in hepatocellular carcinoma (HCC). The molecular structure of Rg3 was obtained, and 100 potential targets were identified using the SwissTargetPrediction database. Univariate Cox regression analysis on the TCGA-LIHC cohort identified 25 genes as candidate targets of Rg3 with significant prognostic relevance. Consensus clustering divided the TCGA-LIHC cohort into two subtypes: C1 and C2. The C2 subtype exhibited worse overall survival, and significant differences in the expression patterns of the 25 candidate genes were observed between the subtypes. Clinical characteristics also differed significantly between the C1 and C2 subtypes. Mutation analysis showed a higher mutation rate and specific gene mutations in the C2 subtype. Increased immune cell infiltration, including macrophages, Th1 cells, and Th17 cells, was observed in the C2 subtype. Here, an orthotopic murine HCC model was established using Hepa1-6 (murine liver carcinoma cells) in immunocompetent C57BL/6 mice. Rg3 was administered via intraperitoneal injection. Tumor volumes were measured using calipers, and the volume was calculated using the formula: width^2 × length × 0.5. This method, while traditional, has been validated and provides consistent and reliable data for assessing tumor progression and treatment efficacy. The function of Rg3on tumor growth and angiogenesis was evaluated in vitro and in vivo. Especially the role of Rg3 in regulating the myeloid-derived suppressor cells (MDSCs) recruitment and Kupffer cells function were investigated. In the present study we found that Rg3 administration suppressed tumor growth and angiogenesis in vivo. In the liver tissues of HCC-bearing mice, Kupffer cells expressed more co-inhibitory molecule CD274 and less co-stimulatory molecules CD86 and MHCII, whereas Rg3 treatment induced the restoration of Kupffer cells function. Rg3 also increased the efficiency of Kupffer cells as antigen-presenting cells. Furthermore, an increased MDSCs proportion in tumor tissues and surrounding parenchyma was detected in HCC-bearing livers, and this enhancement was blocked after Rg3 administration. In vitro, co-culture of Kupffer cells with MDSCs resulted in decreased CD86 expression and increased CD274 expression in Kupffer cells. Kupffer cells also produced decreased IL-6 and IL-18 level and upregulated IL-10 level after co-culture with MDSCs. This study provides insights into the potential targets and mechanisms of Rg3 in HCC and lays a foundation for personalized treatment strategies.
Collapse
Affiliation(s)
- Hetong Zhao
- Department of Traditional Chinese Medicine, The Changhai Hospital, Naval Military Medical University, Shanghai, China; Department of Traditional Chinese Medicine, No. 905 Hospital of Chinese People's Liberation Army Navy, Naval Military Medical University, Shanghai, China
| | - Jun Liu
- Department of Laboratory Medicine, Dongguan Hospital of Guangzhou University of Chinese Medicine, Dongguan, China
| | - Xuan Zhang
- Department of Traditional Chinese Medicine, No. 905 Hospital of Chinese People's Liberation Army Navy, Naval Military Medical University, Shanghai, China
| | - Jingyu Xu
- Department of Traditional Chinese Medicine, The Changhai Hospital, Naval Military Medical University, Shanghai, China
| | - Xiaofeng Zhai
- Department of Traditional Chinese Medicine, The Changhai Hospital, Naval Military Medical University, Shanghai, China.
| |
Collapse
|
26
|
Gan X, Zhou Y, Li Y, Xu L, Liu G. Development of a novel diagnostic model to monitor the progression of metabolic dysfunction-associated steatotic liver disease to hepatocellular carcinoma in females. Discov Oncol 2024; 15:812. [PMID: 39699604 DOI: 10.1007/s12672-024-01636-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Accepted: 11/26/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND AND AIMS The onset of metabolic dysfunction-associated steatotic liver disease-associated hepatocellular carcinoma (MASLD-HCC) is insidious and exhibits sex-specific variations. Effective methods for monitoring MASLD-HCC progression in females have not yet been developed. METHODS Transcriptomic data of female liver tissue samples were obtained from multiple public databases. Differentially expressed genes (DEGs) in MASLD-HCC were identified using differential expression and robust rank aggregation analyses. Diagnostic prediction models for MASLD (DP.MASLD) and HCC (DP.HCC) were developed and validated using elastic net analysis, and diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis. Bioinformatics was used to assess the pathogenesis of MASLD-HCC. RESULTS Seven overlapping DEGs were identified in female patients with MASLD and HCC: AKR1B10, CLEC1B, CYP2C19, FREM2, MT1H, NRG1, and THBS1). The area under the ROC curve (AUC) values for the training and validation groups of the DP.MASLD model were 0.864 and 0.782, 0.932 and 1.000, and 0.920 and 0.969 when differentiating between the steatosis and normal liver, steatohepatitis and steatosis, and steatohepatitis and normal liver groups, respectively. The AUCs for DP.HCC were 0.980 and 0.997 in the training and validation groups, respectively. The oncogenesis of female MASLD-HCC is associated with molecular pathways, including cytochrome P450-associated drug metabolism, tyrosine metabolism, fatty acid degradation, focal adhesion, extracellular matrix receptor interactions, and protein digestion and absorption. CONCLUSION A novel and effective method to quantitatively assess the risk of MASLD-HCC progression in female patients was developed, and this method will aid in the generation of precise diagnostic, preventive, and therapeutic strategies.
Collapse
Affiliation(s)
- Xiaoning Gan
- Department of Medical Oncology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Pan Fu Avenue 1, Guangzhou, 510180, Guangdong Province, China.
- Department of Physiology, Michigan State University, East Lansing, MI, USA.
| | - Yun Zhou
- Department of Medical Oncology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Pan Fu Avenue 1, Guangzhou, 510180, Guangdong Province, China
- Department of Oncology, School of Medicine, South China University of Technology, Guangzhou, Guangdong Province, China
| | - Yonghao Li
- Department of Medical Oncology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Pan Fu Avenue 1, Guangzhou, 510180, Guangdong Province, China
| | - Lin Xu
- Department of Medical Oncology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Pan Fu Avenue 1, Guangzhou, 510180, Guangdong Province, China
| | - Guolong Liu
- Department of Medical Oncology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Pan Fu Avenue 1, Guangzhou, 510180, Guangdong Province, China.
| |
Collapse
|
27
|
Yang CK, Wei ZL, Shen XQ, Jia YX, Wu QY, Wei YG, Su H, Qin W, Liao XW, Zhu GZ, Peng T. Prognostic utility of gamma-glutamyl transpeptidase to platelet ratio in patients with solitary hepatitis B virus-related hepatocellular carcinoma after hepatectomy. World J Gastrointest Oncol 2024; 16:4579-4596. [PMID: 39678799 PMCID: PMC11577363 DOI: 10.4251/wjgo.v16.i12.4579] [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: 02/28/2024] [Revised: 09/12/2024] [Accepted: 09/29/2024] [Indexed: 11/12/2024] Open
Abstract
BACKGROUND The prognostic impact of preoperative gamma-glutamyl transpeptidase to platelet ratio (GPR) levels in patients with solitary hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) following radical resection has not been established. AIM To examine the clinical utility of GPR for prognosis prediction in solitary HBV-related HCC patients. METHODS A total of 1167 solitary HBV-related HCC patients were retrospectively analyzed. GPR levels were compared with 908 non-HCC individuals. Overall survival (OS) and recurrence-free survival (RFS) were evaluated, and cox proportional hazard model analyses were performed to identify independent risk factors. Differences in characteristics were adjusted by propensity score matching (PSM). Subgroup and stratified survival analyses for HCC risks were performed, and a linear trend of the hazard ratio (HR) according to GPR levels was constructed. RESULTS GPR levels of patients with solitary HBV-related HCC were higher than those with hepatic hemangiomas, chronic hepatitis B and healthy control (adjusted P < 0.05). Variable bias was diminished after the PSM balance test. The low GPR group had improved OS (P < 0.001) and RFS (P < 0.001) in the PSM analysis and when combined with other variables. Multivariate cox analyses suggested that low GPR levels were associated with a better OS (HR = 0.5, 95%CI: 0.36-0.7, P < 0.001) and RFS (HR = 0.57, 95%CI: 0.44-0.73, P < 0.001). This same trend was confirmed in subgroup analyses. Prognostic nomograms were constructed and the calibration curves showed that GPR had good survival prediction. Moreover, stratified survival analyses found that GPR > 0.6 was associated with a worse OS and higher recurrence rate (P for trend < 0.001). CONCLUSION Preoperative GPR can serve as a noninvasive indicator to predict the prognosis of patients with solitary HBV-related HCC.
Collapse
Affiliation(s)
- Cheng-Kun Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Zhong-Liu Wei
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Xiao-Qiang Shen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Yu-Xuan Jia
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Qiong-Yuan Wu
- Department of Tuina, Nanning Hospital of Traditional Chinese Medicine, Nanning 530022, Guangxi Zhuang Autonomous Region, China
| | - Yong-Guang Wei
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Hao Su
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Wei Qin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Xi-Wen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Guang-Zhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| |
Collapse
|
28
|
Kamaya A, Fetzer DT, Seow JH, Burrowes DP, Choi HH, Dawkins AA, Fung C, Gabriel H, Hong CW, Khurana A, McGillen KL, Morgan TA, Sirlin CB, Tse JR, Rodgers SK. LI-RADS US Surveillance Version 2024 for Surveillance of Hepatocellular Carcinoma: An Update to the American College of Radiology US LI-RADS. Radiology 2024; 313:e240169. [PMID: 39625378 DOI: 10.1148/radiol.240169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
In 2017, the American College of Radiology introduced the US Liver Imaging Reporting and Data System (LI-RADS) as a framework for US surveillance of patients at risk for developing hepatocellular carcinoma. This has aided in the standardization of technique, clinical reporting, patient management, data collection, and research. Emerging evidence has helped inform changes to the algorithm, now released as LI-RADS US Surveillance version 2024. The updated algorithm, the rationale for changes, and its alignment with the 2023 American Association for the Study of Liver Diseases Practice Guidance are presented.
Collapse
Affiliation(s)
- Aya Kamaya
- From the Department of Radiology, Stanford University, 300 Pasteur Dr, Palo Alto, CA 94304 (A. Kamaya, J.R.T.); The University of Texas Southwestern Medical Center, Dallas, Tex (D.T.F.); Department of Radiology, Royal Perth Hospital, Perth, Western Australia, Australia (J.H.S.); Department of Radiology, University of Calgary, Calgary, Alberta, Canada (D.P.B.); Department of Radiology and Biomedical Imaging, University of California at San Francisco, San Francisco, Calif (H.H.C., C.W.H.); Department of Radiology, University of Kentucky, Lexington, Ky (A.A.D.); MIC Medical Imaging, Edmonton, Alberta, Canada (C.F.); Department of Radiology, Northwestern University, Chicago, Ill (H.G.); Department of Radiology, University of California at San Diego, UC San Diego Medical Center, San Diego, Calif (A. Khurana); Liver Imaging Group, Department of Radiology, UC San Diego, San Diego, Calif (C.B.S.); Penn State Health Milton S. Hershey Medical Center, Hershey, Pa (K.L.M.); Department of Radiology, Mayo Clinic Arizona, Phoenix, Ariz (T.A.M.); and Department of Radiology, Thomas Jefferson University, Cherry Hill, NJ (S.K.R.)
| | - David T Fetzer
- From the Department of Radiology, Stanford University, 300 Pasteur Dr, Palo Alto, CA 94304 (A. Kamaya, J.R.T.); The University of Texas Southwestern Medical Center, Dallas, Tex (D.T.F.); Department of Radiology, Royal Perth Hospital, Perth, Western Australia, Australia (J.H.S.); Department of Radiology, University of Calgary, Calgary, Alberta, Canada (D.P.B.); Department of Radiology and Biomedical Imaging, University of California at San Francisco, San Francisco, Calif (H.H.C., C.W.H.); Department of Radiology, University of Kentucky, Lexington, Ky (A.A.D.); MIC Medical Imaging, Edmonton, Alberta, Canada (C.F.); Department of Radiology, Northwestern University, Chicago, Ill (H.G.); Department of Radiology, University of California at San Diego, UC San Diego Medical Center, San Diego, Calif (A. Khurana); Liver Imaging Group, Department of Radiology, UC San Diego, San Diego, Calif (C.B.S.); Penn State Health Milton S. Hershey Medical Center, Hershey, Pa (K.L.M.); Department of Radiology, Mayo Clinic Arizona, Phoenix, Ariz (T.A.M.); and Department of Radiology, Thomas Jefferson University, Cherry Hill, NJ (S.K.R.)
| | - James H Seow
- From the Department of Radiology, Stanford University, 300 Pasteur Dr, Palo Alto, CA 94304 (A. Kamaya, J.R.T.); The University of Texas Southwestern Medical Center, Dallas, Tex (D.T.F.); Department of Radiology, Royal Perth Hospital, Perth, Western Australia, Australia (J.H.S.); Department of Radiology, University of Calgary, Calgary, Alberta, Canada (D.P.B.); Department of Radiology and Biomedical Imaging, University of California at San Francisco, San Francisco, Calif (H.H.C., C.W.H.); Department of Radiology, University of Kentucky, Lexington, Ky (A.A.D.); MIC Medical Imaging, Edmonton, Alberta, Canada (C.F.); Department of Radiology, Northwestern University, Chicago, Ill (H.G.); Department of Radiology, University of California at San Diego, UC San Diego Medical Center, San Diego, Calif (A. Khurana); Liver Imaging Group, Department of Radiology, UC San Diego, San Diego, Calif (C.B.S.); Penn State Health Milton S. Hershey Medical Center, Hershey, Pa (K.L.M.); Department of Radiology, Mayo Clinic Arizona, Phoenix, Ariz (T.A.M.); and Department of Radiology, Thomas Jefferson University, Cherry Hill, NJ (S.K.R.)
| | - David P Burrowes
- From the Department of Radiology, Stanford University, 300 Pasteur Dr, Palo Alto, CA 94304 (A. Kamaya, J.R.T.); The University of Texas Southwestern Medical Center, Dallas, Tex (D.T.F.); Department of Radiology, Royal Perth Hospital, Perth, Western Australia, Australia (J.H.S.); Department of Radiology, University of Calgary, Calgary, Alberta, Canada (D.P.B.); Department of Radiology and Biomedical Imaging, University of California at San Francisco, San Francisco, Calif (H.H.C., C.W.H.); Department of Radiology, University of Kentucky, Lexington, Ky (A.A.D.); MIC Medical Imaging, Edmonton, Alberta, Canada (C.F.); Department of Radiology, Northwestern University, Chicago, Ill (H.G.); Department of Radiology, University of California at San Diego, UC San Diego Medical Center, San Diego, Calif (A. Khurana); Liver Imaging Group, Department of Radiology, UC San Diego, San Diego, Calif (C.B.S.); Penn State Health Milton S. Hershey Medical Center, Hershey, Pa (K.L.M.); Department of Radiology, Mayo Clinic Arizona, Phoenix, Ariz (T.A.M.); and Department of Radiology, Thomas Jefferson University, Cherry Hill, NJ (S.K.R.)
| | - Hailey H Choi
- From the Department of Radiology, Stanford University, 300 Pasteur Dr, Palo Alto, CA 94304 (A. Kamaya, J.R.T.); The University of Texas Southwestern Medical Center, Dallas, Tex (D.T.F.); Department of Radiology, Royal Perth Hospital, Perth, Western Australia, Australia (J.H.S.); Department of Radiology, University of Calgary, Calgary, Alberta, Canada (D.P.B.); Department of Radiology and Biomedical Imaging, University of California at San Francisco, San Francisco, Calif (H.H.C., C.W.H.); Department of Radiology, University of Kentucky, Lexington, Ky (A.A.D.); MIC Medical Imaging, Edmonton, Alberta, Canada (C.F.); Department of Radiology, Northwestern University, Chicago, Ill (H.G.); Department of Radiology, University of California at San Diego, UC San Diego Medical Center, San Diego, Calif (A. Khurana); Liver Imaging Group, Department of Radiology, UC San Diego, San Diego, Calif (C.B.S.); Penn State Health Milton S. Hershey Medical Center, Hershey, Pa (K.L.M.); Department of Radiology, Mayo Clinic Arizona, Phoenix, Ariz (T.A.M.); and Department of Radiology, Thomas Jefferson University, Cherry Hill, NJ (S.K.R.)
| | - Adrian A Dawkins
- From the Department of Radiology, Stanford University, 300 Pasteur Dr, Palo Alto, CA 94304 (A. Kamaya, J.R.T.); The University of Texas Southwestern Medical Center, Dallas, Tex (D.T.F.); Department of Radiology, Royal Perth Hospital, Perth, Western Australia, Australia (J.H.S.); Department of Radiology, University of Calgary, Calgary, Alberta, Canada (D.P.B.); Department of Radiology and Biomedical Imaging, University of California at San Francisco, San Francisco, Calif (H.H.C., C.W.H.); Department of Radiology, University of Kentucky, Lexington, Ky (A.A.D.); MIC Medical Imaging, Edmonton, Alberta, Canada (C.F.); Department of Radiology, Northwestern University, Chicago, Ill (H.G.); Department of Radiology, University of California at San Diego, UC San Diego Medical Center, San Diego, Calif (A. Khurana); Liver Imaging Group, Department of Radiology, UC San Diego, San Diego, Calif (C.B.S.); Penn State Health Milton S. Hershey Medical Center, Hershey, Pa (K.L.M.); Department of Radiology, Mayo Clinic Arizona, Phoenix, Ariz (T.A.M.); and Department of Radiology, Thomas Jefferson University, Cherry Hill, NJ (S.K.R.)
| | - Christopher Fung
- From the Department of Radiology, Stanford University, 300 Pasteur Dr, Palo Alto, CA 94304 (A. Kamaya, J.R.T.); The University of Texas Southwestern Medical Center, Dallas, Tex (D.T.F.); Department of Radiology, Royal Perth Hospital, Perth, Western Australia, Australia (J.H.S.); Department of Radiology, University of Calgary, Calgary, Alberta, Canada (D.P.B.); Department of Radiology and Biomedical Imaging, University of California at San Francisco, San Francisco, Calif (H.H.C., C.W.H.); Department of Radiology, University of Kentucky, Lexington, Ky (A.A.D.); MIC Medical Imaging, Edmonton, Alberta, Canada (C.F.); Department of Radiology, Northwestern University, Chicago, Ill (H.G.); Department of Radiology, University of California at San Diego, UC San Diego Medical Center, San Diego, Calif (A. Khurana); Liver Imaging Group, Department of Radiology, UC San Diego, San Diego, Calif (C.B.S.); Penn State Health Milton S. Hershey Medical Center, Hershey, Pa (K.L.M.); Department of Radiology, Mayo Clinic Arizona, Phoenix, Ariz (T.A.M.); and Department of Radiology, Thomas Jefferson University, Cherry Hill, NJ (S.K.R.)
| | - Helena Gabriel
- From the Department of Radiology, Stanford University, 300 Pasteur Dr, Palo Alto, CA 94304 (A. Kamaya, J.R.T.); The University of Texas Southwestern Medical Center, Dallas, Tex (D.T.F.); Department of Radiology, Royal Perth Hospital, Perth, Western Australia, Australia (J.H.S.); Department of Radiology, University of Calgary, Calgary, Alberta, Canada (D.P.B.); Department of Radiology and Biomedical Imaging, University of California at San Francisco, San Francisco, Calif (H.H.C., C.W.H.); Department of Radiology, University of Kentucky, Lexington, Ky (A.A.D.); MIC Medical Imaging, Edmonton, Alberta, Canada (C.F.); Department of Radiology, Northwestern University, Chicago, Ill (H.G.); Department of Radiology, University of California at San Diego, UC San Diego Medical Center, San Diego, Calif (A. Khurana); Liver Imaging Group, Department of Radiology, UC San Diego, San Diego, Calif (C.B.S.); Penn State Health Milton S. Hershey Medical Center, Hershey, Pa (K.L.M.); Department of Radiology, Mayo Clinic Arizona, Phoenix, Ariz (T.A.M.); and Department of Radiology, Thomas Jefferson University, Cherry Hill, NJ (S.K.R.)
| | - Cheng William Hong
- From the Department of Radiology, Stanford University, 300 Pasteur Dr, Palo Alto, CA 94304 (A. Kamaya, J.R.T.); The University of Texas Southwestern Medical Center, Dallas, Tex (D.T.F.); Department of Radiology, Royal Perth Hospital, Perth, Western Australia, Australia (J.H.S.); Department of Radiology, University of Calgary, Calgary, Alberta, Canada (D.P.B.); Department of Radiology and Biomedical Imaging, University of California at San Francisco, San Francisco, Calif (H.H.C., C.W.H.); Department of Radiology, University of Kentucky, Lexington, Ky (A.A.D.); MIC Medical Imaging, Edmonton, Alberta, Canada (C.F.); Department of Radiology, Northwestern University, Chicago, Ill (H.G.); Department of Radiology, University of California at San Diego, UC San Diego Medical Center, San Diego, Calif (A. Khurana); Liver Imaging Group, Department of Radiology, UC San Diego, San Diego, Calif (C.B.S.); Penn State Health Milton S. Hershey Medical Center, Hershey, Pa (K.L.M.); Department of Radiology, Mayo Clinic Arizona, Phoenix, Ariz (T.A.M.); and Department of Radiology, Thomas Jefferson University, Cherry Hill, NJ (S.K.R.)
| | - Aman Khurana
- From the Department of Radiology, Stanford University, 300 Pasteur Dr, Palo Alto, CA 94304 (A. Kamaya, J.R.T.); The University of Texas Southwestern Medical Center, Dallas, Tex (D.T.F.); Department of Radiology, Royal Perth Hospital, Perth, Western Australia, Australia (J.H.S.); Department of Radiology, University of Calgary, Calgary, Alberta, Canada (D.P.B.); Department of Radiology and Biomedical Imaging, University of California at San Francisco, San Francisco, Calif (H.H.C., C.W.H.); Department of Radiology, University of Kentucky, Lexington, Ky (A.A.D.); MIC Medical Imaging, Edmonton, Alberta, Canada (C.F.); Department of Radiology, Northwestern University, Chicago, Ill (H.G.); Department of Radiology, University of California at San Diego, UC San Diego Medical Center, San Diego, Calif (A. Khurana); Liver Imaging Group, Department of Radiology, UC San Diego, San Diego, Calif (C.B.S.); Penn State Health Milton S. Hershey Medical Center, Hershey, Pa (K.L.M.); Department of Radiology, Mayo Clinic Arizona, Phoenix, Ariz (T.A.M.); and Department of Radiology, Thomas Jefferson University, Cherry Hill, NJ (S.K.R.)
| | - Kathryn L McGillen
- From the Department of Radiology, Stanford University, 300 Pasteur Dr, Palo Alto, CA 94304 (A. Kamaya, J.R.T.); The University of Texas Southwestern Medical Center, Dallas, Tex (D.T.F.); Department of Radiology, Royal Perth Hospital, Perth, Western Australia, Australia (J.H.S.); Department of Radiology, University of Calgary, Calgary, Alberta, Canada (D.P.B.); Department of Radiology and Biomedical Imaging, University of California at San Francisco, San Francisco, Calif (H.H.C., C.W.H.); Department of Radiology, University of Kentucky, Lexington, Ky (A.A.D.); MIC Medical Imaging, Edmonton, Alberta, Canada (C.F.); Department of Radiology, Northwestern University, Chicago, Ill (H.G.); Department of Radiology, University of California at San Diego, UC San Diego Medical Center, San Diego, Calif (A. Khurana); Liver Imaging Group, Department of Radiology, UC San Diego, San Diego, Calif (C.B.S.); Penn State Health Milton S. Hershey Medical Center, Hershey, Pa (K.L.M.); Department of Radiology, Mayo Clinic Arizona, Phoenix, Ariz (T.A.M.); and Department of Radiology, Thomas Jefferson University, Cherry Hill, NJ (S.K.R.)
| | - Tara A Morgan
- From the Department of Radiology, Stanford University, 300 Pasteur Dr, Palo Alto, CA 94304 (A. Kamaya, J.R.T.); The University of Texas Southwestern Medical Center, Dallas, Tex (D.T.F.); Department of Radiology, Royal Perth Hospital, Perth, Western Australia, Australia (J.H.S.); Department of Radiology, University of Calgary, Calgary, Alberta, Canada (D.P.B.); Department of Radiology and Biomedical Imaging, University of California at San Francisco, San Francisco, Calif (H.H.C., C.W.H.); Department of Radiology, University of Kentucky, Lexington, Ky (A.A.D.); MIC Medical Imaging, Edmonton, Alberta, Canada (C.F.); Department of Radiology, Northwestern University, Chicago, Ill (H.G.); Department of Radiology, University of California at San Diego, UC San Diego Medical Center, San Diego, Calif (A. Khurana); Liver Imaging Group, Department of Radiology, UC San Diego, San Diego, Calif (C.B.S.); Penn State Health Milton S. Hershey Medical Center, Hershey, Pa (K.L.M.); Department of Radiology, Mayo Clinic Arizona, Phoenix, Ariz (T.A.M.); and Department of Radiology, Thomas Jefferson University, Cherry Hill, NJ (S.K.R.)
| | - Claude B Sirlin
- From the Department of Radiology, Stanford University, 300 Pasteur Dr, Palo Alto, CA 94304 (A. Kamaya, J.R.T.); The University of Texas Southwestern Medical Center, Dallas, Tex (D.T.F.); Department of Radiology, Royal Perth Hospital, Perth, Western Australia, Australia (J.H.S.); Department of Radiology, University of Calgary, Calgary, Alberta, Canada (D.P.B.); Department of Radiology and Biomedical Imaging, University of California at San Francisco, San Francisco, Calif (H.H.C., C.W.H.); Department of Radiology, University of Kentucky, Lexington, Ky (A.A.D.); MIC Medical Imaging, Edmonton, Alberta, Canada (C.F.); Department of Radiology, Northwestern University, Chicago, Ill (H.G.); Department of Radiology, University of California at San Diego, UC San Diego Medical Center, San Diego, Calif (A. Khurana); Liver Imaging Group, Department of Radiology, UC San Diego, San Diego, Calif (C.B.S.); Penn State Health Milton S. Hershey Medical Center, Hershey, Pa (K.L.M.); Department of Radiology, Mayo Clinic Arizona, Phoenix, Ariz (T.A.M.); and Department of Radiology, Thomas Jefferson University, Cherry Hill, NJ (S.K.R.)
| | - Justin R Tse
- From the Department of Radiology, Stanford University, 300 Pasteur Dr, Palo Alto, CA 94304 (A. Kamaya, J.R.T.); The University of Texas Southwestern Medical Center, Dallas, Tex (D.T.F.); Department of Radiology, Royal Perth Hospital, Perth, Western Australia, Australia (J.H.S.); Department of Radiology, University of Calgary, Calgary, Alberta, Canada (D.P.B.); Department of Radiology and Biomedical Imaging, University of California at San Francisco, San Francisco, Calif (H.H.C., C.W.H.); Department of Radiology, University of Kentucky, Lexington, Ky (A.A.D.); MIC Medical Imaging, Edmonton, Alberta, Canada (C.F.); Department of Radiology, Northwestern University, Chicago, Ill (H.G.); Department of Radiology, University of California at San Diego, UC San Diego Medical Center, San Diego, Calif (A. Khurana); Liver Imaging Group, Department of Radiology, UC San Diego, San Diego, Calif (C.B.S.); Penn State Health Milton S. Hershey Medical Center, Hershey, Pa (K.L.M.); Department of Radiology, Mayo Clinic Arizona, Phoenix, Ariz (T.A.M.); and Department of Radiology, Thomas Jefferson University, Cherry Hill, NJ (S.K.R.)
| | - Shuchi K Rodgers
- From the Department of Radiology, Stanford University, 300 Pasteur Dr, Palo Alto, CA 94304 (A. Kamaya, J.R.T.); The University of Texas Southwestern Medical Center, Dallas, Tex (D.T.F.); Department of Radiology, Royal Perth Hospital, Perth, Western Australia, Australia (J.H.S.); Department of Radiology, University of Calgary, Calgary, Alberta, Canada (D.P.B.); Department of Radiology and Biomedical Imaging, University of California at San Francisco, San Francisco, Calif (H.H.C., C.W.H.); Department of Radiology, University of Kentucky, Lexington, Ky (A.A.D.); MIC Medical Imaging, Edmonton, Alberta, Canada (C.F.); Department of Radiology, Northwestern University, Chicago, Ill (H.G.); Department of Radiology, University of California at San Diego, UC San Diego Medical Center, San Diego, Calif (A. Khurana); Liver Imaging Group, Department of Radiology, UC San Diego, San Diego, Calif (C.B.S.); Penn State Health Milton S. Hershey Medical Center, Hershey, Pa (K.L.M.); Department of Radiology, Mayo Clinic Arizona, Phoenix, Ariz (T.A.M.); and Department of Radiology, Thomas Jefferson University, Cherry Hill, NJ (S.K.R.)
| |
Collapse
|
29
|
Cao J, Su B, Zhang C, Peng R, Tu D, Deng Q, Jiang G, Jin S, Wang Q, Bai DS. Degradation of PARP1 by MARCHF3 in tumor cells triggers cCAS-STING activation in dendritic cells to regulate antitumor immunity in hepatocellular carcinoma. J Immunother Cancer 2024; 12:e010157. [PMID: 39608977 PMCID: PMC11605840 DOI: 10.1136/jitc-2024-010157] [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: 07/21/2024] [Accepted: 10/26/2024] [Indexed: 11/30/2024] Open
Abstract
BACKGROUND Resistance to immune checkpoint inhibitors (ICIs) significantly limits the efficacy of immunotherapy in patients with hepatocellular carcinoma (HCC). However, the mechanisms underlying immunotherapy resistance remain poorly understood. Our aim was to clarify the role of membrane-associated ring-CH-type finger 3 (MARCHF3) in HCC within the framework of anti-programmed cell death protein-1 (PD-1) therapy. METHODS MARCHF3 was identified in the transcriptomic profiles of HCC tumors exhibiting different responses to ICIs. In humans, the correlation between MARCHF3 expression and the tumor microenvironment (TME) was assessed via multiplex immunohistochemistry. In addition, MARCHF3 expression in tumor cells and immune cell infiltration were assessed by flow cytometry. RESULTS MARCHF3 was significantly upregulated in tumors from patients who responded to ICIs. Increased MARCHF3 expression in HCC cells promoted dendritic cell (DC) maturation and stimulated CD8+ T-cell activation, thereby augmenting tumor control. Mechanistically, we identified MARCHF3 as a pivotal regulator of the DNA damage response. It directly interacted with Poly(ADP-Ribose) Polymerase 1 (PARP1) via K48-linked ubiquitination, leading to PARP1 degradation. This process promoted the release of double-strand DNA and activated cCAS-STING in DCs, thereby initiating DC-mediated antigen cross-presentation and CD8+ T-cell activation. Additionally, ATF4 transcriptionally regulated MARCHF3 expression. Notably, the PARP1 inhibitor olaparib augmented the efficacy of anti-PD-1 immunotherapy in both subcutaneous and orthotopic HCC mouse models. CONCLUSIONS MARCHF3 has emerged as a pivotal regulator of the immune landscape in the HCC TME and is a potent predictive biomarker for HCC. Combining interventions targeting the DNA damage response with ICIs is a promising treatment strategy for HCC.
Collapse
Affiliation(s)
- Jun Cao
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affliated to Yangzhou University, Yangzhou City, Jiangsu Province, China
- General Surgery Institute, Northern Jiangsu People's Hospital, Yangzhou City, Jiangsu Province, China
| | - Bingbing Su
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affliated to Yangzhou University, Yangzhou City, Jiangsu Province, China
| | - Chi Zhang
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affliated to Yangzhou University, Yangzhou City, Jiangsu Province, China
- General Surgery Institute, Northern Jiangsu People's Hospital, Yangzhou City, Jiangsu Province, China
| | - Rui Peng
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affliated to Yangzhou University, Yangzhou City, Jiangsu Province, China
| | - Daoyuan Tu
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affliated to Yangzhou University, Yangzhou City, Jiangsu Province, China
| | - Qiangwei Deng
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affliated to Yangzhou University, Yangzhou City, Jiangsu Province, China
| | - Guoqing Jiang
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affliated to Yangzhou University, Yangzhou City, Jiangsu Province, China
| | - Shengjie Jin
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affliated to Yangzhou University, Yangzhou City, Jiangsu Province, China
| | - Qian Wang
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affliated to Yangzhou University, Yangzhou City, Jiangsu Province, China
| | - Dou-Sheng Bai
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affliated to Yangzhou University, Yangzhou City, Jiangsu Province, China
- General Surgery Institute, Northern Jiangsu People's Hospital, Yangzhou City, Jiangsu Province, China
| |
Collapse
|
30
|
Liu H, Yang L, Qin Q, Cui L. Efficacy of arterial compression hemostasis devices in liver cancer treatment: a systematic review and meta-analysis. World J Surg Oncol 2024; 22:312. [PMID: 39587611 PMCID: PMC11590351 DOI: 10.1186/s12957-024-03599-9] [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: 08/07/2024] [Accepted: 11/19/2024] [Indexed: 11/27/2024] Open
Abstract
OBJECTIVE To systematically evaluate the efficacy of arterial compression hemostasis devices after femoral artery puncture interventions for hepatocellular carcinoma (HCC). METHODS We systematically searched 10 electronic databases (PubMed, Scopus, EMBASE, The Cochrane Library, CINAHL, Web of Science, CNKI, Wanfang, VIP, and CBM) up to October 20, 2024, to identify randomized controlled trials (RCTs) of arterial compression hemostasis devices used after HCC interventions through femoral artery puncture. We used the Cochrane risk of bias assessment tool to evaluate the trial quality, and we analyzed the data with Review Manager 5.4 software. RESULTS 17 RCTs involving 2,338 participants met the inclusion criteria. The meta-analysis demonstrated that, compared with conventional manual compression combined with sandbags, the use of arterial compression hemostasis devices significantly shortened the compression hemostasis time [MD = -13.9 min, 95% CI, -14.19 to -12.19; P < 0.00001] and limb immobilization time [MD = -8.79 min, 95% CI, -12.65 to -4.94; P < 0.00001]. Additionally, it significantly reduced the incidence of local bleeding [RR = 0.28, 95% CI, 0.20 to 0.40; P < 0.00001], hematoma formation [RR = 0.29, 95% CI, 0.18 to 0.46; P < 0.00001], skin ecchymosis [RR = 0.25, 95% CI, 0.18 to 0.35; P < 0.00001], dysuria [RR = 0.22, 95% CI, 0.14 to 0.34; P = 0.0002], skin damage [RR = 0.16, 95% CI, 0.05 to 0.54; P = 0.003], backache [RR = 0.28, 95% CI, 0.13 to 0.64; P = 0.002], and pseudoaneurysm [RR = 0.22, 95% CI, 0.10 to 0.51; P = 0.0004]. CONCLUSIONS The analysis revealed that arterial compression hemostasis devices significantly reduce hemostasis and immobilization time, as well as vascular complications in liver cancer patients undergoing interventional therapy.
Collapse
Affiliation(s)
- Handan Liu
- Department of Ophthalmology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Li Yang
- School of Nursing, North Sichuan Medical College, Nanchong, China
| | - Qin Qin
- School of Nursing, North Sichuan Medical College, Nanchong, China
| | - Lijun Cui
- Department of Blood Transfusion, Affiliated Hospital of North Sichuan Medical College, Nanchong, China.
| |
Collapse
|
31
|
Gao H, Hu C, Wu Q, Fang Z. BAMBI Is a Prognostic Biomarker Associated with Macrophage Polarization, Glycolysis, and Lipid Metabolism in Hepatocellular Carcinoma. Int J Mol Sci 2024; 25:12713. [PMID: 39684424 DOI: 10.3390/ijms252312713] [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: 09/25/2024] [Revised: 11/15/2024] [Accepted: 11/22/2024] [Indexed: 12/18/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common types of cancer worldwide. Affected patients have poor prognoses due to high rates of post-surgical recurrence and metastasis. Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) reportedly contributes to the development and progression of various human cancers. Thus far, there have been no comprehensive studies regarding the expression of BAMBI in HCC; similarly, no studies have investigated the prognostic significance of BAMBI and its associated mechanisms in HCC. In this study, we analyzed the expression profiles of BAMBI, along with its contributions to pathological findings, metastasis characteristics, and prognosis, in multiple human cancers. We found that upregulation of BAMBI was associated with poor prognosis in HCC. Next, we explored the associations of BAMBI with multiple cell signaling pathways, immune cells, and immune checkpoints in HCC. The results showed that BAMBI was associated with tumor proliferation, epithelial-mesenchymal transition (EMT) markers, glycolysis, fatty acid biosynthesis and degradation pathways, and immune checkpoint regulation in HCC. In vitro and in vivo experiments showed that BAMBI promoted polarization of M1 macrophages and is linked to the expression of key genes involved in glycolipid metabolism. Furthermore, protein-protein interaction analysis suggested that BAMBI plays multiple roles in HCC by regulating genes in the transforming growth factor (TGF)-β and Wnt signaling pathways. Our findings elucidated that BAMBI is a prognostic biomarker and is associated with macrophage polarization, glycolysis, and lipid metabolism in HCC.
Collapse
Affiliation(s)
- Huijie Gao
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Cuimin Hu
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Qing Wu
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Tianjin Medical University, Tianjin 300070, China
| | - Zhongze Fang
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Tianjin Medical University, Tianjin 300070, China
| |
Collapse
|
32
|
Gawi Ermi A, Sarkar D. Resistance to Tyrosine Kinase Inhibitors in Hepatocellular Carcinoma (HCC): Clinical Implications and Potential Strategies to Overcome the Resistance. Cancers (Basel) 2024; 16:3944. [PMID: 39682130 DOI: 10.3390/cancers16233944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 11/12/2024] [Accepted: 11/19/2024] [Indexed: 12/18/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, and the development of effective treatment strategies remains a significant challenge in the management of advanced HCC patients. The emergence of tyrosine kinase inhibitors (TKIs) has been a significant advancement in the treatment of HCC, as these targeted therapies have shown promise in prolonging the survival of patients with advanced disease. Although immunotherapy is currently considered as the first line of treatment for advanced HCC patients, many such patients do not meet the clinical criteria to be eligible for immunotherapy, and in many parts of the world there is still lack of accessibility to immunotherapy. As such, TKIs still serve as the first line of treatment and play a major role in the treatment repertoire for advanced HCC patients. However, the development of resistance to these agents is a major obstacle that must be overcome. In this review, we explore the underlying mechanisms of resistance to TKIs in HCC, the clinical implications of this resistance, and the potential strategies to overcome or prevent the emergence of resistance.
Collapse
Affiliation(s)
- Ali Gawi Ermi
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| |
Collapse
|
33
|
Goldberg D, Reese PP, Kaplan DA, Zarnegarnia Y, Gaddipati N, Gaddipati S, John B, Blandon C. Predicting long-term survival among patients with HCC. Hepatol Commun 2024; 8:e0581. [PMID: 39495142 PMCID: PMC11537595 DOI: 10.1097/hc9.0000000000000581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 09/03/2024] [Indexed: 11/05/2024] Open
Abstract
BACKGROUND Prognosticating survival among patients with HCC and cirrhosis must account for both the tumor burden/stage, as well as the severity of the underlying liver disease. Although there are many staging systems used to guide therapy, they have not been widely adopted to predict patient-level survival after the diagnosis of HCC. We sought to develop a score to predict long-term survival among patients with early- to intermediate-stage HCC using purely objective criteria. METHODS Retrospective cohort study among patients with HCC confined to the liver, without major medical comorbidities within the Veterans Health Administration from 2014 to 2023. Tumor data were manually abstracted and combined with clinical and laboratory data to predict 5-year survival from HCC diagnosis using accelerated failure time models. The data were randomly split using a 75:25 ratio for training and validation. Model discrimination and calibration were assessed and compared to other HCC staging systems. RESULTS The cohort included 1325 patients with confirmed HCC. A risk score using baseline clinical, laboratory, and HCC-related survival had excellent discrimination (integrated AUC: 0.71 in the validation set) and calibration (based on calibration plots and Brier scores). Models had superior performance to the BCLC and ALBI scores and similar performance to the combined BCLC-ALBI score. CONCLUSIONS We developed a risk score using purely objective data to accurately predict long-term survival for patients with HCC. This score, if validated, can be used to prognosticate survival for patients with HCC, and, in the setting of liver transplantation, can be incorporated to consider the net survival benefit of liver transplantation versus other curative options.
Collapse
Affiliation(s)
- David Goldberg
- Department of Medicine, Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA
- Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, Florida, USA
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Peter P. Reese
- Department of Medicine, Renal-Electrolyte and Hypertension Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - David A. Kaplan
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
- Department of Medicine, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA
| | - Yalda Zarnegarnia
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Neelima Gaddipati
- Department of Medicine, Jackson Memorial Hospital, Miami, Florida, USA
| | - Sirisha Gaddipati
- Department of Medicine, Jackson Memorial Hospital, Miami, Florida, USA
| | - Binu John
- Department of Medicine, Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA
- Department of Medicine, Bruce Carter VA Medical Center, Miami, Florida, USA
| | - Catherine Blandon
- Department of Medicine, Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA
| |
Collapse
|
34
|
Waki Y, Morine Y, Saito Y, Teraoku H, Yamada S, Ikemoto T, Tominaga T, Shimada M. Lenvatinib-resistant hepatocellular carcinoma promotes malignant potential of tumor-associated macrophages via exosomal miR-301a-3p. Ann Gastroenterol Surg 2024; 8:1084-1095. [PMID: 39502738 PMCID: PMC11533007 DOI: 10.1002/ags3.12814] [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: 02/05/2024] [Revised: 04/09/2024] [Accepted: 04/15/2024] [Indexed: 11/08/2024] Open
Abstract
Background The interactions between cancer cells and tumor-associated macrophages (TAMs) via microRNAs (miRNAs) play crucial roles in malignant potential and drug resistance. However, it remains unclear how lenvatinib-resistant hepatocellular carcinoma (LR HCC) promotes TAM tumor biology. Here we investigated the crosstalk between LR HCC cells and TAMs for cancer progression and lenvatinib resistance, focusing on an exosomal miRNA. Methods We used two bioinformatics software programs to identify miRNAs that target PTEN in gastrointestinal cancers, then investigated exosomal miRNA expression in LR HCC conditioned medium (CM). After modifying TAMs with LR HCC CM (LR TAM), macrophage phenotype and PTEN-Nrf2 signaling pathway component expression were analyzed in LR TAMs. The malignant potential and drug resistance were investigated in naïve HCC cells cultured with LR TAM CM. Results LR HCC cells highly induced M2-like properties in macrophages compared with naïve HCC cells. Exosomal miR-301a-3p expression was increased in LR HCC CM, with higher activation of the PTEN/PI3K/GSK3β/Nrf2 signaling pathway in LR TAMs. Naïve HCC cells were educated with LR TAM CM to promote malignant potential and lenvatinib resistance. Inhibition of exosomal miR-301a-3p prevented the malignant potential of LR TAMs. Activation of Nrf2 signaling by LR HCC cell-derived exosomal miR-301a-3p skewed the transformation of macrophages to the M2 phenotype. Conclusion Our study provides new findings on the role of miR-301a-3p, suggesting it is a promising therapeutic target to improve HCC lenvatinib resistance.
Collapse
Affiliation(s)
- Yuhei Waki
- Department of Digestive and Transplant SurgeryTokushima UniversityTokushimaJapan
| | - Yuji Morine
- Department of Digestive and Transplant SurgeryTokushima UniversityTokushimaJapan
| | - Yu Saito
- Department of Digestive and Transplant SurgeryTokushima UniversityTokushimaJapan
| | - Hiroki Teraoku
- Department of Digestive and Transplant SurgeryTokushima UniversityTokushimaJapan
| | - Shinichiro Yamada
- Department of Digestive and Transplant SurgeryTokushima UniversityTokushimaJapan
| | - Tetsuya Ikemoto
- Department of Digestive and Transplant SurgeryTokushima UniversityTokushimaJapan
| | - Tatsuya Tominaga
- Department of Bioanalytical TechnologyTokushima UniversityTokushimaJapan
| | - Mitsuo Shimada
- Department of Digestive and Transplant SurgeryTokushima UniversityTokushimaJapan
| |
Collapse
|
35
|
Liu B, Chen H, Liu X, Wang G, Shen X. Separation Operation Followed by Stereotactic Radiotherapy in the Treatment of Spinal Metastasis From Hepatocellular Carcinoma: A Retrospective Cohort Study. Global Spine J 2024; 14:2366-2373. [PMID: 37277967 PMCID: PMC11528724 DOI: 10.1177/21925682231182332] [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] [Indexed: 06/07/2023] Open
Abstract
STUDY DESIGN Retrospective cohort study. OBJECTIVE Spinal metastasis from hepatocellular carcinoma is rapidly progressive and predisposes to spinal disability, cord compression and further neural injury, leading to poor prognosis. Currently, it is still challenging to look for a treatment strategy that can improve the quality of life of patients and even directly prolong the survival time. This study attempts to evaluate the clinical efficacy of separation operation combined with postoperative stereotactic radiotherapy (SRT/SRS) in the treatment of hepatocellular carcinoma patients developing spinal metastasis and epidural spinal cord compression. METHODS Patients with metastases spinal cord compression from hepatocellular carcinoma were studied retrospectively and divided into two groups, the SO group (who undergo separation operations combined with postoperative SRS, n = 32) and RT group (who received only SRS, n = 28). The visual Analogue Scale (VAS) pain score, Frankel grade, Karnofsky performance score, and Quality of Life (SF-36) score were comparatively analyzed between the two groups. RESULTS Significantly higher VAS pain scores, Frankel grades, Karnofsky performance scores and Quality of Life (SF-36) scores were demonstrated in patients with combination treatment than in patients with SRS alone. CONCLUSION Separation operations are effective surgical procedure for the treatment of spinal metastatic tumor from hepatocellular carcinoma with spinal cord compression. The combination with postoperative SRS can significantly improve the quality of life in this patient population via spinal canal decompression and spinal stability reconstruction.
Collapse
Affiliation(s)
- Bin Liu
- Department of Spine Surgery, Hunan Provincial People’s Hospital (The First-affiliated Hospital of Hunan Normal University), China
| | - Haoliang Chen
- Department of Spine Surgery, Hunan Provincial People’s Hospital (The First-affiliated Hospital of Hunan Normal University), China
| | - Xiangyang Liu
- Department of Spine Surgery, Hunan Provincial People’s Hospital (The First-affiliated Hospital of Hunan Normal University), China
| | - Guoping Wang
- Department of Spine Surgery, Hunan Provincial People’s Hospital (The First-affiliated Hospital of Hunan Normal University), China
| | - Xiongjie Shen
- Department of Spine Surgery, Hunan Provincial People’s Hospital (The First-affiliated Hospital of Hunan Normal University), China
| |
Collapse
|
36
|
Boye A, Osei SA, Brah AS. Therapeutic prospects of sex hormone receptor signaling in hormone-responsive cancers. Biomed Pharmacother 2024; 180:117473. [PMID: 39326105 DOI: 10.1016/j.biopha.2024.117473] [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: 07/18/2024] [Revised: 09/11/2024] [Accepted: 09/19/2024] [Indexed: 09/28/2024] Open
Abstract
Globally, hormone-responsive cancers afflict millions of people contributing to cancer-related morbidity and mortality. While hormone-responsive cancers overburden patients, their close families, and even health budgets at the local levels, knowledge of these cancers particularly their biology and possible avenues for therapy remains poorly exploited. Herewith, this review highlights the role of sex hormones (estrogens and androgens) in the pathophysiology of hormone-responsive cancers and the exploration of therapeutic targets. Major scientific databases including but not limited to Scopus, PubMed, Science Direct, Web of Science core collections, and Google Scholar were perused using a string of search terms: Hormone-responsive cancers, androgens and cancers, estrogens and cancer, androgen receptor signalling, estrogen receptor signalling, etc.
Collapse
Affiliation(s)
- Alex Boye
- Department of Medical Laboratory Science, School of Allied Health Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana.
| | - Silas Acheampong Osei
- Department of Pharmacology, School of Pharmacy and Pharmaceutical Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Augustine Suurinobah Brah
- Department of Biomedical Sciences, School of Allied Health Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
| |
Collapse
|
37
|
Singh A, Anjum B, Naz Q, Raza S, Sinha RA, Ahmad MK, Mehdi AA, Verma N. Night shift-induced circadian disruption: links to initiation of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and risk of hepatic cancer. HEPATOMA RESEARCH 2024:2394-5079.2024.88. [PMID: 39525867 PMCID: PMC7616786 DOI: 10.20517/2394-5079.2024.88] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
The circadian system plays a crucial role in regulating metabolic homeostasis at both systemic and tissue levels by synchronizing the central and peripheral clocks with exogenous time cues, known as zeitgebers (such as the light/dark cycle). Our body's behavioral rhythms, including sleep-wake cycles and feeding-fasting patterns, align with these extrinsic time cues. The body cannot effectively rest and repair itself when circadian rhythms are frequently disrupted. In many shift workers, the internal rhythms fail to fully synchronize with the end and start times of their shifts. Additionally, exposure to artificial light at night (LAN), irregular eating patterns, and sleep deprivation contribute to circadian disruption and misalignment. Shift work and jet lag disrupt the normal circadian rhythm of liver activity, resulting in a condition known as "circadian disruption". This disturbance adversely affects the metabolism and homeostasis of the liver, contributing to excessive fat accumulation and abnormal liver function. Additionally, extended working hours, such as prolonged night shifts, may worsen the progression of non-alcoholic fatty liver disease (NAFLD) toward non-alcoholic steatohepatitis (NASH) and increase disease severity. Studies have demonstrated a positive correlation between night shift work (NSW) and elevated liver enzymes, indicative of hepatic metabolic dysfunction, potentially increasing the risk of hepatocellular carcinoma (HCC) related to NAFLD. This review consolidates research findings on circadian disruption caused by NSW, late chronotype, jet lag, and social jet lag, drawing insights from studies involving both humans and animal models that investigate the effects of these factors on circadian rhythms in liver metabolism.
Collapse
Affiliation(s)
- Anjali Singh
- Department of Physiology, King George’s Medical University, Lucknow226003, India
| | - Baby Anjum
- Department of Neurology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow226014, India
| | - Qulsoom Naz
- Department of Medicine, King George’s Medical University, Lucknow226003, India
| | - Sana Raza
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow226014, India
| | - Rohit A. Sinha
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow226014, India
| | | | | | - Narsingh Verma
- Hind Institute of Medical Sciences, Sitapur 261304, India
| |
Collapse
|
38
|
Critelli RM, Casari F, Borghi A, Serino G, Caporali C, Magistri P, Pecchi A, Shahini E, Milosa F, Di Marco L, Pivetti A, Lasagni S, Schepis F, De Maria N, Dituri F, Martínez-Chantar ML, Di Benedetto F, Giannelli G, Villa E. The Neoangiogenic Transcriptomic Signature Impacts Hepatocellular Carcinoma Prognosis and Can Be Triggered by Transarterial Chemoembolization Treatment. Cancers (Basel) 2024; 16:3549. [PMID: 39456643 PMCID: PMC11505901 DOI: 10.3390/cancers16203549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 10/05/2024] [Accepted: 10/15/2024] [Indexed: 10/28/2024] Open
Abstract
Background/Objectives: We evaluated the relationship between the neoangiogenic transcriptomic signature (nTS) and clinical symptoms, treatment outcomes, and survival in hepatocellular carcinoma (HCC) patients. Methods: This study prospectively followed 328 patients in the derivation and 256 in the validation cohort (with a median follow-up of 31 and 22 months, respectively). The nTS was associated with disease presentation, treatments administered, and overall survival rates. Additionally, this study investigated how multiple treatments influenced changes in nTS status and alterations in microRNA expression. Results: The nTS was identified in 27.4% of patients, linked to aggressive features like multifocality and elevated alpha-fetoprotein (AFP), a pattern consistent with that of the validation cohort. Most patients in both cohorts received treatment for HCC. nTS+ patients had limited access to, and benefited less from, liver transplantation or radiofrequency ablation (RFA) compared to nTS- patients. By the end, 78.9% had died, with nTS- patients showing better median survival and response to treatments than their nTS+ counterparts, who had lower survival across all treatment types. Among those who received transarterial chemoembolization (TACE), 31.2% (21/80 patients after the initial treatment and another four following a second TACE) transitioned from an nTS- to an nTS+ status. This shift was associated with lower survival and alterations in microRNA expressions related to oncogenic pathways. Conclusions: The nTS markedly influences treatment eligibility and survival in patients with HCC. Notably, the nTS can develop after repeated TACE procedures, significantly impacting patient survival and altering oncogenic microRNA expression patterns. These findings highlight the critical role of the nTS in guiding treatment decisions and prognostication in HCC management.
Collapse
Affiliation(s)
- Rosina Maria Critelli
- Gastroenterology Unit, CHIMOMO Department, University of Modena and Reggio Emilia, 41124 Modena, Italy; (R.M.C.); (F.M.); (A.P.); (S.L.); (N.D.M.)
| | - Federico Casari
- Radiology, Azienda Ospedaliero-Universitaria di Modena, University of Modena and Reggio Emilia, 41125 Modena, Italy; (F.C.); (C.C.); (A.P.)
| | - Alberto Borghi
- Internal Medicine, Ospedale di Faenza, 48018 Faenza, Italy;
| | - Grazia Serino
- National Institute of Gastroenterology “IRCCS Saverio de Bellis”, Research Hospital, 70013 Castellana Grotte, Italy; (G.S.); (E.S.); (F.D.); (G.G.)
| | - Cristian Caporali
- Radiology, Azienda Ospedaliero-Universitaria di Modena, University of Modena and Reggio Emilia, 41125 Modena, Italy; (F.C.); (C.C.); (A.P.)
| | - Paolo Magistri
- HPB Surgery and Liver Transplant Unit, Azienda Ospedaliero-Universitaria di Modena, University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Annarita Pecchi
- Radiology, Azienda Ospedaliero-Universitaria di Modena, University of Modena and Reggio Emilia, 41125 Modena, Italy; (F.C.); (C.C.); (A.P.)
| | - Endrit Shahini
- National Institute of Gastroenterology “IRCCS Saverio de Bellis”, Research Hospital, 70013 Castellana Grotte, Italy; (G.S.); (E.S.); (F.D.); (G.G.)
| | - Fabiola Milosa
- Gastroenterology Unit, CHIMOMO Department, University of Modena and Reggio Emilia, 41124 Modena, Italy; (R.M.C.); (F.M.); (A.P.); (S.L.); (N.D.M.)
| | - Lorenza Di Marco
- Clinical and Experimental Medicine PhD Program, 41125 Modena, Italy;
| | - Alessandra Pivetti
- Gastroenterology Unit, CHIMOMO Department, University of Modena and Reggio Emilia, 41124 Modena, Italy; (R.M.C.); (F.M.); (A.P.); (S.L.); (N.D.M.)
| | - Simone Lasagni
- Gastroenterology Unit, CHIMOMO Department, University of Modena and Reggio Emilia, 41124 Modena, Italy; (R.M.C.); (F.M.); (A.P.); (S.L.); (N.D.M.)
| | - Filippo Schepis
- M.E.C. Dipartimental Unit, University of Modena and Reggio Emilia, 41125 Modena, Italy;
| | - Nicola De Maria
- Gastroenterology Unit, CHIMOMO Department, University of Modena and Reggio Emilia, 41124 Modena, Italy; (R.M.C.); (F.M.); (A.P.); (S.L.); (N.D.M.)
| | - Francesco Dituri
- National Institute of Gastroenterology “IRCCS Saverio de Bellis”, Research Hospital, 70013 Castellana Grotte, Italy; (G.S.); (E.S.); (F.D.); (G.G.)
| | - María Luz Martínez-Chantar
- Liver Disease Laboratory, Centre for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain;
- Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), 28200 Madrid, Spain
| | - Fabrizio Di Benedetto
- HPB Surgery and Liver Transplant Unit, Azienda Ospedaliero-Universitaria di Modena, University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Gianluigi Giannelli
- National Institute of Gastroenterology “IRCCS Saverio de Bellis”, Research Hospital, 70013 Castellana Grotte, Italy; (G.S.); (E.S.); (F.D.); (G.G.)
| | - Erica Villa
- M.E.C. Dipartimental Unit, University of Modena and Reggio Emilia, 41125 Modena, Italy;
| |
Collapse
|
39
|
Mohammed WH, Sulaiman GM, Abomughaid MM, Klionsky DJ, Abu-Alghayth MH. The dual role of autophagy in suppressing and promoting hepatocellular carcinoma. Front Cell Dev Biol 2024; 12:1472574. [PMID: 39463763 PMCID: PMC11502961 DOI: 10.3389/fcell.2024.1472574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 09/25/2024] [Indexed: 10/29/2024] Open
Abstract
The 5-year survival rate for hepatocellular carcinoma (HCC), a deadly form of liver cancer, is quite low. Although drug therapy is successful, patients with advanced liver cancer frequently develop resistance because of the significant phenotypic and genetic heterogeneity of these cells. The overexpression of drug efflux transporters, downstream adaptive responses, malfunctioning DNA damage repair, epigenetic modification, the tumor microenvironment, and the extracellular matrix can all be linked to drug resistance. The evolutionary process of autophagy, which is in charge of intracellular breakdown, is intimately linked to medication resistance in HCC. Autophagy is involved in both the promotion and suppression of cancer by influencing treatment resistance, metastasis, carcinogenesis, and the viability of stem cells. Certain autophagy regulators are employed in anticancer treatment; however, because of the dual functions of autophagy, their use is restricted, and therapeutic failure is increased. By focusing on autophagy, it is possible to reduce HCC expansion and metastasis, and enhance tumor cell reactivity to treatment. Macroautophagy, the best-characterized type of autophagy, involves the formation of a sequestering compartment termed a phagophore, which surrounds and encloses aberrant or superfluous components. The phagophore matures into a double-membrane autophagosome that delivers the cargo to the lysosome; lysosomes and autophagosomes fuse to degrade and recycle the cargo. Macroautophagy plays dual functions in both promoting and suppressing cancer in a variety of cancer types.
Collapse
Affiliation(s)
- Wasnaa H. Mohammed
- Department of Biotechnology, College of Applied Sciences, University of Technology, Baghdad, Iraq
| | - Ghassan M. Sulaiman
- Department of Biotechnology, College of Applied Sciences, University of Technology, Baghdad, Iraq
| | - Mosleh M. Abomughaid
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, Bisha, Saudi Arabia
| | - Daniel J. Klionsky
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, United States
| | - Mohammed H. Abu-Alghayth
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, Bisha, Saudi Arabia
| |
Collapse
|
40
|
Xuan M, Gu X, Xing H. Multi-omic analysis identifies the molecular mechanism of hepatocellular carcinoma with cirrhosis. Sci Rep 2024; 14:23832. [PMID: 39394373 PMCID: PMC11470084 DOI: 10.1038/s41598-024-75609-5] [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: 07/16/2024] [Accepted: 10/07/2024] [Indexed: 10/13/2024] Open
Abstract
Hepatocellular carcinoma with cirrhosis promotes the advancement of malignancy and the development of fibrosis in normal liver tissues. Understanding the pathological mechanisms underlying the development of HCC with cirrhosis is important for developing effective therapeutic strategies. Herein, the RNA-sequencing (RNA-seq) data and corresponding clinical features of patients with HCC were extracted from The Cancer Genome Atlas (TCGA) database using the University of California Santa Cruz (UCSC) Xena platform. The enrichment degree of hallmarkers for each TCGA-LIHC cohort was quantified by ssGSEA algorithm. Weighted gene co-expression network analysis (WGCNA) revealed two gene module eigengenes (MEs) associated with cirrhosis, namely, MEbrown and MEgreen. Analysis of these modules using AUCell showed that MEbrown had higher enrichment scores in all immune cells, whereas MEgreen had higher enrichment scores in malignant cells. The CellChat package revealed that both immune and malignant cells contributed to the fibrotic activity of myofibroblasts through diverse signaling pathways. Additionally, spatial transcriptomic data showed that hepatocytes, proliferating hepatocytes, macrophages, and myofibroblasts were located in closer proximity in HCC tissues. These cells may potentially participate in the process of stimulating myofibroblast fibrotic activity, which may be related to the development of liver fibrosis. In summary, we made full use of multi-omics data to explore gene networks and cell types that may be involved in the development and progression of cirrhosis in HCC.
Collapse
Affiliation(s)
- Mengjuan Xuan
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Xinyu Gu
- Department of Oncology, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, 471000, Henan, China
| | - Huiwu Xing
- Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Erqi District, Zhengzhou, 450052, Henan, China.
| |
Collapse
|
41
|
Martín-Sierra C, Martins R, Coucelo M, Abrantes AM, Caetano Oliveira R, Tralhão JG, Botelho MF, Furtado E, Domingues MR, Paiva A, Laranjeira P. Tumor Resection in Hepatic Carcinomas Restores Circulating T Regulatory Cells. J Clin Med 2024; 13:6011. [PMID: 39408071 PMCID: PMC11478317 DOI: 10.3390/jcm13196011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 10/07/2024] [Accepted: 10/07/2024] [Indexed: 10/20/2024] Open
Abstract
Background/Objectives: Cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC) represent major primary liver cancers, affecting one of the most vital organs in the human body. T regulatory (Treg) cells play an important role in liver cancers through the immunosuppression of antitumor immune responses. The current study focuses on the characterization of circulating natural killer (NK) cells and T cell subsets, including Treg cells, in CCA and HCC patients, before and after surgical tumor resection, in order to understand the effect of tumor resection on the homeostasis of peripheral blood NK cells and T cells. Methods: Whole blood assays were performed to monitor immune alterations and the functional competence of circulating lymphocytes in a group of ten healthy individuals, eight CCA patients, and twenty HCC patients, before and one month after the surgical procedure, using flow cytometry, cell sorting, and qRT-PCR. Results: Before tumor resection, both HCC and CCA patients display increased percentages of CD8+ Treg cells and decreased frequencies of circulating CD4+ Treg cells. Notwithstanding, no functional impairment was detected on circulating CD4+ Treg cells, neither in CCA nor in HCC patients. Interestingly, the frequency of peripheral CD4+ Treg cells increased from 0.55% ± 0.49 and 0.71% ± 0.54 (in CCA and HCC, respectively) at T0 to 0.99% ± 0.91 and 1.17% ± 0.33 (in CCA and HCC, respectively) at T1, following tumor resection. Conclusions: Our results suggest mechanisms of immune modulation induced by tumor resection.
Collapse
Affiliation(s)
- Carmen Martín-Sierra
- Flow Cytometry Unit, Department of Clinical Pathology, Hospitais da Universidade de Coimbra, Unidade Local de Saúde de Coimbra, 3000-076 Coimbra, Portugal;
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Center of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal; (R.M.); (M.C.); (A.M.A.); (R.C.O.); (J.G.T.); (M.F.B.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3000-061 Coimbra, Portugal
| | - Ricardo Martins
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Center of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal; (R.M.); (M.C.); (A.M.A.); (R.C.O.); (J.G.T.); (M.F.B.)
- Unidade Transplantação Hepática Pediátrica e de Adultos, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Portugal;
- Serviço de Cirurgia Geral, Unidade HBP, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Portugal
- University of Coimbra, Faculty of Medicine, Biophysics Institute, 3000-548 Coimbra, Portugal
| | - Margarida Coucelo
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Center of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal; (R.M.); (M.C.); (A.M.A.); (R.C.O.); (J.G.T.); (M.F.B.)
- Unidade Funcional de Hematologia Molecular, Serviço de Hematologia Clínica, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Portugal
| | - Ana Margarida Abrantes
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Center of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal; (R.M.); (M.C.); (A.M.A.); (R.C.O.); (J.G.T.); (M.F.B.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3000-061 Coimbra, Portugal
- University of Coimbra, Faculty of Medicine, Biophysics Institute, 3000-548 Coimbra, Portugal
| | - Rui Caetano Oliveira
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Center of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal; (R.M.); (M.C.); (A.M.A.); (R.C.O.); (J.G.T.); (M.F.B.)
- University of Coimbra, Faculty of Medicine, Biophysics Institute, 3000-548 Coimbra, Portugal
- Serviço de Anatomia Patológica, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Portugal
| | - José Guilherme Tralhão
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Center of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal; (R.M.); (M.C.); (A.M.A.); (R.C.O.); (J.G.T.); (M.F.B.)
- Clinical Academic Center of Coimbra (CACC), 3000-061 Coimbra, Portugal
- Unidade Transplantação Hepática Pediátrica e de Adultos, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Portugal;
- Serviço de Cirurgia Geral, Unidade HBP, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Portugal
- University of Coimbra, Faculty of Medicine, Biophysics Institute, 3000-548 Coimbra, Portugal
| | - Maria Filomena Botelho
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Center of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal; (R.M.); (M.C.); (A.M.A.); (R.C.O.); (J.G.T.); (M.F.B.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3000-061 Coimbra, Portugal
- University of Coimbra, Faculty of Medicine, Biophysics Institute, 3000-548 Coimbra, Portugal
| | - Emanuel Furtado
- Unidade Transplantação Hepática Pediátrica e de Adultos, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Portugal;
| | - Maria Rosário Domingues
- CESAM—Centre for Environmental and Marine Studies, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal;
- Mass Spectrometry Center, LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Artur Paiva
- Flow Cytometry Unit, Department of Clinical Pathology, Hospitais da Universidade de Coimbra, Unidade Local de Saúde de Coimbra, 3000-076 Coimbra, Portugal;
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Center of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal; (R.M.); (M.C.); (A.M.A.); (R.C.O.); (J.G.T.); (M.F.B.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3000-061 Coimbra, Portugal
- Instituto Politécnico de Coimbra, ESTESC-Coimbra Health School, Ciências Biomédicas Laboratoriais, 3046-854 Coimbra, Portugal
| | - Paula Laranjeira
- Flow Cytometry Unit, Department of Clinical Pathology, Hospitais da Universidade de Coimbra, Unidade Local de Saúde de Coimbra, 3000-076 Coimbra, Portugal;
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Center of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal; (R.M.); (M.C.); (A.M.A.); (R.C.O.); (J.G.T.); (M.F.B.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3000-061 Coimbra, Portugal
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-504 Coimbra, Portugal
| |
Collapse
|
42
|
Mahmoud M, Lin KH, Lee RC, Liu CA. Assessment of Y-90 Radioembolization Treatment Response for Hepatocellular Carcinoma Cases Using MRI Radiomics. Mol Imaging Radionucl Ther 2024; 33:156-166. [PMID: 39373149 PMCID: PMC11589346 DOI: 10.4274/mirt.galenos.2024.59365] [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: 10/19/2023] [Accepted: 08/04/2024] [Indexed: 10/08/2024] Open
Abstract
Objectives This study aimed to investigate the ability of radiomics features extracted from magnetic resonance imaging (MRI) images to differentiate between responders and non-responders for hepatocellular carcinoma (HCC) cases who received Y-90 transarterial radioembolization treatment. Methods Thirty-six cases of HCC who underwent MRI scans after Y-90 radioembolization were included in this study. Tumors were segmented from MRI T2 images, and then 87 radiomic features were extracted through the LIFEx package software. Treatment response was determined 9 months after treatment through the modified response evaluation criteria in solid tumours (mRECIST). Results According to mRECIST, 28 cases were responders and 8 cases were non-responders. Two radiomics features, "Grey Level Size Zone Matrix (GLSZM)-Small Zone Emphasis" and "GLSZM-Normalized Zone Size Non-Uniformity", were the radiomics features that could predict treatment response with the area under curve (AUC)= 0.71, sensitivity= 0.93, and specificity= 0.62 for both features. Whereas the other 4 features (kurtosis, intensity histogram root mean square, neighbourhood gray-tone difference matrix strength, and GLSZM normalized grey level non-uniformity) have a relatively lower but acceptable discrimination ability range from AUC= 0.6 to 0.66. Conclusion MRI radiomics analysis could be used to assess the treatment response for HCC cases treated with Y-90 radioembolization.
Collapse
Affiliation(s)
| | - Ko-Han Lin
- Taipei Veterans General Hospital, Clinic of Nuclear Medicine, Taipei, Taiwan
| | - Rheun-Chuan Lee
- Taipei Veterans General Hospital, Clinic of Radiology, Taipei, Taiwan
| | - Chien-an Liu
- Taipei Veterans General Hospital, Clinic of Radiology, Taipei, Taiwan
| |
Collapse
|
43
|
Penrice DD, Jalan-Sakrikar N, Jurk D, Passos JF, Simonetto DA. Telomere dysfunction in chronic liver disease: The link from aging. Hepatology 2024; 80:951-964. [PMID: 37102475 PMCID: PMC10848919 DOI: 10.1097/hep.0000000000000426] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 04/20/2023] [Indexed: 04/28/2023]
Affiliation(s)
- Daniel D. Penrice
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Nidhi Jalan-Sakrikar
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Diana Jurk
- Department of Physiology and Biomedical Engineering, Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota, USA
| | - João F. Passos
- Department of Physiology and Biomedical Engineering, Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota, USA
| | - Douglas A. Simonetto
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| |
Collapse
|
44
|
Balaji N, Kukal S, Bhat A, Pradhan N, Minocha S, Kumar S. A quartet of cancer stem cell niches in hepatocellular carcinoma. Cytokine Growth Factor Rev 2024; 79:39-51. [PMID: 39217065 DOI: 10.1016/j.cytogfr.2024.08.007] [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: 07/03/2024] [Revised: 08/20/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024]
Abstract
Hepatocellular Carcinoma (HCC), the most prevalent type of primary liver cancer, is known for its aggressive behavior and poor prognosis. The Cancer Stem Cell theory, which postulates the presence of a small population of self-renewing cells called Cancer Stem Cells (CSCs), provides insights into various clinical and molecular features of HCC such as tumor heterogeneity, metabolic adaptability, therapy resistance, and recurrence. These CSCs are nurtured in the tumor microenvironment (TME), where a mix of internal and external factors creates a tumor-supportive niche that is continuously evolving both spatially and temporally, thus enhancing the tumor's complexity. This review details the origins of hepatic CSCs (HCSCs) and the factors influencing their stem-like qualities. It highlights the reciprocal crosstalk between HCSCs and the TME (hypoxic, vascular, invasive, and immune niches), exploring the signaling pathways involved and how these interactions control the malignant traits of CSCs. Additionally, it discusses potential therapeutic approaches targeting the HCSC niche and their possible uses in clinical practice.
Collapse
Affiliation(s)
- Neha Balaji
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, 110016, India
| | - Samiksha Kukal
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, 110016, India
| | - Anjali Bhat
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, 110016, India
| | - Nikita Pradhan
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, 110016, India
| | - Shilpi Minocha
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, 110016, India.
| | - Saran Kumar
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, 110016, India.
| |
Collapse
|
45
|
Wang Y, Chen W, Qiao S, Zou H, Yu XJ, Yang Y, Li Z, Wang J, Chen MS, Xu J, Zheng L. Lipid droplet accumulation mediates macrophage survival and Treg recruitment via the CCL20/CCR6 axis in human hepatocellular carcinoma. Cell Mol Immunol 2024; 21:1120-1130. [PMID: 38942796 PMCID: PMC11443046 DOI: 10.1038/s41423-024-01199-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 06/17/2024] [Indexed: 06/30/2024] Open
Abstract
Metabolic changes play a crucial role in determining the status and function of macrophages, but how lipid reprogramming in macrophages contributes to tumor progression is not yet fully understood. Here, we investigated the phenotype, contribution, and regulatory mechanisms of lipid droplet (LD)-laden macrophages (LLMs) in hepatocellular carcinoma (HCC). Enriched LLMs were found in tumor tissues and were associated with disease progression in HCC patients. The LLMs displayed immunosuppressive phenotypes (with extensive expression of TREM2, PD-L1, CD206, and CD163) and attenuated the antitumor activities of CD8+ T cells. Mechanistically, tumor-induced reshuffling of cellular lipids and TNFα-mediated uptake of tumoral fatty acids contribute to the generation of triglycerides and LDs in macrophages. LDs prolong LLM survival and promote CCL20 secretion, which further recruits CCR6+ Tregs to HCC tissue. Inhibiting LLM formation by targeting DGAT1 and DGAT2, which catalyze the synthesis of triglycerides, significantly reduced Treg recruitment, and delayed tumor growth in a mouse hepatic tumor model. Our results reveal the suppressive phenotypes and mechanisms of LLM enrichment in HCC and suggest the therapeutic potential of targeting LLMs for HCC patients.
Collapse
Affiliation(s)
- Yongchun Wang
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
- Key Laboratory of Gene Function and Regulation of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Weibai Chen
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
- Key Laboratory of Gene Function and Regulation of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Shuang Qiao
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
| | - Hao Zou
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
| | - Xing-Juan Yu
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
| | - Yanyan Yang
- Key Laboratory of Gene Function and Regulation of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Zhixiong Li
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
| | - Junfeng Wang
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
| | - Min-Shan Chen
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, PR China
| | - Jing Xu
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China.
| | - Limin Zheng
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China.
- Key Laboratory of Gene Function and Regulation of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China.
| |
Collapse
|
46
|
Grossar L, Verhelst X. Liver transplantation for cirrhosis and its complications. Acta Clin Belg 2024; 79:377-383. [PMID: 39834202 DOI: 10.1080/17843286.2025.2456183] [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: 12/13/2024] [Accepted: 01/13/2025] [Indexed: 01/22/2025]
Abstract
OBJECTIVES To review the current indications for liver transplantation (LT) in cirrhosis, including evolving criteria for hepatocellular carcinoma (HCC) and other malignancies, how donor organ allocation is established, and to address challenges of long-term complications post-transplantation. METHODS A comprehensive review of the literature was conducted to evaluate advancements in LT indications, pretransplant evaluation protocols, organ allocation strategies, and management approaches for long-term post-transplant complications. RESULTS Liver transplantation remains the definitive treatment for cirrhosis and offers substantial survival benefits for patients with early-stage HCC. Recent advancements have expanded eligibility criteria to include patients with multiple comorbidities, advanced-stage HCC, and select malignancies, provided they meet specific selection criteria. The increasing demand for donor organs has driven innovations in donor pool expansion, which presents new challenges in recipient management, including the need for tailored pretransplant workups and strategies to mitigate long-term complications. CONCLUSION The field of liver transplantation continues to evolve, with broader indications and innovative approaches to donor pool expansion. These advancements necessitate careful patient selection, rigorous pretransplant evaluation, and effective long-term management strategies to optimize outcomes for transplant recipients.
Collapse
Affiliation(s)
- Lorenz Grossar
- Department of Internal Medicine and Pediatrics, Hepatology Research Unit, Ghent University, Ghent, Belgium
- Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium
| | - Xavier Verhelst
- Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
| |
Collapse
|
47
|
Kim JY, Kang W, Yang S, Park SH, Ha SY, Paik YH. NADPH oxidase 4 deficiency promotes hepatocellular carcinoma arising from hepatic fibrosis by inducing M2-macrophages in the tumor microenvironment. Sci Rep 2024; 14:22358. [PMID: 39333166 PMCID: PMC11437090 DOI: 10.1038/s41598-024-72721-4] [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: 12/03/2023] [Accepted: 09/10/2024] [Indexed: 09/29/2024] Open
Abstract
Hepatocellular carcinoma (HCC) often arises in the cirrhotic livers, highlighting the intricate link between hepatic fibrosis and carcinogenesis. Reactive oxygen species produced by NADPH oxidase 4 (NOX4) contribute to liver injury leading to hepatic fibrosis. Paradoxically, NOX4 is known to inhibit HCC progression. This study aims to elucidate the role of NOX4 in hepatocarcinogenesis in the background of hepatic fibrosis. We established the mouse model of HCC arising from the fibrotic liver by administering diethylnitrosamine and carbon tetrachloride to wild-type (WT) or NOX4-/- mice. Hepatic fibrogenesis, tumorigenesis, and macrophage polarization were assessed by immunohistochemistry, PCR, and flow cytometry using in vivo and in vitro models. In NOX4-/- mice, hepatic fibrosis was attenuated, while the number of tumors and the proliferation of HCC cells were increased compared to WT mice. Notably, a significant increase in M2-polarized macrophages was observed in NOX4-/- mice through immunohistochemistry and PCR analysis. Subsequent experiments demonstrated that NOX4-silenced HCC cells promote macrophage polarization toward M2. In addition to attenuating hepatic fibrogenesis, NOX4 deficiency triggers macrophage polarization towards the M2 phenotype in the fibrotic liver, thereby promoting hepatocellular carcinogenesis. These findings provide novel insights into the mechanism of NOX4-mediated tumor suppression in HCC arising from fibrotic livers.
Collapse
Affiliation(s)
- Ji Young Kim
- Department of Health Sciences and Technology, Samsung Advanced Institute of Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, 06355, Republic of Korea
| | - Wonseok Kang
- Department of Health Sciences and Technology, Samsung Advanced Institute of Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, 06355, Republic of Korea
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea
- Research Institute for Future Medicine, Samsung Medical Center, Seoul, 06351, Republic of Korea
- Samsung Genome Institute, Samsung Medical Center, Seoul, 06351, Republic of Korea
| | - Sera Yang
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea
| | - Su Hyun Park
- Department of Health Sciences and Technology, Samsung Advanced Institute of Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, 06355, Republic of Korea
| | - Sang Yun Ha
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea
| | - Yong-Han Paik
- Department of Health Sciences and Technology, Samsung Advanced Institute of Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, 06355, Republic of Korea.
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea.
| |
Collapse
|
48
|
Liu B, Liu L, Liu Y. Targeting cell death mechanisms: the potential of autophagy and ferroptosis in hepatocellular carcinoma therapy. Front Immunol 2024; 15:1450487. [PMID: 39315094 PMCID: PMC11416969 DOI: 10.3389/fimmu.2024.1450487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 08/21/2024] [Indexed: 09/25/2024] Open
Abstract
Ferroptosis is a type of cell death that plays a remarkable role in the growth and advancement of malignancies including hepatocellular carcinoma (HCC). Non-coding RNAs (ncRNAs) have a considerable impact on HCC by functioning as either oncogenes or suppressors. Recent research has demonstrated that non-coding RNAs (ncRNAs) have the ability to control ferroptosis in HCC cells, hence impacting the advancement of tumors and the resistance of these cells to drugs. Autophagy is a mechanism that is conserved throughout evolution and plays a role in maintaining balance in the body under normal settings. Nevertheless, the occurrence of dysregulation of autophagy is evident in the progression of various human disorders, specifically cancer. Autophagy plays dual roles in cancer, potentially influencing both cell survival and cell death. HCC is a prevalent kind of liver cancer, and genetic mutations and changes in molecular pathways might worsen its advancement. The role of autophagy in HCC is a subject of debate, as it has the capacity to both repress and promote tumor growth. Autophagy activation can impact apoptosis, control proliferation and glucose metabolism, and facilitate tumor spread through EMT. Inhibiting autophagy can hinder the growth and spread of HCC and enhance the ability of tumor cells to respond to treatment. Autophagy in HCC is regulated by several signaling pathways, such as STAT3, Wnt, miRNAs, lncRNAs, and circRNAs. Utilizing anticancer drugs to target autophagy may have advantageous implications for the efficacy of cancer treatment.
Collapse
Affiliation(s)
- Beibei Liu
- Department of Radiology and Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ling Liu
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yang Liu
- Day Surgery Center, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| |
Collapse
|
49
|
Sharma B, Dhiman C, Hasan GM, Shamsi A, Hassan MI. Pharmacological Features and Therapeutic Implications of Plumbagin in Cancer and Metabolic Disorders: A Narrative Review. Nutrients 2024; 16:3033. [PMID: 39275349 PMCID: PMC11397539 DOI: 10.3390/nu16173033] [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: 08/16/2024] [Revised: 08/30/2024] [Accepted: 09/06/2024] [Indexed: 09/16/2024] Open
Abstract
Plumbagin (PLB) is a naphthoquinone extracted from Plumbago indica. In recent times, there has been a growing body of evidence suggesting the potential importance of naphthoquinones, both natural and artificial, in the pharmacological world. Numerous studies have indicated that PLB plays a vital role in combating cancers and other disorders. There is substantial evidence indicating that PLB may have a significant role in the treatment of breast cancer, brain tumours, lung cancer, hepatocellular carcinoma, and other conditions. Moreover, its potent anti-oxidant and anti-inflammatory properties offer promising avenues for the treatment of neurodegenerative and cardiovascular diseases. A number of studies have identified various pathways that may be responsible for the therapeutic efficacy of PLB. These include cell cycle regulation, apoptotic pathways, ROS induction pathways, inflammatory pathways, and signal transduction pathways such as PI3K/AKT/mTOR, STAT3/PLK1/AKT, and others. This review aims to provide a comprehensive analysis of the diverse pharmacological roles of PLB, examining the mechanisms through which it operates and exploring its potential applications in various medical conditions. In addition, we have conducted a review of the various formulations that have been reported in the literature with the objective of enhancing the efficacy of the compound. However, the majority of the reviewed data are based on in vitro and in vivo studies. To gain a comprehensive understanding of the safety and efficacy of PLB in humans and to ascertain its potential integration into therapeutic regimens for cancer and chronic diseases, rigorous clinical trials are essential. Finally, by synthesizing current research and identifying gaps in knowledge, this review seeks to enhance our understanding of PLB and its therapeutic prospects, paving the way for future studies and clinical applications.
Collapse
Affiliation(s)
- Bhoomika Sharma
- Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Chitra Dhiman
- Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Gulam Mustafa Hasan
- Department of Basic Medical Science, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Anas Shamsi
- Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman P.O. Box 346, United Arab Emirates
| | - Md Imtiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| |
Collapse
|
50
|
Kumar D, Prasad MK, Kumar S, Aziz T, Prasad ML, Sinha R, Guria RT, Kumar A, Vidyapati, Kumar S, Kumar P. Serum zinc level in liver cirrhosis with hepatic encephalopathy and its correlation with different stages of hepatic encephalopathy. J Family Med Prim Care 2024; 13:3979-3987. [PMID: 39464910 PMCID: PMC11504758 DOI: 10.4103/jfmpc.jfmpc_537_24] [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: 04/01/2024] [Revised: 05/12/2024] [Accepted: 05/16/2024] [Indexed: 10/29/2024] Open
Abstract
Background Hepatic encephalopathy (HE) severe complication of liver cirrhosis with high mortality. Few studies have found zinc deficiency in liver cirrhosis and HE patients and found it as a precipitating factor for the development of HE. This study was done to measure the serum zinc level in patients with liver cirrhosis with HE and a correlation was obtained between serum zinc level with grades of HE. Material and Methods A cross-sectional observational study was done on 150 patients with liver cirrhosis with HE at a tertiary care center in Jharkhand. All cases were evaluated by history taking, clinical examination, and a questionnaire and classified into different WHC grades of HE and CPC classes of cirrhosis. Routine blood investigations, imaging studies, and morning serum zinc levels were done for all patients. Results Majority of patients with liver cirrhosis with HE had zinc deficiency. There was a statistically highly significant (P < .00001) association between low serum zinc levels and WHC grades of HE. The serum zinc levels in different classes of cirrhosis showed highly significant differences (P < .00001). The mean serum zinc level was significantly low in patients who died (35.56 ± 11.65 vs 48.36 ± 10.91, P < .0001). The study revealed a strong positive correlation (r = .88, P = .048) between serum zinc and serum albumin levels. Conclusion Serum zinc is deficient in patients with liver cirrhosis and HE. Zinc deficiency is significantly associated with higher severity of cirrhosis and higher grades of HE. All patients with liver cirrhosis with HE and hypoalbuminemia should be evaluated for zinc deficiency.
Collapse
Affiliation(s)
- Divakar Kumar
- Department of Medicine, Rajendra Institute of Medical Sciences Ranchi, Ranchi, Jharkhand, India
| | - Manoj Kumar Prasad
- Department of Medicine, Rajendra Institute of Medical Sciences Ranchi, Ranchi, Jharkhand, India
| | - Sandeep Kumar
- Department of Medicine, Anugrah Narayan Magadh Medical College and Hospital, Gaya, Bihar, India
| | - Tarique Aziz
- Department of Biochemistry, Rajendra Institute of Medical Sciences Ranchi, Ranchi, Jharkhand, India
| | - Manohar Lal Prasad
- Department of Medicine, Rajendra Institute of Medical Sciences Ranchi, Ranchi, Jharkhand, India
| | - Rashmi Sinha
- Department of Medicine, Rajendra Institute of Medical Sciences Ranchi, Ranchi, Jharkhand, India
| | - Rishi T. Guria
- Department of Medicine, Rajendra Institute of Medical Sciences Ranchi, Ranchi, Jharkhand, India
| | - Abhay Kumar
- Department of Medicine, Rajendra Institute of Medical Sciences Ranchi, Ranchi, Jharkhand, India
| | - Vidyapati
- Department of Medicine, Rajendra Institute of Medical Sciences Ranchi, Ranchi, Jharkhand, India
| | - Sameer Kumar
- Department of Medicine, Anugrah Narayan Magadh Medical College and Hospital, Gaya, Bihar, India
| | - Pramod Kumar
- Department of Biochemistry, Hi-Tech Medical College, Rourkela, Odisha, India
| |
Collapse
|