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Heng Q, Hou M, Leng Y, Yu H. Establishment of a prognostic nomogram and risk stratification system for patients with combined hepatocellular-cholangiocarcinoma. Sci Rep 2025; 15:16726. [PMID: 40369041 DOI: 10.1038/s41598-025-01817-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Accepted: 05/08/2025] [Indexed: 05/16/2025] Open
Abstract
Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is an exceptionally rare form of primary liver malignancy and currently lacks prognostic prediction models. This study aims to develop a nomogram designed to predict cancer-specific survival (CSS) in patients diagnosed with cHCC-CCA. A total of 420 patients diagnosed with cHCC-CCA between 2004 and 2019 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were randomly assigned to training and validation cohorts in a 7:3 ratio. Cox proportional hazards regression analysis was employed to identify prognostic factors for the construction of the nomogram. The performance and clinical utility of the nomogram were evaluated using the concordance index (C-index), area under the curve (AUC) values, calibration curves, decision curve analysis (DCA), net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Ultimately, Multivariate Cox regression analysis identified 6 variables for the establishment of a nomogram for cHCC-CCA. The C-index, AUC value and calibration curve of the nomogram show that the model has satisfactory accuracy. Additionally, DCA, NRI values (training set: 0.392 for 1-year, 0.425 for 3-year and 0.414 for 5-year CSS prediction), and IDI (training set: 0.165 for 1-year, 0.151 for 3-year and 0.151 for 5-year CSS prediction) indicate that the performance of the established nomogram is significantly better than that based solely on the AJCC standard tumor staging (P < 0.05). Furthermore, a risk classification system with enhanced capability to identify patients at varying risk levels was established. Therefore, we developed a nomogram that can help clinicians assess the prognosis of patients with cHCC-CCA.
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Affiliation(s)
- Qiuhan Heng
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Mingxing Hou
- Department of General Surgery, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Ying Leng
- The Fifth People's Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, 611130, China
| | - Hua Yu
- Department of General Surgery, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
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Tang H, Chai C, Miao X, Su Y, Yu C, Yi J, Wang Z, Zhang H, Zhao Z, Wang L, Zhou W, Xu H. Establishment and characterization of CHC-X1: the third human combined hepatocellular-cholangiocarcinoma cell line. BMC Cancer 2025; 25:472. [PMID: 40087624 PMCID: PMC11908078 DOI: 10.1186/s12885-025-13876-9] [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: 08/16/2024] [Accepted: 03/06/2025] [Indexed: 03/17/2025] Open
Abstract
Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) represents an uncommon variant of primary liver cancer. In recent years, its incidence rate has increased. Thus, it is essential to perform comprehensive investigations into cHCC-CCA to develop suitable treatment strategies. So far, only two cell lines (CLs) of this cancer type have been reported. More cHCC-CCA CLs need to be established for research purposes. In this investigation, we developed a stable cHCC-CCA CL, named CHC-X1. STR analysis confirmed that CHC-X1 is a new human cHCC-CCA CL. CHC-X1 is a complex karyotype. Its population doubling time is 50.72 h. Under suspended conditions, CHC-X1 can form tumor spheres and organoids in Matrigel. These cells exhibit sensitivity to paclitaxel while demonstrating resistance against oxaliplatin, gemcitabine, and 5-FU. After inoculation into NXG mice, CHC-X1 can quickly form subcutaneous transplant tumors, exhibiting a tumor establishment rate of 67%. Immunohistochemical staining showed that CHC-X1 is a tumor CL with both liver cell differentiation and bile duct cell differentiation characteristics. It may function as a useful model for identifying the origins of cHCC-CCA and the advancement of potential treatments.
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Affiliation(s)
- Huan Tang
- The Second Clinical Medical School of Lanzhou University, Lanzhou, 730000, China
| | - Changpeng Chai
- The Fourth Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730000, China
- The First Clinical Medical School of Lanzhou University, Lanzhou, 730000, China
| | - Xin Miao
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Provincial Hospital of Chinese Medicine, Hangzhou, 310006, China
| | - Yuanhui Su
- The Second Clinical Medical School of Lanzhou University, Lanzhou, 730000, China
| | - Cheng Yu
- The Second Clinical Medical School of Lanzhou University, Lanzhou, 730000, China
- Department of Anesthesiology, Lanzhou University Second Hospital, Lanzhou, 730000, China
| | - Jianfeng Yi
- The First Clinical Medical School of Lanzhou University, Lanzhou, 730000, China
- The First School of Clinical Medicine of Gansu University of Chinese Medicine, Lanzhou, 730000, China
| | - Zhengfeng Wang
- The Fourth Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730000, China
- The First Clinical Medical School of Lanzhou University, Lanzhou, 730000, China
| | - Hui Zhang
- The Second Clinical Medical School of Lanzhou University, Lanzhou, 730000, China
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, 730000, China
| | - Zhenjie Zhao
- The Fourth Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730000, China
- The First Clinical Medical School of Lanzhou University, Lanzhou, 730000, China
| | - Linpei Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, China.
- , No. 54 Youdian Road, Shangcheng District, Hangzhou, Zhejiang, China.
| | - Wence Zhou
- The Second Clinical Medical School of Lanzhou University, Lanzhou, 730000, China.
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, 730000, China.
- , No. 54 Youdian Road, Shangcheng District, Hangzhou, Zhejiang, China.
| | - Hao Xu
- The Fourth Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730000, China.
- The First Clinical Medical School of Lanzhou University, Lanzhou, 730000, China.
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Provincial Hospital of Chinese Medicine, Hangzhou, Zhejiang, 310006, China.
- , No. 54 Youdian Road, Shangcheng District, Hangzhou, Zhejiang, China.
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Shi H, Li Z, Zhu M. Circulating Immune Cells Predict Prognosis and Clinical Response to Chemotherapy in Cholangiocarcinoma. Curr Med Chem 2025; 32:595-607. [PMID: 38698750 DOI: 10.2174/0109298673296618240424095548] [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: 01/04/2024] [Revised: 03/11/2024] [Accepted: 03/18/2024] [Indexed: 05/05/2024]
Abstract
BACKGROUND The immune system is linked to the prognosis and response to treatment of patients with cancer. However, the clinical implication of peripheral blood immune cells in cholangiocarcinoma (CCA) remains vague. Thus, we aimed to assess whether peripheral circulating immune cells could be used as an indicator for prognosis and chemotherapeutic efficacy in CCA. METHODS The distributions of immune subsets were analyzed in peripheral blood samples from 141 patients with CCA and 131 healthy volunteers by using flow cytometry. The variation in the subset distribution in the two groups and the relationship between clinicopathological features and the subpopulations were investigated. Meanwhile, we assessed the implications of lymphocyte subsets as predictors of chemotherapy outcomes and overall survival (OS). RESULTS The proportion of total lymphocytes decreased, while the percentages of activated T cells as well as CD4+CD25+ regulatory T cells (Tregs) increased in CCA. Notably, lymphocyte proportion decreased in patients with regional lymph node (N) (p=0.016) and distant metastasis (M) (p= 0.001). Furthermore, our study showed that peripheral blood lymphocyte subsets were significantly correlated with chemotherapy efficacy, with increased proportions of CD3+ cells (p=0.021) and CD4+ cells (p=0.016) in the effective group. Finally, the Kaplan-Meier analysis indicated that patients with high natural killer (NK) cell proportion might have prolonged OS (p = 0.028). CONCLUSION The relationship between circulating immune cells with prognosis and chemotherapy response in patients with CCA highlights their potential application as an indicator of CCA prognosis and stratification of chemotherapy response.
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Affiliation(s)
- Huina Shi
- Department of Clinical Laboratory, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Zhaosheng Li
- Department of Clinical Laboratory, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Mingchen Zhu
- Department of Clinical Laboratory, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
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Jiang K, Li J, Liu Z, Chen M, Cai W, Liu L, Yin D. Impact of major hepatectomy on recurrence after resection of hepatocellular carcinoma at CNLC Ib stage: a propensity score matching study. Int J Surg 2025; 111:857-864. [PMID: 38913430 PMCID: PMC11745688 DOI: 10.1097/js9.0000000000001879] [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: 05/02/2024] [Accepted: 06/17/2024] [Indexed: 06/26/2024]
Abstract
OBJECTIVE Patients with hepatocellular carcinoma (HCC) who undergo curative hepatectomy may experience varying remnant liver volumes. Our study aimed to evaluate whether the extent of liver resection has an effect on postoperative recurrence in HCC patients at China Liver Cancer Staging (CNLC) Ib stage. METHODS A retrospective analysis was conducted on 197 patients who underwent hepatectomy for a solitary HCC lesion measuring ≥5 cm (CNLC Ιb stage) between January 2019 and June 2022. Patients were divided into a major hepatectomy (MAH) group ( n =70) and a minor hepatectomy (MIH) group ( n =127) based on the extent of liver resection. Recurrence-free survival (RFS) was compared between the two groups. Propensity score matching (PSM) was employed to minimize bias in the retrospective analysis. RESULTS Patients who underwent MAH had a greater total complication rate than those who underwent MIH (35.7 vs. 11.8%, P <0.001). The median RFS was 14.6 months (95% CI: 11.1-18.1) for the MAH group and 24.1 months (95% CI: 21.2-27.1) for the MIH group ( P <0.001). After PSM, patients who underwent MAH still had a greater total complication rate than those who underwent MIH (36.7 vs. 16.3%, P =0.037). The median RFS was 13.2 months (95% CI: 15.1-21.7) for the MAH group and 22.3 months (95% CI: 18.1-26.5) for the MIH group ( P =0.0013). The Cox regression model identified MAH as an independent poor predictor for HCC recurrence (hazard ratios of 1.826 and 2.062 before and after PSM, respectively; both P <0.05). CONCLUSION MIH can be performed with fewer postoperative complications and contributes to improved RFS in patients with HCC at CNLC Ιb stage compared to MAH. Parenchyma-sparing resection should be considered the first choice for these HCCs.
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Affiliation(s)
- Kunyuan Jiang
- Department of General Surgery, Anhui Provincial Hospital, Anhui Medical University
| | - Jingfei Li
- Department of General Surgery, Anhui Provincial Hospital, Anhui Medical University
| | - Zihao Liu
- Department of General Surgery, Anhui Provincial Hospital, Anhui Medical University
| | - Miao Chen
- Department of Hepatobiliary surgery, The First Affiliated Hospital of University of Science and Technology of China
| | - Wei Cai
- Department of Hepatobiliary surgery, The First Affiliated Hospital of University of Science and Technology of China
| | - Lianxin Liu
- Department of Hepatobiliary surgery, The First Affiliated Hospital of University of Science and Technology of China
- Department of Hepatobiliary Surgery and Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated HospitalDivision of Life Sciences and Medicine, University of Science and Technology of China
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, People’s Republic of China
| | - Dalong Yin
- Department of General Surgery, Anhui Provincial Hospital, Anhui Medical University
- Department of Hepatobiliary Surgery and Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated HospitalDivision of Life Sciences and Medicine, University of Science and Technology of China
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Lin RY, Kahramangil D, Ozer M, George TJ, Nassour I, Hughes SJ, Zarrinpar A, Sahin I. Patient Outcomes in Resected Combined Hepatocellular Cholangiocarcinoma (cHCC-ICC) and Intrahepatic Cholangiocarcinoma: A Single Center Study. Cancers (Basel) 2024; 16:3878. [PMID: 39594833 PMCID: PMC11592994 DOI: 10.3390/cancers16223878] [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: 11/04/2024] [Revised: 11/16/2024] [Accepted: 11/18/2024] [Indexed: 11/28/2024] Open
Abstract
BACKGROUND/OBJECTIVES Combined hepatocellular cholangiocarcinoma (cHCC-ICC) is a rare malignancy that involves a combination of features of hepatocellular carcinoma and intrahepatic cholangiocarcinoma (ICC) and exhibits a more aggressive clinical course; however, its risk factors and outcomes remain largely undefined. METHODS This study is a single-center retrospective study of 82 patients diagnosed with ICC or cHCC-ICC who underwent surgical resection from June 2011 to January 2023. Our analysis included 70 patients with resected ICC and 12 with resected cHCC-ICC. RESULTS The overall survival (OS) for the entire cohort was 21.6 months, with a recurrence-free survival (RFS) of 11.8 months. The cHCC-ICC group had significantly higher levels of AST and ALT (AST median 206 U/L vs. 46 U/L; ALT median 165.5 U/L vs. 48 U/L; p = 0.012 and p = 0.013, respectively), whereas the ICC group had higher alkaline phosphatase (median 66 U/L vs. 104 U/L; p = 0.03). CA 19-9 values (76 U/mL vs. 22 U/mL; p = 0.02) were higher in the ICC group, while AFP values were higher in the cHCC-ICC group (7.3 ng/mL vs. 3.2 ng/mL; p = 0.0004). The cHCC-ICC group had a significantly higher rate of recurrence (83% vs. 47%, p = 0.028) with a significantly decreased RFS (4.7 months vs. 12.4 months; log-rank p = 0.007). In multivariate analysis, patients with resected ICC had a significantly reduced risk of recurrence by 73% compared to their counterparts (HR 0.27 [0.10-0.73], p = 0.01). CONCLUSIONS cHCC-ICC is a rare entity that needs to be further studied to improve patient outcomes. Further studies are warranted and may suggest the need for more aggressive initial treatment strategies in patients diagnosed with cHCC-ICC.
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Affiliation(s)
- Rick Y. Lin
- Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA;
| | - Doga Kahramangil
- Department of Medicine, Division of Hematology and Oncology, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (D.K.); (T.J.G.)
| | - Muhammet Ozer
- Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA;
| | - Thomas J. George
- Department of Medicine, Division of Hematology and Oncology, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (D.K.); (T.J.G.)
| | - Ibrahim Nassour
- Department of Surgery, University of Florida, Gainesville, FL 32610, USA; (I.N.); (S.J.H.); (A.Z.)
| | - Steven J. Hughes
- Department of Surgery, University of Florida, Gainesville, FL 32610, USA; (I.N.); (S.J.H.); (A.Z.)
| | - Ali Zarrinpar
- Department of Surgery, University of Florida, Gainesville, FL 32610, USA; (I.N.); (S.J.H.); (A.Z.)
| | - Ilyas Sahin
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA
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Ru Q, Li Y, Chen L, Wu Y, Min J, Wang F. Iron homeostasis and ferroptosis in human diseases: mechanisms and therapeutic prospects. Signal Transduct Target Ther 2024; 9:271. [PMID: 39396974 PMCID: PMC11486532 DOI: 10.1038/s41392-024-01969-z] [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: 03/27/2024] [Revised: 08/08/2024] [Accepted: 09/02/2024] [Indexed: 10/15/2024] Open
Abstract
Iron, an essential mineral in the body, is involved in numerous physiological processes, making the maintenance of iron homeostasis crucial for overall health. Both iron overload and deficiency can cause various disorders and human diseases. Ferroptosis, a form of cell death dependent on iron, is characterized by the extensive peroxidation of lipids. Unlike other kinds of classical unprogrammed cell death, ferroptosis is primarily linked to disruptions in iron metabolism, lipid peroxidation, and antioxidant system imbalance. Ferroptosis is regulated through transcription, translation, and post-translational modifications, which affect cellular sensitivity to ferroptosis. Over the past decade or so, numerous diseases have been linked to ferroptosis as part of their etiology, including cancers, metabolic disorders, autoimmune diseases, central nervous system diseases, cardiovascular diseases, and musculoskeletal diseases. Ferroptosis-related proteins have become attractive targets for many major human diseases that are currently incurable, and some ferroptosis regulators have shown therapeutic effects in clinical trials although further validation of their clinical potential is needed. Therefore, in-depth analysis of ferroptosis and its potential molecular mechanisms in human diseases may offer additional strategies for clinical prevention and treatment. In this review, we discuss the physiological significance of iron homeostasis in the body, the potential contribution of ferroptosis to the etiology and development of human diseases, along with the evidence supporting targeting ferroptosis as a therapeutic approach. Importantly, we evaluate recent potential therapeutic targets and promising interventions, providing guidance for future targeted treatment therapies against human diseases.
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Affiliation(s)
- Qin Ru
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China
| | - Yusheng Li
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Lin Chen
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China
| | - Yuxiang Wu
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China.
| | - Junxia Min
- The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
| | - Fudi Wang
- The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China.
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Li W, You L, Lin J, Zhang J, Zhou Z, Wang T, Wu Y, Zheng C, Gao Y, Kong X, Sun X. An herbal formula Shenlian decoction upregulates M1/M2 macrophage proportion in hepatocellular carcinoma by suppressing complement cascade. Biomed Pharmacother 2024; 177:116943. [PMID: 38878636 DOI: 10.1016/j.biopha.2024.116943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 06/04/2024] [Accepted: 06/10/2024] [Indexed: 07/28/2024] Open
Abstract
The immunosuppressive microenvironment is a vital factor for the hepatocellular carcinoma (HCC) progression. However, effective treatment is lacking at current. Shenlian decoction (SLD) is a registered herbal therapy for the HCC treatment, but the underlying mechanism of SLD remains largely elusive. Here, we aimed to explore the anti-tumor effect of SLD in the treatment of HCC. SLD was intragastrically given after the tumor initiation in β-catenin/C-Met or DEN and CCl4 induced HCC mouse model. The tumor growth levels were evaluated by liver weight and histological staining. The tumor-infiltrating immune cells were detected by immunological staining and flow cytometry. The mechanism of the SLD was detected by non-targeted proteomics and verified by a cell co-culture system. The result showed that SLD significantly attenuated HCC progression. SLD promoted macrophage infiltration and increased the M1/M2 macrophage ratio within the tumor tissues. Non-targeted proteomics showed the inhibition of complement C5/C5a signaling is the key mechanism of SLD. Immunological staining showed SLD inhibited C5/C5a expression and C5aR1+ macrophage infiltration. The suggested mechanism was demonstrated by application of C5aR1 inhibitor, PMX-53 in mouse HCC model. Hepatoma cell-macrophage co-culture showed SLD targeted hepatoma cells and inhibited the supernatant-induced macrophage M2 polarization. SLD inhibited AMPK/p38 signaling which is an upstream mechanism of C5 transcription. In conclusion, we found SLD relieved immune-suppressive environment by inhibiting C5 expression. SLD could suppress the C5 secretion in hepatoma cells via inhibition of AMPK/p38 signaling. We suggested that SLD is a potential herbal therapy for the treatment of HCC by alleviating immune-suppressive status.
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Affiliation(s)
- Wenxuan Li
- Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China; Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Liping You
- Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China; Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiacheng Lin
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jinghao Zhang
- Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhijia Zhou
- Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China; Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tao Wang
- Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China; Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuelan Wu
- Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China; Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chao Zheng
- Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yueqiu Gao
- Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China; Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Xiaoni Kong
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Xuehua Sun
- Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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Vij M, Veerankutty FH, Rammohan A, Rela M. Combined hepatocellular cholangiocarcinoma: A clinicopathological update. World J Hepatol 2024; 16:766-775. [PMID: 38818284 PMCID: PMC11135265 DOI: 10.4254/wjh.v16.i5.766] [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: 12/04/2023] [Revised: 01/31/2024] [Accepted: 04/09/2024] [Indexed: 05/22/2024] Open
Abstract
Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer associated with an appalling prognosis. The diagnosis and management of this entity have been challenging to physicians, radiologists, surgeons, pathologists, and oncologists alike. The diagnostic and prognostic value of biomarkers such as the immunohistochemical expression of nestin, a progenitor cell marker, have been explored recently. With a better understanding of biology and the clinical course of cHCC-CCA, newer treatment modalities like immune checkpoint inhibitors are being tried to improve the survival of patients with this rare disease. In this review, we give an account of the recent developments in the pathology, diagnostic approach, and management of cHCC-CCA.
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Affiliation(s)
- Mukul Vij
- Department of Pathology, Institute of Liver Disease and Transplantation, Chennai 600044, India
| | - Fadl H Veerankutty
- Comprehensive Liver Care Institute, VPS Lakeshore, Cochin 682040, India
- Institute of Liver Disease and Transplantation, Dr. Rela Institute and Medical Centre, Chennai 600044, India.
| | - Ashwin Rammohan
- Institute of Liver Disease and Transplantation, Dr. Rela Institute and Medical Centre, Chennai 600044, India
| | - Mohamed Rela
- Institute of Liver Disease and Transplantation, Dr. Rela Institute and Medical Centre, Chennai 600044, India
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Wang X, Wang X. The regulation of hypoxia-related lncRNAs in hepatocellular carcinoma. Discov Oncol 2024; 15:144. [PMID: 38713276 PMCID: PMC11076439 DOI: 10.1007/s12672-024-01002-3] [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: 12/04/2023] [Accepted: 04/30/2024] [Indexed: 05/08/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is still a public health disease with its high prevalence and morbidity. Short of early diagnosis biomarkers and effective therapy, the treatment of HCC patients hasn't achieved ideal effect. Hypoxia is a hallmark of HCC, which is mainly induced by imbalance of tumor cell proliferation and insufficient supply of oxygen. Recently, amounting evidence suggested lncRNAs, especially hypoxia-related lncRNAs play a pivotal role in regulating HCC. Hypoxia-related lncRNAs are involved in altering glucose metabolism, maintaining of cancer stem cell-like properties (CSCs), cell apotosis, proliferation and immune escape, which all contribute to the poor prognosis of HCC patients. The novel identified hypoxia-related lncRNAs could be the potential target or biomarkers of HCC, which are beneficial to the clinical treatment. Herein, we summarized currently reported hypoxia-related lncRNAs and their related mechanisms, providing potential application and future perspective of hypoxia-related lncRNAs as a potential therapeutic target.
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Affiliation(s)
- Xuejing Wang
- Department of Integrated Traditional Chinese and Western Medicine, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China
| | - Xiaojun Wang
- Department of Integrated Traditional Chinese and Western Medicine, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China.
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10
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Gigante E, Bouattour M, Bedoya JU, Regnault H, Ziol M, Assenat E, Paradis V, Calderaro J, Ganne‐Carrié N, Bouhier‐Leporrier K, Amaddeo G, Nault JC. Atezolizumab and bevacizumab for non-resectable or metastatic combined hepatocellular-cholangiocarcinoma: A multicentric retrospective study. United European Gastroenterol J 2024; 12:429-439. [PMID: 38059651 PMCID: PMC11091777 DOI: 10.1002/ueg2.12503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 10/11/2023] [Indexed: 12/08/2023] Open
Abstract
BACKGROUNDS The efficacy of atezolizumab/bevacizumab has never been reported in patients with metastatic/unresectable combined hepatocellular-cholangiocarcinoma (cHCC-CCA). PATIENTS AND METHODS We retrospectively included patients with a histological diagnosis of unresectable/metastatic cHCC-CCA and treated with atezolizumab/bevacizumab (2020-2022) in 7 centers. Clinical and radiological features were collected at the beginning of atezolizumab/bevacizumab. We reported the radiological response using RECIST criteria, overall survival (OS) and progression-free survival (PFS). RESULTS Sixteen patients with cHCC-CCA were included and were predominantly male (75%) with advanced fibrosis/cirrhosis (69%). Nine patients received atezolizumab/bevacizumab as a first-line systemic treatment, 5 as a second line, 1 as a third line and 1 as a fifth line. Severe digestive bleeding occurred in 2 patients. Among the 9 patients treated in the first line, 4 experienced radiological progression, 3 partial response and 1 had stable disease. Patients treated with atezolizumab/bevacizumab in the first line had a median OS of 13 months and a median PFS of 3 months. Among the 7 patients receiving atezolizumab/bevacizumab as a second line or more, 4 patients harbored a stable disease, 2 a partial response, and 1 a progressive disease. CONCLUSIONS The combination of atezolizumab and bevacizumab showed signs of anti-tumor efficacy in patients with unresectable/metastatic cHCC-CCA.
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Affiliation(s)
- Elia Gigante
- Université de Reims Champagne‐ArdenneCHU ReimsService d'Hépato‐Gastroentérologie et de Cancérologie digestiveReimsFrance
| | - Mohamed Bouattour
- Unité Fonctionnelle Oncologie HépatiqueHôpital BeaujonAP‐HPClichyFrance
| | - José Ursic Bedoya
- Department of HepatogastroenterologyHepatology and Liver Transplantation UnitSaint Eloi HospitalInstitut de Génétique Moléculaire de MontpellierUniversity of MontpellierCNRSMontpellierFrance
- University of MontpellierMontpellierFrance
| | | | - Marianne Ziol
- Service d'Anatomo‐PathologieHôpital AvicenneAP‐HPBobignyFrance
- Université Sorbonne Paris NordBobigny& INSERM UMR 1138Centre de Recherche des CordeliersUniversité de Paris CitéBobignyFrance
| | - Eric Assenat
- Department of HepatogastroenterologyHepatology and Liver Transplantation UnitSaint Eloi HospitalInstitut de Génétique Moléculaire de MontpellierUniversity of MontpellierCNRSMontpellierFrance
- University of MontpellierMontpellierFrance
| | - Valérie Paradis
- Service d'Anatomo‐PathologieHôpital BeaujonAP‐HPClichyFrance
- Centre de recherche sur l'inflammationInsermUniversité de ParisINSERM UMR 1149 « De l'inflammation au cancer »ClichyFrance
| | - Julien Calderaro
- Université Paris Est CréteilINSERMIMRBCréteilFrance
- Department of PathologyAssistance Publique‐Hôpitaux de ParisHenri Mondor‐Albert Chenevier University HospitalCréteilFrance
- InsermU955CréteilFrance
| | - Nathalie Ganne‐Carrié
- Service d'hépatologieHôpital AvicenneAP‐HPBobignyFrance
- Université Sorbonne Paris NordBobignyFrance
- INSERM UMR 1138Centre de Recherche des CordeliersUniversité de Paris CitéBobignyFrance
| | - Karine Bouhier‐Leporrier
- Service d'Hépato‐Gastroentérologie et de Cancérologie digestiveCHU Normandie côte de NacreCaenFrance
| | | | - Jean Charles Nault
- Service d'hépatologieHôpital AvicenneAP‐HPBobignyFrance
- Université Sorbonne Paris NordBobignyFrance
- INSERM UMR 1138Centre de Recherche des CordeliersUniversité de Paris CitéBobignyFrance
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11
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Zhu JQ, Zhu Y, Qi M, Zeng Y, Liu ZJ, Ding C, Zhang T, Li XL, Han DD, He Q. Granzyme B+ B cells detected by single-cell sequencing are associated with prognosis in patients with intrahepatic cholangiocarcinoma following liver transplantation. Cancer Immunol Immunother 2024; 73:58. [PMID: 38386050 PMCID: PMC10884120 DOI: 10.1007/s00262-023-03609-x] [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: 09/26/2023] [Accepted: 12/05/2023] [Indexed: 02/23/2024]
Abstract
B cells possess anti-tumor functions mediated by granzyme B, in addition to their role in antigen presentation and antibody production. However, the variations in granzyme B+ B cells between tumor and non-tumor tissues have been largely unexplored. Therefore, we integrated 25 samples from the Gene Expression Omnibus database and analyzed the tumor immune microenvironment. The findings uncovered significant inter- and intra-tumoral heterogeneity. Notably, single-cell data showed higher proportions of granzyme B+ B cells in tumor samples compared to control samples, and these levels were positively associated with disease-free survival. The elevated levels of granzyme B+ B cells in tumor samples resulted from tumor cell chemotaxis through the MIF- (CD74 + CXCR4) signaling pathway. Furthermore, the anti-tumor function of granzyme B+ B cells in tumor samples was adversely affected, potentially providing an explanation for tumor progression. These findings regarding granzyme B+ B cells were further validated in an independent clinic cohort of 40 liver transplant recipients with intrahepatic cholangiocarcinoma. Our study unveils an interaction between granzyme B+ B cells and intrahepatic cholangiocarcinoma, opening up potential avenues for the development of novel therapeutic strategies against this disease.
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Affiliation(s)
- Ji-Qiao Zhu
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020, People's Republic of China
| | - Ying Zhu
- Department of Clinical Psychology, Mental Hospital of Jianqu Administration Bureau of Jiangsu Province, Nanjing, 210031, Jiangsu, People's Republic of China
| | - Man Qi
- Pathology Department, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, People's Republic of China
| | - Ye Zeng
- Clinical Lab, Tongji Medical College, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Huazhong University of Science & Technology, Wuhan, 430070, Hubei, People's Republic of China
| | - Zhen-Jia Liu
- Department of Infectious Diseases and Clinical Microbiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, People's Republic of China
| | - Cheng Ding
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020, People's Republic of China
| | - Tao Zhang
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020, People's Republic of China
| | - Xian-Liang Li
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020, People's Republic of China
| | - Dong-Dong Han
- Department of Hepatobiliary Surgery, China-Japan Friendship Hospital, No. 2 Yinghua East Street, Chaoyang District, Beijing, 100029, People's Republic of China.
| | - Qiang He
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020, People's Republic of China.
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12
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Zhang M, Zhang S, Guo W, He Y. Novel molecular hepatocellular carcinoma subtypes and RiskScore utilizing apoptosis-related genes. Sci Rep 2024; 14:3913. [PMID: 38365931 PMCID: PMC10873508 DOI: 10.1038/s41598-024-54673-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Accepted: 02/15/2024] [Indexed: 02/18/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of global cancer-related deaths. Despite immunotherapy offering hope for patients with HCC, only some respond to it. However, it remains unclear how to pre-screen eligible patients. Our study aimed to address this issue. In this study, we identified 13 prognostic genes through univariate Cox regression analysis of 87 apoptosis-related genes. Subsequently, these 13 genes were analyzed using ConsensusClusterPlus, and patients were categorized into three molecular types: C1, C2, and C3. A prognostic model and RiskScore were constructed using Lasso regression analysis of 132 significant genes identified between C1 and C3. We utilized quantitative polymerase chain reaction to confirm the model's transcript level in Huh7 and THLE2 cell lines. Both molecular subtypes and RiskScores effectively predicted patients benefiting from immunotherapy. Cox regression analysis revealed RiskScore as the most significant prognosis factor, suggesting its clinical application potential and providing a foundation for future experimental research.
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Affiliation(s)
- Menggang Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Open and Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
| | - Shuijun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Open and Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
| | - Wenzhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
- Open and Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China.
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China.
| | - Yuting He
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
- Open and Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China.
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China.
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13
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Chen Y, Yang Y, Wang N, Liu R, Wu Q, Pei H, Li W. β-Sitosterol suppresses hepatocellular carcinoma growth and metastasis via FOXM1-regulated Wnt/β-catenin pathway. J Cell Mol Med 2024; 28:e18072. [PMID: 38063438 PMCID: PMC10844700 DOI: 10.1111/jcmm.18072] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 11/20/2023] [Accepted: 11/24/2023] [Indexed: 02/08/2024] Open
Abstract
β-Sitosterol is a natural compound with demonstrated anti-cancer properties against various cancers. However, its effects on hepatocellular carcinoma (HCC) and the underlying mechanisms are not well understood. This study aims to investigate the impact of β-sitosterol on HCC. In this study, we investigated the effects of β-sitosterol on HCC tumour growth and metastasis using a xenograft mouse model and a range of molecular analyses, including bioinformatics, real-time PCR, western blotting, lentivirus transfection, CCK8, scratch and transwell assays. The results found that β-sitosterol significantly inhibits HepG2 cell proliferation, migration and invasion both in vitro and in vivo. Bioinformatics analysis identifies forkhead box M1 (FOXM1) as a potential target for β-sitosterol in HCC treatment. FOXM1 is upregulated in HCC tissues and cell lines, correlating with poor prognosis in patients. β-Sitosterol downregulates FOXM1 expression in vitro and in vivo. FOXM1 overexpression mitigates β-sitosterol's inhibitory effects on HepG2 cells. Additionally, β-sitosterol suppresses epithelial-mesenchymal transition (EMT) in HepG2 cells, while FOXM1 overexpression promotes EMT. Mechanistically, β-sitosterol inhibits Wnt/β-catenin signalling by downregulating FOXM1, regulating target gene transcription related to HepG2 cell proliferation and metastasis. β-Sitosterol shows promising potential as a therapeutic candidate for inhibiting HCC growth and metastasis through FOXM1 downregulation and Wnt/β-catenin signalling inhibition.
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Affiliation(s)
- Yuankun Chen
- Department of Infectious and Tropical DiseasesThe Second Affiliated Hospital of Hainan Medical UniversityHaikouHainanChina
- Key Laboratory of Tropical Translational Medicine of Ministry of HealthHainan Medical UniversityHaikouHainanChina
- Department of Clinical LaboratoryThe Second Affiliated Hospital of Hainan Medical UniversityHaikouHainanChina
| | - Yijun Yang
- Department of Infectious and Tropical DiseasesThe Second Affiliated Hospital of Hainan Medical UniversityHaikouHainanChina
- Key Laboratory of Tropical Translational Medicine of Ministry of HealthHainan Medical UniversityHaikouHainanChina
| | - Nengyi Wang
- Department of Infectious and Tropical DiseasesThe Second Affiliated Hospital of Hainan Medical UniversityHaikouHainanChina
- Key Laboratory of Tropical Translational Medicine of Ministry of HealthHainan Medical UniversityHaikouHainanChina
| | - Rui Liu
- Department of Infectious and Tropical DiseasesThe Second Affiliated Hospital of Hainan Medical UniversityHaikouHainanChina
- Key Laboratory of Tropical Translational Medicine of Ministry of HealthHainan Medical UniversityHaikouHainanChina
| | - Qiuping Wu
- Department of Infectious and Tropical DiseasesThe Second Affiliated Hospital of Hainan Medical UniversityHaikouHainanChina
- Key Laboratory of Tropical Translational Medicine of Ministry of HealthHainan Medical UniversityHaikouHainanChina
| | - Hua Pei
- Department of Infectious and Tropical DiseasesThe Second Affiliated Hospital of Hainan Medical UniversityHaikouHainanChina
- Key Laboratory of Tropical Translational Medicine of Ministry of HealthHainan Medical UniversityHaikouHainanChina
- Department of Clinical LaboratoryThe Second Affiliated Hospital of Hainan Medical UniversityHaikouHainanChina
| | - Wenting Li
- Department of Infectious and Tropical DiseasesThe Second Affiliated Hospital of Hainan Medical UniversityHaikouHainanChina
- Key Laboratory of Tropical Translational Medicine of Ministry of HealthHainan Medical UniversityHaikouHainanChina
- Department of Infectious DiseasesThe First Affiliated Hospital of Anhui Medical UniversityHefeiAnhuiChina
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14
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Amory B, Goumard C, Laurent A, Langella S, Cherqui D, Salame E, Barbier L, Soubrane O, Farges O, Hobeika C, Kawai T, Regimbeau JM, Faitot F, Pessaux P, Truant S, Boleslawski E, Herrero A, Mabrut JY, Chiche L, Di Martino M, Rhaiem R, Schwarz L, Resende V, Calderaro J, Augustin J, Caruso S, Sommacale D, Hofmeyr S, Ferrero A, Fuks D, Vibert E, Torzilli G, Scatton O, Brustia R. Combined hepatocellular-cholangiocarcinoma compared to hepatocellular carcinoma and intrahepatic cholangiocarcinoma: Different survival, similar recurrence: Report of a large study on repurposed databases with propensity score matching. Surgery 2024; 175:413-423. [PMID: 37981553 DOI: 10.1016/j.surg.2023.09.040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 09/06/2023] [Accepted: 09/26/2023] [Indexed: 11/21/2023]
Abstract
BACKGROUND Combined hepatocholangiocarcinoma is a rare cancer with a grim prognosis composed of both hepatocellular carcinoma and intrahepatic cholangiocarcinoma morphologic patterns in the same tumor. The aim of this multicenter, international cohort study was to compare the oncologic outcomes after surgery of combined hepatocholangiocarcinoma to hepatocellular carcinoma and intrahepatic cholangiocarcinoma. METHODS Patients treated by surgery for combined hepatocholangiocarcinoma, hepatocellular carcinoma, and intrahepatic cholangiocarcinoma from 2000 to 2021 from multicenter international databases were analyzed retrospectively. Patients with combined hepatocholangiocarcinoma (cases) were compared with 2 control groups of hepatocellular carcinoma or intrahepatic cholangiocarcinoma, sequentially matched using a propensity score based on 8 preoperative characteristics. Overall and disease-free survival were compared, and predictors of mortality and recurrence were analyzed with Cox regression after propensity score matching. RESULTS During the study period, 3,196 patients were included. Propensity score adjustment and 2 sequential matching processes produced a new cohort (n = 244) comprising 3 balanced groups was obtained (combined hepatocholangiocarcinoma = 56, intrahepatic cholangiocarcinoma = 66, and hepatocellular carcinoma = 122). Kaplan-Meier overall survival estimations at 1, 3, and 5 years were 67%, 45%, and 28% for combined hepatocholangiocarcinoma, 92%, 75%, and 55% for hepatocellular carcinoma, and 86%, 53%, and 42% for the intrahepatic cholangiocarcinoma group, respectively (P = .0014). Estimations of disease-free survival at 1, 3, and 5 years were 51%, 25%, and 17% for combined hepatocholangiocarcinoma, 63%, 35%, and 26% for the hepatocellular carcinoma group, and 51%, 31%, and 28% for the intrahepatic cholangiocarcinoma group, respectively (P = .19). Predictors of mortality were combined hepatocholangiocarcinoma subtype, metabolic syndrome, preoperative tumor markers alpha-fetoprotein and carbohydrate antigen 19-9, and satellite nodules, and recurrence was associated with satellite nodules rather than cancer subtype. CONCLUSION Despite data limitations, overall survival among patients with combined hepatocholangiocarcinoma was worse than both groups and closer intrahepatic cholangiocarcinoma, whereas disease-free survival was similar among the 3 groups. Future research on immunophenotypic profiling may hold more promise than traditional nonmodifiable clinical characteristics (as found in this study) in predicting recurrence or response to salvage treatments.
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Affiliation(s)
- Boris Amory
- Department of Digestive and Hepato-pancreatic-biliary Surgery, AP-HP, Hôpital Henri-Mondor, Paris Est Créteil University, UPEC, France; Assistance Publique-Hôpitaux de Paris, Créteil, France
| | - Claire Goumard
- Department of Hepatobiliary and Liver Transplantation Surgery, AP-HP, Hôpital Pitié Salpêtrière, CRSA, Sorbonne Université, Paris, France
| | - Alexis Laurent
- Department of Digestive and Hepato-pancreatic-biliary Surgery, DMU CARE, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Henri Mondor, Créteil, France; Paris Est Créteil University, UPEC, France; Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers," INSERM U955, Créteil, France; Assistance Publique-Hôpitaux de Paris, Créteil, France
| | - Serena Langella
- Department of General and Oncological Surgery, Ospedale Mauriziano, Torino, Italy
| | - Daniel Cherqui
- Center Hepato-Biliaire, AP-HP Paul Brousse Hospital, Paris-Saclay University, Villejuif, France
| | - Ephrem Salame
- Department of Digestive Surgery and Liver Transplantation, University Hospital of Tours, University of Tours, France; FHU Support, Tours, France
| | - Louise Barbier
- Department of Digestive Surgery and Liver Transplantation, University Hospital of Tours, University of Tours, France; FHU Support, Tours, France
| | - Olivier Soubrane
- Department of Digestive, Oncological, and Metabolic Surgery, Institut Mutualiste Montsouris, Paris, France
| | - Olivier Farges
- Department of HPB Surgery and Liver Transplantation, AP-HP Beaujon Hospital, University of Paris, Clichy, France
| | - Christian Hobeika
- Department of HPB Surgery and Liver Transplantation, AP-HP Beaujon Hospital, University of Paris, Clichy, France
| | - Takayuki Kawai
- Department of Surgery, Medical Research Institute, Kitano Hospital, Osaka and Graduate School of Medicine, Kyoto University, Japan
| | - Jean-Marc Regimbeau
- SSPC (Simplification of Surgical Patients Care) - Clinical Research Unit, University of Picardie Jules Verne, Amiens, France; Department of Digestive Surgery, Amiens University Medical Center, France
| | - François Faitot
- Service de Chirurgie Hépato-Biliaire et Transplantation Hépatique, Hôpital de Hautepierre, Strasbourg, France
| | - Patrick Pessaux
- Unité Chirurgie HBP, Pôle hépato-digestif Nouvel Hôpital Civil, Strasbourg, France; Institut of Viral and Liver Disease, Inserm U1110, Strasbourg, France
| | - Stéphanie Truant
- Department of Digestive Surgery and Transplantation, University Hospitals, Lille, France
| | - Emmanuel Boleslawski
- Department of Digestive Surgery and Transplantation, University Hospitals, Lille, France
| | - Astrid Herrero
- Department of HBP Surgery and Liver Transplantation, Montpellier University Hospital, University of Montpellier, France
| | - Jean-Yves Mabrut
- Croix Rousse University Hospital, Department of General Surgery and Liver Transplantation, Lyon, France; Cancer Research Center of Lyon, INSERM U1052, France
| | - Laurence Chiche
- Department of Hepato-Bilio-Pancreatic Surgery and Liver Transplantation, Haut Lévêque Hospital, Center Hospitalier Universitaire de Bordeaux, France; Inserm UMR 1312-Team 3 "Liver Cancers and Tumoral Invasion," Bordeaux Institute of Oncology, University of Bordeaux, France
| | - Marcello Di Martino
- HPB Unit, Department of General and Digestive Surgery, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid (UAM), Madrid, Spain
| | - Rami Rhaiem
- Department of Hepatobiliary, Pancreatic, and Digestive Surgery, Robert Debré University Hospital, Reims, France; University Reims Champagne-Ardenne, France
| | - Lilian Schwarz
- Department of Genomic and Personalized Medicine in Cancer and Neurological Disorders, Rouen University Hospital, UNIROUEN, UMR 1245 INSERM, Normandie Rouen University, France
| | - Vivian Resende
- Federal University of Minas Gerais School of Medicine, Belo Horizonte, Brazil
| | - Julien Calderaro
- Université Paris Est Créteil, INSERM, IMRB, Créteil, France; Assistance Publique-Hôpitaux de Paris, Henri Mondor-Albert Chenevier University Hospital, Department of Pathology, Créteil, France; Inserm, U955, Team 18, Créteil, France
| | - Jérémy Augustin
- Université Paris Est Créteil, INSERM, IMRB, Créteil, France; Assistance Publique-Hôpitaux de Paris, Henri Mondor-Albert Chenevier University Hospital, Department of Pathology, Créteil, France; Inserm, U955, Team 18, Créteil, France
| | - Stefano Caruso
- Université Paris Est Créteil, INSERM, IMRB, Créteil, France; Assistance Publique-Hôpitaux de Paris, Henri Mondor-Albert Chenevier University Hospital, Department of Pathology, Créteil, France; Inserm, U955, Team 18, Créteil, France
| | - Daniele Sommacale
- Department of Digestive and Hepato-pancreatic-biliary Surgery, DMU CARE, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Henri Mondor, Créteil, France; Paris Est Créteil University, UPEC, Créteil, France; Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers," INSERM U955, Créteil, France; Assistance Publique-Hôpitaux de Paris, Créteil, France
| | - Stefan Hofmeyr
- Division of Surgery, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Academic Hospital, Cape Town, South Africa
| | - Alessandro Ferrero
- Department of General and Oncological Surgery, Ospedale Mauriziano, Torino, Italy
| | - David Fuks
- Department of Hepato-Pancreatic-Biliary and Endocrine Surgery, Hopital Cochin, Assistance Publique-Hôpitaux de Paris, France; Université Paris Cité, France
| | - Eric Vibert
- Center Hepato-Biliaire, AP-HP Paul Brousse Hospital, Paris-Saclay University, Villejuif, France
| | - Guido Torzilli
- Division of Hepatobiliary and General Surgery, Department of Surgery, Humanitas Research Hospital - IRCCS, Humanitas University, Rozzano, Milan, Italy
| | - Olivier Scatton
- Department of Hepatobiliary and Liver Transplantation Surgery, AP-HP, Hôpital Pitié Salpêtrière, CRSA, Sorbonne Université, Paris, France
| | - Raffaele Brustia
- Department of Digestive and Hepato-pancreatic-biliary Surgery, DMU CARE, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Henri Mondor, Créteil, France; Paris Est Créteil University, UPEC, France; Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers," INSERM U955, Créteil, France; Assistance Publique-Hôpitaux de Paris, Créteil, France.
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15
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Ye L, Schneider JS, Ben Khaled N, Schirmacher P, Seifert C, Frey L, He Y, Geier A, De Toni EN, Zhang C, Reiter FP. Combined Hepatocellular-Cholangiocarcinoma: Biology, Diagnosis, and Management. Liver Cancer 2024; 13:6-28. [PMID: 38344449 PMCID: PMC10857821 DOI: 10.1159/000530700] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 04/03/2023] [Indexed: 01/04/2025] Open
Abstract
BACKGROUND Combined hepatocellular-cholangiocarcinoma (cHCC-iCCA) is a rare type of primary liver cancer displaying characteristics of both hepatocytic and cholangiocytic differentiation. SUMMARY Because of its aggressive nature, patients with cHCC-iCCA exhibit a poorer prognosis than those with HCC. Surgical resection and liver transplantation may be considered curative treatment approaches; however, only a minority of patients are eligible at the time of diagnosis, and postoperative recurrence rates are high. For cases that are not eligible for surgery, locoregional and systemic therapy are often administered based on treatment protocols applied for HCC or iCCA. Owing to the rarity of this cancer, there are still no established standard treatment protocols; therefore, the choice of therapy is often personalized and guided by the suspected predominant component. Further, the genomic and molecular heterogeneity of cHCC-iCCA can severely compromise the efficacy of the available therapies. KEY MESSAGES In the present review, we summarize the latest advances in cHCC-iCCA and attempt to clarify its terminology and molecular biology. We provide an overview of the etiology of cHCC-iCCA and present new insights into the molecular pathology of this disease that could contribute to further studies aiming to improve the patient outcomes through new systemic therapies.
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Affiliation(s)
- Liangtao Ye
- Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Julia S. Schneider
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Najib Ben Khaled
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | | | - Carolin Seifert
- Institute for Pathology, University Würzburg, Würzburg, Germany
| | - Lea Frey
- Institute for Pathology, University Würzburg, Würzburg, Germany
| | - Yulong He
- Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Andreas Geier
- Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Germany
| | - Enrico N. De Toni
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Changhua Zhang
- Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Florian P. Reiter
- Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Germany
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16
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Lv TR, Hu HJ, Ma WJ, Liu F, Jin YW, Li FY. Meta-analysis of prognostic factors for overall survival and disease-free survival among resected patients with combined hepatocellular carcinoma and cholangiocarcinoma. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2024; 50:107279. [PMID: 38000116 DOI: 10.1016/j.ejso.2023.107279] [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: 06/14/2023] [Revised: 11/09/2023] [Accepted: 11/15/2023] [Indexed: 11/26/2023]
Abstract
BACKGROUND Combined hepatocellular carcinoma and cholangiocarcinoma (CHCC-CC) is a rare subtype of primary liver malignancy and has been treated equally as intra-hepatic cholangiocarcinoma (IHCC) according to the 8th AJCC staging system. Owing to its rarity, its prognostic factors have been rarely explored and defined. METHODS PubMed, EMBASE, the Cochrane Library and Web of Science were searched up till January 1st, 2023 and eligible studies were restricted to studies reported prognostic factors of resected CHCC-CC. Standard Parmar modifications were used to determine pooled univariable hazard ratios (HRs). RESULTS A total of eleven studies with 1286 patients with resected classical CHCC-CC were finally included. Pooled results indicated that serum tumor biomarkers, including AFP, CA199, and CEA, were prognostic factors for postoperative overall survival (OS) and disease-free survival (DFS). Moreover, liver cirrhosis (P = 0.010), HBV infection (P = 0.030), and HCV infection (P < 0.001) were prognostic factors for OS. Age (HR = 1.03, P = 0.005) was a prognostic factor for DFS. Tumor size (OS: HR = 2, P < 0.001, DFS: HR = 2.15, P < 0.001), tumor number (OS: HR = 2.05, P < 0.001; DFS: HR = 1.96, P = 0.006), surgical margin (OS: HR = 2.33, <0.001001; DFS: HR = 2.35, P < 0.001), node metastasis (OS: HR = 2.96, P < 0.001; DFS: HR = 2.1, P < 0.001), vascular invasion (OS: HR = 2.17, P < 0.001; DFS: HR = 2.64, P < 0.001), and postoperative prophylactic trans-arterial chemotherapy embolization (PPTACE) (OS: HR = 1.67, P = 0.04; DFS: HR = 2.31, P < 0.001) were common prognostic factors for OS and DFS. CONCLUSION Various risk factors unmentioned in the 8th AJCC staging system were identified. These promising findings would facilitate a more personalized predictive model and help clinicians to stratify patients with different survival outcomes.
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Affiliation(s)
- Tian-Run Lv
- Department of Biliary Tract Surgery, General Surgrey, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Hai-Jie Hu
- Department of Biliary Tract Surgery, General Surgrey, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Wen-Jie Ma
- Department of Biliary Tract Surgery, General Surgrey, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Fei Liu
- Department of Biliary Tract Surgery, General Surgrey, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Yan-Wen Jin
- Department of Biliary Tract Surgery, General Surgrey, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Fu-Yu Li
- Department of Biliary Tract Surgery, General Surgrey, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China.
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Mei XC, Chen Q, Zuo S. Transient receptor potential-related risk model predicts prognosis of hepatocellular carcinoma patients. World J Gastrointest Oncol 2023; 15:2064-2076. [PMID: 38173438 PMCID: PMC10758653 DOI: 10.4251/wjgo.v15.i12.2064] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 10/17/2023] [Accepted: 11/10/2023] [Indexed: 12/14/2023] Open
Abstract
BACKGROUND Members of the transient receptor potential (TRP) protein family shape oncogenic development, but the specific relevance of TRP-related genes in hepatocellular carcinoma (HCC) has yet to be defined. AIM To investigate the role of TRP genes in HCC, their association with HCC development and treatment was examined. METHODS HCC patient gene expression and clinical data were downloaded from The Cancer Genome Atlas database, and univariate and least absolute shrinkage and selection operator Cox regression models were employed to explore the TRP-related risk spectrum. Based on these analyses, clinically relevant TRP family genes were selected, and the association between the key TRP canonical type 1 (TRPC1) gene and HCC patient prognosis was evaluated. RESULTS In total, 28 TRP family genes were screened for clinical relevance, with multivariate analyses ultimately revealing three of these genes (TRPC1, TRP cation channel subfamily M member 2, and TRP cation channel subfamily M member 6) to be significantly associated with HCC patient prognosis (P < 0.05). These genes were utilized to establish a TRP-related risk model. Patients were separated into low- and high-risk groups based on the expression of these genes, and high-risk patients exhibited a significantly poorer prognosis (P = 0.001). Functional analyses highlighted pronounced differences in the immune status of patients in these two groups and associated enriched immune pathways. TRPC1 was identified as a candidate gene in this family worthy of further study, with HCC patients expressing higher TRPC1 levels exhibiting poorer survival outcomes. Consistently, quantitative, immunohistochemistry, and western blot analyses revealed increased TRPC1 expression in HCC. CONCLUSION These three TRP genes help determine HCC patient prognosis, providing insight into tumor immune status and immunological composition. These findings will help design combination therapies including immunotherapeutic and anti-TRP agents.
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Affiliation(s)
- Xiao-Cai Mei
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang 550000, Guizhou Province, China
| | - Qian Chen
- Department of Organ Transplantation, Affiliated Hospital of Guizhou Medical University, Guiyang 550000, Guizhou Province, China
| | - Shi Zuo
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang 550000, Guizhou Province, China
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Yi S, Zhang C, Li M, Qu T, Wang J. Machine learning and experiments identifies SPINK1 as a candidate diagnostic and prognostic biomarker for hepatocellular carcinoma. Discov Oncol 2023; 14:231. [PMID: 38093163 PMCID: PMC10719188 DOI: 10.1007/s12672-023-00849-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 12/08/2023] [Indexed: 12/17/2023] Open
Abstract
Machine learning techniques have been widely used in predicting disease prognosis, including cancer prognosis. One of the major challenges in cancer prognosis is to accurately classify cancer types and stages to optimize early screening and detection, and machine learning techniques have proven to be very useful in this regard. In this study, we aimed at identifying critical genes for diagnosis and outcomes of hepatocellular carcinoma (HCC) patients using machine learning. The HCC expression dataset was downloaded from GSE65372 datasets and TCGA datasets. Differentially expressed genes (DEGs) were identified between 39 HCC and 15 normal samples. For the purpose of locating potential biomarkers, the LASSO and the SVM-RFE assays were performed. The ssGSEA method was used to analyze the TCGA to determine whether there was an association between SPINK1 and tumor immune infiltrates. RT-PCR was applied to examine the expression of SPINK1 in HCC specimens and cells. A series of functional assays were applied to examine the function of SPINK1 knockdown on the proliferation of HCC cells. In this study, 103 DEGs were obtained. Based on LASSO and SVM-RFE analysis, we identified nine critical diagnostic genes, including C10orf113, SPINK1, CNTLN, NRG3, HIST1H2AI, GPRIN3, SCTR, C2orf40 and PITX1. Importantly, we confirmed SPINK1 as a prognostic gene in HCC. Multivariate analysis confirmed that SPINK1 was an independent prognostic factor for overall survivals of HCC patients. We also found that SPINK1 level was positively associated with Macrophages, B cells, TFH, T cells, Th2 cells, iDC, NK CD56bright cells, Th1 cells, aDC, while negatively associated with Tcm and Eosinophils. Finally, we demonstrated that SPINK1 expression was distinctly increased in HCC specimens and cells. Functionally, silence of SPINK1 distinctly suppressed the proliferation of HCC cells via regulating Wnt/β-catenin pathway. The evidence provided suggested that SPINK1 may possess oncogenic properties by inducing dysregulated immune infiltration in HCC. Additionally, SPINK1 was identified as a novel biomarker and therapeutic target for HCC.
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Affiliation(s)
- Shiming Yi
- Department of Hepatobiliary Surgery, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China
| | - Chunlei Zhang
- Department of Colorectal and Anus Surgery, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China
| | - Ming Li
- Department of Gastroenterology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China
| | - Tianyi Qu
- Emergency Department, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China
| | - Jiafeng Wang
- Department of Hepatobiliary Surgery, the Affiliated Taian City Central Hospital of Qingdao University, Taian, China.
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Tang J, Long G, Xiao D, Liu S, Xiao L, Zhou L, Tao Y. ATR-dependent ubiquitin-specific protease 20 phosphorylation confers oxaliplatin and ferroptosis resistance. MedComm (Beijing) 2023; 4:e463. [PMID: 38124786 PMCID: PMC10732327 DOI: 10.1002/mco2.463] [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: 06/14/2023] [Revised: 12/02/2023] [Accepted: 12/04/2023] [Indexed: 12/23/2023] Open
Abstract
Oxaliplatin (OXA) resistance is a major clinic challenge in hepatocellular carcinoma (HCC). Ferroptosis is a kind of iron-dependent cell death. Triggering ferroptosis is considered to restore sensitivity to chemotherapy. In the present study, we found that USP20 was overexpressed in OXA-resistant HCC cells. High expression of USP20 in HCC was associated with poor prognosis. USP20 contributes OXA resistance and suppress ferroptosis in HCC. Pharmacological inhibition or knockdown of USP20 triggered ferroptosis and increased the sensitivity of HCC cells to OXA both in vitro and in vivo. Coimmunoprecipitation results revealed that the UCH domain of USP20 interacted with the N terminal of SLC7A11. USP20 stabilized SLC7A11 via removing K48-linked polyubiquitination of SLC7A11 protein at K30 and K37. Most importantly, DNA damage-induced ATR activation was required for Ser132 and Ser368 phosphorylation of USP20. USP20 phosphorylation at Ser132 and Ser368 enhanced its stability and thus conferred OXA and ferroptosis resistance of HCC cells. Our study reveals a previously undiscovered association between OXA and ferroptosis and provides new insight into mechanisms regarding how DNA damage therapies always lead to therapeutic resistance. Therefore, targeting USP20 may mitigate the development of drug resistance and promote ferroptosis of HCC in patients receiving chemotherapy.
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Affiliation(s)
- Jianing Tang
- Department of Liver SurgeryXiangya HospitalCentral South UniversityChangshaHunanChina
- National Clinical Research Center for Geriatric DisordersXiangya HospitalCentral South UniversityChangshaHunanChina
| | - Guo Long
- Department of Liver SurgeryXiangya HospitalCentral South UniversityChangshaHunanChina
| | - Desheng Xiao
- Department of PathologyXiangya HospitalCentral South UniversityChangshaHunanChina
| | - Shuang Liu
- Department of OncologyInstitute of Medical SciencesNational Clinical Research Center for Geriatric DisordersXiangya HospitalCentral South UniversityChangshaHunanChina
| | - Liang Xiao
- Department of Liver SurgeryXiangya HospitalCentral South UniversityChangshaHunanChina
| | - Ledu Zhou
- Department of Liver SurgeryXiangya HospitalCentral South UniversityChangshaHunanChina
| | - Yongguang Tao
- Department of PathologyKey Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education)Xiangya HospitalCentral South UniversityHunanChina
- Cancer Research Institute and School of Basic MedicineNHC Key Laboratory of Carcinogenesis (Central South University)Central South UniversityChangshaHunanChina
- Department of Thoracic SurgeryHunan Key Laboratory of Early Diagnosis and Precision Therapy in Lung Cancer and Hunan Key Laboratory of Tumor Models and Individualized MedicineSecond Xiangya HospitalCentral South UniversityChangshaHunanChina
- Hunan Key Laboratory of Cancer MetabolismHunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangshaHunanChina
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Koksal AR, Ekmen N, Aydin Y, Nunez K, Sandow T, Delk M, Moehlen M, Thevenot P, Cohen A, Dash S. A Single-Step Immunocapture Assay to Quantify HCC Exosomes Using the Highly Sensitive Fluorescence Nanoparticle-Tracking Analysis. J Hepatocell Carcinoma 2023; 10:1935-1954. [PMID: 37936599 PMCID: PMC10627088 DOI: 10.2147/jhc.s423043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 10/07/2023] [Indexed: 11/09/2023] Open
Abstract
Introduction Extracellular vesicles could serve as a non-invasive biomarker for early cancer detection. However, limited methods to quantitate cancer-derived vesicles in the native state remain a significant barrier to clinical translation. Aim This research aims to develop a rapid, one-step immunoaffinity approach to quantify HCC exosomes directly from a small serum volume. Methods HCC-derived exosomes in the serum were captured using fluorescent phycoerythrin (PE)-conjugated antibodies targeted to GPC3 and alpha-fetoprotein (AFP). Total and HCC-specific exosomes were then quantified in culture supernatant or patient-derived serums using fluorescence nanoparticle tracking analysis (F-NTA). The performance of HCC exosome quantification in the serum was compared with the tumor size determined by MRI. Results Initially we tested the detection limits of the F-NTA using synthetic fluorescent and non-fluorescent beads. The assay showed an acceptable sensitivity with a detection range of 104-108 particles/mL. Additionally, the combination of immunocapture followed by size-exclusion column purification allows the isolation of smaller-size EVs and quantification by F-NTA. Our assay demonstrated that HCC cell culture releases a significantly higher quantity of GPC3 or GPC3+AFP positive EVs (100-200 particles/cell) compared to non-HCC culture (10-40 particles/cell) (p<0.01 and p<0.05 respectively). The F-NTA enables absolute counting of HCC-specific exosomes in the clinical samples with preserved biological immunoreactivity. The performance of F-NTA was clinically validated in serum from patients ± cirrhosis and with confirmed HCC. F-NTA quantification data show selective enrichment of AFP and GPC3 positive EVs in HCC serum compared to malignancy-free cirrhosis (AUC values for GPC3, AFP, and GPC3/AFP were found 0.79, 0.71, and 0.72 respectively). The MRI-confirmed patient cohort indicated that there was a positive correlation between total tumor size and GPC3-positive exosome concentration (r:0.78 and p<0.001). Conclusion We developed an immunocapture assay that can be used for simultaneous isolation and quantification of HCC-derived exosomes from a small serum volume with high accuracy.
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Affiliation(s)
- Ali Riza Koksal
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA
| | - Nergiz Ekmen
- Department of Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, LA, USA
| | - Yucel Aydin
- Department of Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, LA, USA
| | - Kelley Nunez
- Department of Gastroenterology and Hepatology, Institute of Translational Research, Ochsner Health, New Orleans, LA, USA
| | - Tyler Sandow
- Department of Radiology, Institute of Translational Research, Ochsner Health, New Orleans, LA, USA
| | - Molly Delk
- Department of Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, LA, USA
| | - Martin Moehlen
- Department of Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, LA, USA
| | - Paul Thevenot
- Department of Gastroenterology and Hepatology, Institute of Translational Research, Ochsner Health, New Orleans, LA, USA
| | - Ari Cohen
- Department of Gastroenterology and Hepatology, Institute of Translational Research, Ochsner Health, New Orleans, LA, USA
- Multi-Organ Transplant Institute, Ochsner Health, New Orleans, LA, USA
| | - Srikanta Dash
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA
- Department of Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, LA, USA
- Southeast Louisiana Veterans Health Care System, New Orleans, LA, USA
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Zhu Y, Xiao B, Liu M, Chen M, Xia N, Guo H, Huang J, Liu Z, Wang F. N6-methyladenosine-modified oncofetal lncRNA MIR4435-2HG contributed to stemness features of hepatocellular carcinoma cells by regulating rRNA 2'-O methylation. Cell Mol Biol Lett 2023; 28:89. [PMID: 37891494 PMCID: PMC10612268 DOI: 10.1186/s11658-023-00493-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 09/20/2023] [Indexed: 10/29/2023] Open
Abstract
BACKGROUND The unique expression pattern endows oncofetal genes with great value in cancer diagnosis and treatment. However, only a few oncofetal genes are available for clinical use and the underlying mechanisms that drives the fetal-like reprogramming of cancer cells remain largely unknown. METHODS Microarray assays and bioinformatic analyses were employed to screen for potential oncofetal long non-coding RNAs (lncRNAs) in hepatocellular carcinoma (HCC). The expression levels of MIR4435-2HG, NOP58 ribonucleoprotein (NOP58), insulin like growth factor 2 mRNA binding protein 1 (IGF2BP1) and stem markers were detected by quantitative polymerase chain reaction. The 2'-O-methylation (2'-O-Me) status of rRNA were detected through reverse transcription at low dNTP concentrations followed by PCR. The regulation of MIR4435-2HG by IGF2BP1 was explored by RNA immunoprecipitation (RIP), methylated RIP (MeRIP) and dual-luciferase assays. The interaction between MIR4435-2HG and NOP58 was investigated by RNA Pulldown, RIP and protein stability assays. In vitro and in vivo function assays were performed to detect the roles of MIR4435-2HG/NOP58 in HCC. RESULTS MIR4435-2HG was an oncofetal lncRNA associated with poor prognosis in HCC. Functional experiments showed that overexpression of MIR4435-2HG remarkably enhanced the stem-cell properties of HCC cells, promoting tumorigenesis in vitro and in vivo. Mechanically, MIR4435-2HG directly bound NOP58 and IGF2BP1. IGF2BP1 upregulated MIR4435-2HG expression in HCC through N6-methyladenosine (m6A) modification. Moreover, MIR4435-2HG protected NOP58 from degradation, which raised rRNA 2'-O-Me levels and promoted internal ribosome entry site (IRES)-dependent translation of oncogenes. CONCLUSIONS This study identified an oncofetal lncRNA MIR4435-2HG, characterized the role of MIR4435-2HG/NOP58 in stemness maintenance and proliferation of HCC cells, and confirmed m6A as a 'driver' that reactivated MR4435-2HG expression in HCC.
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Affiliation(s)
- Yiqing Zhu
- Department of Medical Genetics, Naval Medical University, Shanghai, 200433, China
| | - Bang Xiao
- Department of Medical Genetics, Naval Medical University, Shanghai, 200433, China
| | - Meng Liu
- Department of Medical Genetics, Naval Medical University, Shanghai, 200433, China
| | - Meiting Chen
- Department of Medical Genetics, Naval Medical University, Shanghai, 200433, China
| | - Ningqi Xia
- Department of Medical Genetics, Naval Medical University, Shanghai, 200433, China
| | - Haiyan Guo
- Department of Assisted Reproduction, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai, 200011, China
| | - Jinfeng Huang
- Department of Medical Genetics, Naval Medical University, Shanghai, 200433, China.
| | - Zhiyong Liu
- Department of Urology, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, China.
| | - Fang Wang
- Department of Medical Genetics, Naval Medical University, Shanghai, 200433, China.
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Sheng R, Yang C, Zhang Y, Wang H, Zheng B, Han J, Sun W, Zeng M. The significance of the predominant component in combined hepatocellular-cholangiocarcinoma: MRI manifestation and prognostic value. LA RADIOLOGIA MEDICA 2023; 128:1047-1060. [PMID: 37474663 DOI: 10.1007/s11547-023-01682-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Accepted: 07/07/2023] [Indexed: 07/22/2023]
Abstract
PURPOSE To investigate the significance of the predominant component of combined hepatocellular-cholangiocarcinoma (cHCC-CC) in terms of MRI manifestation and its potential prognostic value compared to hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). MATERIALS AND METHODS A total of 300 patients with chronic liver disease from two centers were retrospectively enrolled, including 100 surgically proven cases of cHCC-CC, HCC, and ICC each. Univariate and multivariate regression analyses were performed to identify independent predictors for distinguishing HCC-predominant cHCC-CC and ICC-predominant cHCC-CC from HCC and ICC, respectively. Diagnostic models were constructed based on the independent features. Recurrence-free survival (RFS) was estimated and compared between groups. RESULTS The predominant component was an independent predictor for RFS in cHCC-CC (hazard ratio = 1.957, P = 0.044). The presence of targetoid appearance (odds ratio(OR) = 10.907, P = 0.001), lack of enhancing capsule (OR = 0.072, P = 0.001) and arterial peritumoral enhancement (OR = 0.091, P = 0.003) were independent predictors suggestive of HCC-predominant cHCC-CC over HCC; their combination yielded an area under the curve of 0.756. No significant differences were observed in RFS between HCC-predominant cHCC-CC and HCC (P = 0.864). Male gender (OR = 4.049, P = 0.015), higher alpha fetoprotein (OR = 16.789, P < 0.001) and normal carbohydrate antigen 19-9 (OR = 0.343, P = 0.036) levels, presence of enhancing capsule (OR = 7.819, P < 0.001) and hemorrhage (OR = 23.526, P = 0.004), and lack of targetoid appearance (OR = 0.129, P = 0.005) and liver surface retraction (OR = 0.190, P = 0.021) were independent predictors suggestive of ICC-predominant cHCC-CC over ICC; their combination yielded an area under the curve value of 0.898. ICC-predominant cHCC-CC exhibited poorer survival with shorter RFS than ICC (P = 0.009). CONCLUSION The predominant histopathological component is closely related to the imaging manifestation of cHCC-CC; and more importantly, it plays a significant prognostic role, which may alter the RFS prognosis of cHCC-CC.
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Affiliation(s)
- Ruofan Sheng
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Department of Radiology, Zhongshan Hospital (Xiamen), Fudan University, Shanghai , 361006, Fujian, China
- Shanghai Institute of Medical Imaging, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Chun Yang
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Institute of Medical Imaging, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Yunfei Zhang
- Shanghai Institute of Medical Imaging, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
- Central Research Institute, United Imaging Healthcare, Shanghai, 201800, China
| | - Heqing Wang
- Department of Radiology, Zhongshan Hospital (Xiamen), Fudan University, Shanghai , 361006, Fujian, China
| | - Beixuan Zheng
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jing Han
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Wei Sun
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Institute of Medical Imaging, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Mengsu Zeng
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Shanghai Institute of Medical Imaging, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China.
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Hu X, Li D, Zhu H, Yu T, Xiong X, Xu X. ATP6V1F is a novel prognostic biomarker and potential immunotherapy target for hepatocellular carcinoma. BMC Med Genomics 2023; 16:188. [PMID: 37587505 PMCID: PMC10428557 DOI: 10.1186/s12920-023-01624-6] [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: 02/02/2023] [Accepted: 08/02/2023] [Indexed: 08/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest malignancies worldwide, with late detection, ineffective treatment and poor overall survival. Immunotherapy, including immune checkpoint inhibitor (ICI) therapy, holds great potential for treatment of HCC. Although some patients respond well to ICIs, many fail to obtain a significant benefit. It is therefore of great interest to find appropriate markers to stratify patient responses to immunotherapy and to explore suitable targets for modulating the TME and immune cell infiltration. ATP6V1F encodes a constituent of vacuolar ATPase (V-ATPase). V-ATPase-mediated acidification of organelles is required for intracellular processes such as zymogen activation, receptor-mediated endocytosis, protein sorting and synaptic vesicle proton gradient generation. In this study, we confirmed for the first time that ATP6V1F is overexpressed in HCC and related to poor prognosis in these patients. We identified that overexpression of ATP6V1F is associated with infiltration of some immune cells and expression of several immune checkpoints. Furthermore, we explored the possible mechanisms of action of ATP6V1F. Finally, we conducted in vitro experiments, including wound healing, Transwell invasion, and apoptosis assays, to verify that ATP6V1F promotes development of HCC by promoting migration and invasion and inhibiting apoptosis of HCC cells. Our findings will contribute to providing precise immunotherapy to patients with HCC.
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Affiliation(s)
- Xinyao Hu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Dan Li
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, China
| | - Hua Zhu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Tao Yu
- Department of Oncology, Integrated Traditional Chinese and Western Medicine, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoxing Xiong
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China.
| | - Ximing Xu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China.
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Su LH, Ma WJ, Ma YB, Li TZ, Geng CA, Dong W, He XF, Chen JJ. Artemiprinolides A-M, thirteen undescribed sesquiterpenoid dimers from Artemisia princeps and their antihepatoma activity. PHYTOCHEMISTRY 2023; 211:113714. [PMID: 37156434 DOI: 10.1016/j.phytochem.2023.113714] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 05/05/2023] [Accepted: 05/05/2023] [Indexed: 05/10/2023]
Abstract
Bioassay-guided investigation of the active fraction of Artemisia princeps led to 13 undescribed sesquiterpenoid dimers, artemiprinolides A-M (1-13), together with 11 known ones (14-24). Their structures were elucidated by comprehensive spectroscopic data and absolute configurations were assigned based on single crystal X-ray diffraction data and ECD calculations. Structurally, all compounds were postulated to be derived from the Diels-Alder cycloaddition. The isolated dimers except 11 and 15 were assayed for their cytotoxicity against HepG2, Huh7, and SK-Hep-1 cell lines, of which four compounds (3, 13, 17, 18) exhibited obvious cytotoxicity with IC50 values ranging from 8.8 to 20.1 μM. Interestingly, the most active compounds 1 and 16 manifested significant cytotoxicity on the three tested hepatoma cell lines with IC50 values of 5.4, 4.1 (HepG2), 7.7, 5.6 (Huh7), and 11.8, 15.7 μM (SK-Hep-1), respectively, which were better than sorafenib. Compound 1 dose-dependently inhibited cell migration and invasion, and significantly induced the HepG2 cell arrest in G2/M phase by downregulating cdc2 and pcdc2 and upregulating cyclinB1; and induced apoptosis by downregulating Bcl-2 expression and upregulating Bax level. The molecular docking study implied that the carbonyl at the C-12' of 1 had a strong binding affinity with PRKACA.
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Affiliation(s)
- Li-Hua Su
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, People's Republic of China
| | - Wen-Jing Ma
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, People's Republic of China
| | - Yun-Bao Ma
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, People's Republic of China
| | - Tian-Ze Li
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, People's Republic of China
| | - Chang-An Geng
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, People's Republic of China
| | - Wei Dong
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, People's Republic of China; University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China
| | - Xiao-Feng He
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, People's Republic of China
| | - Ji-Jun Chen
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, People's Republic of China; University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China.
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Liver Organoids as an In Vitro Model to Study Primary Liver Cancer. Int J Mol Sci 2023; 24:ijms24054529. [PMID: 36901961 PMCID: PMC10003131 DOI: 10.3390/ijms24054529] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 02/16/2023] [Accepted: 02/22/2023] [Indexed: 03/02/2023] Open
Abstract
Primary liver cancers (PLC), including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are among the leading causes of cancer-related mortality worldwide. Bi-dimensional in vitro models are unable to recapitulate the key features of PLC; consequently, recent advancements in three-dimensional in vitro systems, such as organoids, opened up new avenues for the development of innovative models for studying tumour's pathological mechanisms. Liver organoids show self-assembly and self-renewal capabilities, retaining essential aspects of their respective in vivo tissue and allowing modelling diseases and personalized treatment development. In this review, we will discuss the current advances in the field of liver organoids focusing on existing development protocols and possible applications in regenerative medicine and drug discovery.
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Zhao J, Stephan-Falkenau S, Schuler M, Arndt B. Management of Locally Advanced or Metastatic Combined Hepatocellular Cholangiocarcinoma. Cancers (Basel) 2023; 15:988. [PMID: 36765942 PMCID: PMC9913543 DOI: 10.3390/cancers15030988] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/25/2023] [Accepted: 02/01/2023] [Indexed: 02/09/2023] Open
Abstract
Combined hepatocellular cholangiocarcinoma (cHCC-CC) is a rare primary liver malignancy that comprises features of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). Due to the rarity of this tumor, the treatment of choice has not yet been defined. For resectable disease, liver resection is the mainstay treatment. However, most patients relapse or display advanced disease and were not surgical candidates. Although the majority of patients are either primarily or secondarily treated in palliative intent, no guideline recommendations or prospective trial reports exist to allow reliable evaluation of debated treatment options. We review different locoregional or medical treatment options for advanced combined hepatocellular cholangiocarcinoma (cHCC-CC) in the neoadjuvant, adjuvant, or palliative setting and discuss the possibility of predictive biomarker-guided therapeutic options.
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Affiliation(s)
- Jemmy Zhao
- National Center of Tumor Diseases, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Susann Stephan-Falkenau
- Institute of Pathology, Medizinisches Versorgungszentrum am Helios Klinikum Emil von Behring, Walterhöferstr. 11, 14165 Berlin, Germany
| | - Markus Schuler
- Onkologischer Schwerpunkt am Oskar-Helene Heim, Clayallee 225a, 14195 Berlin, Germany
| | - Börge Arndt
- Department of Hematology and Oncology, Helios Klinikum Emil von Behring, Walterhöferstr. 11, 14165 Berlin, Germany
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Pomej K, Balcar L, Shmanko K, Welland S, Himmelsbach V, Scheiner B, Mahyera A, Mozayani B, Trauner M, Finkelmeier F, Weinmann A, Vogel A, Pinter M. Clinical characteristics and outcome of patients with combined hepatocellular-cholangiocarcinoma-a European multicenter cohort. ESMO Open 2023; 8:100783. [PMID: 36753993 PMCID: PMC10024130 DOI: 10.1016/j.esmoop.2023.100783] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 12/16/2022] [Accepted: 01/03/2023] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND There is no clear consensus on the optimal systemic treatment regimen in combined hepatocellular-cholangiocarcinoma (cHCC-CCA) patients. We describe clinical characteristics and outcome of cHCC-CCA patients, with a special focus on patients receiving palliative systemic therapy, including immune checkpoint inhibitors (ICIs). METHODS In this European retrospective, multicenter study, patients with histologically proven cHCC-CCA treated at four institutions between April 2003 and June 2022 were included. In patients receiving palliative systemic therapy, outcome was compared between cytotoxic chemotherapy (CHT)- and non-cytotoxic CHT (nCHT)-treated patients. RESULTS Of 101 patients, the majority were male (n = 70, 69%) with a mean age of 64.6 ± 10.6 years. Only type of first-line treatment was independently associated with overall survival (OS). Palliative systemic therapy was administered to 44 (44%) patients. Of those, 25 (57%) patients received CHT and 19 (43%) had nCHT (n = 16 of them sorafenib) in systemic first line. Although there was no significant difference in overall response rate (ORR; CHT versus nCHT: 8% versus 5%), disease control rate (24% versus 21%), and median progression-free survival {3.0 months [95% confidence interval (CI) 1.4-4.6 months] versus 3.2 months (95% CI 2.8-3.6 months), P = 0.725}, there was a trend towards longer median OS in the CHT group [15.5 months (95% CI 8.0-23.0 months) versus 5.3 months (95% CI 0-12.5 months), P = 0.052]. However, in multivariable analysis, type of first-line regimen (CHT versus sorafenib) was not associated with OS. ORR in patients receiving ICIs (n = 7) was 29%. CONCLUSIONS In patients with cHCC-CCA, OS, progression-free survival, ORR, and disease control rate were not significantly different between individuals receiving CHT and patients receiving nCHT. Immunotherapy may be effective in a subset of patients. Prospective studies are needed to identify optimal systemic treatment regimens in cHCC-CCA.
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Affiliation(s)
- K Pomej
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna; Liver Cancer (HCC) Study Group Vienna, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - L Balcar
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna; Liver Cancer (HCC) Study Group Vienna, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - K Shmanko
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz
| | - S Welland
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover
| | - V Himmelsbach
- Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt/Main, Germany
| | - B Scheiner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna; Liver Cancer (HCC) Study Group Vienna, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - A Mahyera
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna; Liver Cancer (HCC) Study Group Vienna, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - B Mozayani
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - M Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna
| | - F Finkelmeier
- Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt/Main, Germany
| | - A Weinmann
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz
| | - A Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover
| | - M Pinter
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna; Liver Cancer (HCC) Study Group Vienna, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
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Paradis V, Zucman-Rossi J. Pathogenesis of primary liver carcinomas. J Hepatol 2023; 78:448-449. [PMID: 36064762 DOI: 10.1016/j.jhep.2022.05.037] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 05/09/2022] [Accepted: 05/30/2022] [Indexed: 01/24/2023]
Affiliation(s)
- Valérie Paradis
- Centre de recherche sur l'inflammation, INSERM1149, Université Paris Cité, Paris, France; Pathology Department, Beaujon Hospital, APHP.Nord, Clichy, France.
| | - Jessica Zucman-Rossi
- Centre de recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, Paris, France; APHP, Institut du Cancer Paris CARPEM, APHP.centre, Hôpital Européen Georges Pompidou, Paris, France
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Surgical Strategies for Combined Hepatocellular-Cholangiocarcinoma (cHCC-CC). Cancers (Basel) 2023; 15:cancers15030774. [PMID: 36765731 PMCID: PMC9913263 DOI: 10.3390/cancers15030774] [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: 12/31/2022] [Revised: 01/17/2023] [Accepted: 01/19/2023] [Indexed: 01/28/2023] Open
Abstract
Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a tumor entity presenting features of hepatocellular and cholangiocellular epithelial differentiation. Due to the likeness between cHCC-CC, HCC and CC, accurate pretherapeutical diagnosis is challenging and advanced stages are prevalent. Radical oncological surgery is the only curative therapeutical option in patients with cHCC-CC. To reach this goal a profound understanding of this rare liver tumor is crucial. Factors such as clinicopathological characteristics, growth patterns and biological behavior are of central importance. To explore onco-surgical strategies and aspects for complete resection of cHCC-CC and to answer important key questions, an extensive review of the literature was conducted to answer the following questions: What are the best surgical options? Is there a significance for nonanatomical resections? Is there a prognostic value of concomitant lymphadenectomy? What about multimodal concepts in local advanced cHCC-CC? The role of minimally invasive liver surgery (MILS) including the role of robotic liver surgery for cHCC-CC will be discussed. While liver transplantation (LT) is standard for patients with unresectable HCC, the role of LT in cHCC-CC patients is still controversial. How can patients with high risk for early tumor recurrence be identified to avoid aggressive surgical treatment without clinical benefit? The comprehensive understanding of this challenging liver tumor will help to improve future treatment options for these patients.
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Mixed Hepatocellular Cholangiocarcinoma: A Comparison of Survival between Mixed Tumors, Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma from a Single Center. Cancers (Basel) 2023; 15:cancers15030639. [PMID: 36765596 PMCID: PMC9913586 DOI: 10.3390/cancers15030639] [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: 12/31/2022] [Revised: 01/16/2023] [Accepted: 01/17/2023] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most frequent primary liver malignancy, followed by intrahepatic cholangiocarcinoma (ICC). In addition, there is a mixed form for which only limited data are available. The aim of this study was to compare recurrence and survival of the mixed form within the cohorts of patients with HCC and ICC from a single center. METHODS Between January 2008 and December 2020, all patients who underwent surgical exploration for ICC, HCC, or mixed hepatocellular cholangiocarcinoma (mHC-CC) were included in this retrospective analysis. The data were analyzed, focusing on preoperative and operative details, histological outcome, and tumor recurrence, as well as overall and recurrence-free survival. RESULTS A total of 673 surgical explorations were performed, resulting in 202 resections for ICC, 344 for HCC (225 non-cirrhotic HCC, ncHCC; 119 cirrhotic HCC, cHCC), and 14 for mHC-CC. In addition, six patients underwent orthotopic liver transplant (OLT) in the belief of dealing with HCC. In 107 patients, tumors were irresectable (resection rate of 84%). Except for the cHCC group, major or even extended liver resections were required. Vascular or visceral extensions were performed regularly. Overall survival (OS) was highly variable, with a median OS of 17.6 months for ICC, 26 months for mHC-CC, 31.8 months for cHCC, and 37.2 months for ncHCC. Tumor recurrence was common, with a rate of 45% for mHC-CC, 48.9% for ncHCC, 60.4% for ICC, and 67.2% for cHCC. The median recurrence-free survival was 7.3 months for ICC, 14.4 months for cHCC, 16 months for mHC-CC, and 17 months for ncHCC. The patients who underwent OLT for mHC-CC showed a median OS of 57.5 and RFS of 56.5 months. CONCLUSIONS mHC-CC has a comparable course and outcome to ICC. The cholangiocarcinoma component seems to be the dominant one and, therefore, may be responsible for the prognosis. 'Accidental' liver transplant for mHC-CC within the Milan criteria offers a good long-term outcome. This might be an option in countries with no or minor organ shortage.
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31
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Wu JY, Huang WT, He WB, Dai GF, Lv JH, Qiu FN. Long-term outcomes of anatomic vs. non-anatomic resection in intrahepatic cholangiocarcinoma with hepatolithiasis: A multicenter retrospective study. Front Med (Lausanne) 2023; 10:1130692. [PMID: 37020678 PMCID: PMC10067634 DOI: 10.3389/fmed.2023.1130692] [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: 12/23/2022] [Accepted: 02/24/2023] [Indexed: 04/07/2023] Open
Abstract
Background The benefits of anatomic resection (AR) vs. non-anatomic resection (NAR) in patients with primary intrahepatic cholangiocarcinoma (ICC) with hepatolithiasis (HICC) are unclear. This study aimed to compare the long-term outcomes of AR vs. NAR in patients with HICC. Methods A total of 147 consecutive patients with HICC who underwent R0 hepatectomy were included. Overall survival (OS) and recurrence-free survival (RFS) following AR vs. NARs were compared using a 1:1 propensity score matching (PSM) analysis. A subgroup analysis was also conducted according to whether there are lymph node metastases (LNM). Results In a multivariate analysis, CA 19-9 (>39 U/L), microvascular invasion, LNM, and NAR were independent risk factors for poor RFS and OS rates, whereas multiple tumors were independent risk factors for OS. AR had better 1-, 3-, and 5-year RFS and OS rates than NAR (OS: 78.7, 58.9, and 28.5%, respectively, vs. 61.2, 25.4, and 8.8%, respectively; RFS: 59.5, 36.5, and 20.5%, respectively, vs. 38.2, 12.1, and 6.9%, respectively). After PSM, 100 patients were enrolled. The NAR group also had significantly poorer OS and RFS (OS: 0.016; RFS: p = 0.010) than the AR group. The subgroup analysis demonstrated that in HICC without LNM, OS and RFS were significantly poorer in the NAR group than the AR group, while no significant differences were observed in HICC with LNM before or after PSM. Conclusion Anatomic resection was associated with better long-term survival outcomes than NAR in patients with HICC, except for patients with LNM.
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Affiliation(s)
- Jun-Yi Wu
- Shengli Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, China
| | - Wen-Tao Huang
- Shengli Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, China
| | - Wen-bin He
- Shengli Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, China
| | - Gao-Fan Dai
- Department of Surgical Intensive Care Unit, First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Jia-Hui Lv
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Fu-Nan Qiu
- Shengli Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, China
- *Correspondence: Fu-Nan Qiu
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Coiled-Coil Domain-Containing Protein 45 Is a Potential Prognostic Biomarker and Is Associated with Immune Cell Enrichment of Hepatocellular Carcinoma. DISEASE MARKERS 2022; 2022:7745315. [PMID: 36618966 PMCID: PMC9815921 DOI: 10.1155/2022/7745315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 12/11/2022] [Accepted: 12/13/2022] [Indexed: 12/31/2022]
Abstract
Objective The role of coiled-coil domain-containing protein 45 (CCDC45) in the development of hepatocellular carcinoma (HCC) has not been reported. The present study is aimed at investigating the expression and prognosis of CCDC45 in HCC and its relevance to immune infiltration. Methods We conducted CCDC45 expression analysis using The Cancer Genome Atlas (TCGA) tumor database, the Human Protein Atlas (HPA) database, and the Tumor Immunological Evaluation Resource (TIMER). We used the University of Alabama at Birmingham Cancer data analysis Portal (UALCAN) database to show the correlation of CCDC45 with clinical features. We examined the prognostic impact of CCDC45 expression levels on HCC patients with the Kaplan-Meier mapper database. Genes coexpressed with CCDC45 and its regulators were also identified using LinkedOmics. The enriched Gene Ontology (GO) categories and associated signaling pathways were estimated using GO, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Assay (GSEA) pathway data. Correlations between CCDC45 and cancer immune infiltration was analyzed through the TIMER and an integrated repository portal for Tumor-Immune System Interactions (TISIDB) databases. Results The expression of CCDC45 was elevated in HCC tissues compared to adjacent liver tissues, and overexpression of CCDC45 was significantly correlated with tumor stage. Furthermore, HCC patients with CCDC45 overexpression had a shorter overall survival (OS). Functional network analysis indicated that CCDC45 was involved in homologous recombination, spliceosome, and DNA replication. Interestingly, CCDC45 expression was positively correlated with the level of immune cell infiltration. Conclusions CCDC45 is associated with prognosis and immune infiltration of HCC and may be a potential therapeutic target for HCC.
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Wang L, Wu M, Zhu C, Li R, Bao S, Yang S, Dong J. Ensemble learning based on efficient features combination can predict the outcome of recurrence-free survival in patients with hepatocellular carcinoma within three years after surgery. Front Oncol 2022; 12:1019009. [PMID: 36439437 PMCID: PMC9686395 DOI: 10.3389/fonc.2022.1019009] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Accepted: 10/25/2022] [Indexed: 04/11/2024] Open
Abstract
Preoperative prediction of recurrence outcome in hepatocellular carcinoma (HCC) facilitates physicians' clinical decision-making. Preoperative imaging and related clinical baseline data of patients are valuable for evaluating prognosis. With the widespread application of machine learning techniques, the present study proposed the ensemble learning method based on efficient feature representations to predict recurrence outcomes within three years after surgery. Radiomics features during arterial phase (AP) and clinical data were selected for training the ensemble models. In order to improve the efficiency of the process, the lesion area was automatically segmented by 3D U-Net. It was found that the mIoU of the segmentation model was 0.8874, and the Light Gradient Boosting Machine (LightGBM) was the most superior, with an average accuracy of 0.7600, a recall of 0.7673, a F1 score of 0.7553, and an AUC of 0.8338 when inputting radiomics features during AP and clinical baseline indicators. Studies have shown that the proposed strategy can relatively accurately predict the recurrence outcome within three years, which is helpful for physicians to evaluate individual patients before surgery.
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Affiliation(s)
- Liyang Wang
- School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Meilong Wu
- Division of Hepatobiliary and Pancreas Surgery, Department of General Surgery, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China
| | - Chengzhan Zhu
- Department of Pediatric Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Rui Li
- Department of Pediatric Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Shiyun Bao
- Division of Hepatobiliary and Pancreas Surgery, Department of General Surgery, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China
| | - Shizhong Yang
- Hepato-pancreato-biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsing-hua University, Beijing, China
| | - Jiahong Dong
- School of Clinical Medicine, Tsinghua University, Beijing, China
- Hepato-pancreato-biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsing-hua University, Beijing, China
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The Study of Exosomes-Encapsulated mPEG-PLGA Polymer Drug-Loaded Particles for Targeted Therapy of Liver Cancer. JOURNAL OF ONCOLOGY 2022; 2022:4234116. [PMID: 36164346 PMCID: PMC9509232 DOI: 10.1155/2022/4234116] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 08/09/2022] [Accepted: 08/24/2022] [Indexed: 11/30/2022]
Abstract
The emergence of targeted drugs brings hope to patients with advanced liver cancer. However, due to the complex and diverse environment in the human body, the overall response rate of targeted drugs is not high. Therefore, how to efficiently deliver targeted drugs to tumor sites is a major challenge for current research. The project intends to construct mPEG-PLGA nanoparticles loaded with Sora and encapsulate them with exosomes for targeted therapy of hepatocellular carcinoma. mPEG-PLGA drug-loaded nanoparticles were prepared by the dialysis method and characterized by TEM and DLS. The obtained nanoparticles were incubated with the exosomes of liver cancer cells, and the exosomes-encapsulated drug-loaded nanoparticles (Exo-Sora-NPs) were obtained under pulsed ultrasound conditions, and they were characterized by Western blot, transmission electron microscopy (TEM), and dynamic light scattering (DLS). The toxic effect of Exo-Sora-NPs on liver cancer cells was detected by the CCK-8 experiment. The uptake efficiency of nanoparticles by liver cancer cells was detected by a confocal microscope. The accumulation and infiltration depth of nanomedicine in liver cancer tissues were observed by confocal microscope on frozen sections of liver cancer tissue after the H22 liver cancer subcutaneous tumor transplantation model was constructed. The tumor size, body weight, pathology, and serology analysis of mice were measured after administration. The mPEG-PLGA polymer drug-loaded particles encapsulated by exosomes have high targeting ability and biosafety. To a certain extent, they can target the drug to the tumor site with a smaller systemic response and have a highly effective killing effect on the tumor. Nanodrug-loaded particles encapsulated by exosomes have great potential as drug carriers.
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Liu Z, Lv C. RNA binding protein PUM2 promotes hepatocellular carcinoma proliferation and apoptosis via binding to the 3'UTR of BTG3. Oncol Lett 2022; 24:346. [PMID: 36072004 PMCID: PMC9434726 DOI: 10.3892/ol.2022.13466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 05/27/2022] [Indexed: 12/09/2022] Open
Affiliation(s)
- Zhenhua Liu
- Department of General Surgery, The First People's Hospital of Lin Ping District, Hangzhou, Zhejiang 311100, P.R. China
| | - Chunye Lv
- Department of General Surgery, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, Jiangsu 211100, P.R. China
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Gigante E, Hobeika C, Le Bail B, Paradis V, Tougeron D, Lequoy M, Bouattour M, Blanc JF, Ganne-Carrié N, Tran H, Hollande C, Allaire M, Amaddeo G, Regnault H, Vigneron P, Ronot M, Elkrief L, Verset G, Trepo E, Zaanan A, Ziol M, Ningarhari M, Calderaro J, Edeline J, Nault JC. Systemic Treatments with Tyrosine Kinase Inhibitor and Platinum-Based Chemotherapy in Patients with Unresectable or Metastatic Hepatocholangiocarcinoma. Liver Cancer 2022; 11:460-473. [PMID: 36158591 PMCID: PMC9485952 DOI: 10.1159/000525488] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 05/22/2022] [Indexed: 02/04/2023] Open
Abstract
BACKGROUNDS AND AIMS Even if no systemic treatment is currently validated for unresectable hepatocellular-cholangiocarcinoma (cHCC-CCA), tyrosine kinase inhibitors (TKIs) and platinum-based chemotherapy are frequently used in clinical practice. Our study aims to describe the effectiveness of first-line systemic treatments in patients with cHCC-CCA. PATIENTS AND METHODS Patients with histological diagnosis of unresectable or metastatic cHCC-CCA confirmed by a centralized review (WHO classification 2019) and who received systemic treatment from 2009 to 2020 were included retrospectively in 11 centers. The outcomes of patients with cHCC-CCA were compared with patients with hepatocellular carcinoma (HCC) treated by sorafenib (n = 117) and with intrahepatic cholangiocarcinoma (iCCA, n = 94) treated mainly by platinum-based chemotherapy using a frailty Cox model. The efficacy of TKIs and platinum-based chemotherapies in patients with cHCC-CCA was assessed using a doubly robust estimator. RESULTS A total of 83 patients with cHCC-CCA were included and were predominantly male (72%) with underlying cirrhosis (55%). 67% of patients had extrahepatic metastases and 31% macrovascular tumor invasion. cHCC-CCAs were more often developed on cirrhosis (55.4%) than iCCA (26.6%) but less frequently than HCC (80.2%) (p < 0.001). Both HCC (36.8% and cHCC-CCA (66.2%) had less frequent extrahepatic metastases than iCCA (81%) (p < 0.001). Unadjusted overall survival (OS) was better in iCCA (13 months) compared to cHCC-CCA (12 months) and HCC (11 months) (p = 0.130). In multivariable analysis, after adjustment by a Cox frailty model, patients with cHCC-CCA had the same survival as HCC and iCCA (HR = 0.67, 95% CI: 0.37-1.22, p = 0.189 and HR = 0.66, 95% CI: 0.43-1.02, p = 0.064, respectively). ALBI score (HR = 2.15; 95% CI: 1.23-3.76; p = 0.009), ascites (HR = 3.45, 95% CI: 1.31-9.03, p = 0.013), and tobacco use (HR = 2.29, 95% CI: 1.08-4.87, p = 0.032) were independently associated with OS in patients with cHCC-CCA. Among patients with cHCC-CCA, 25 patients treated with TKI were compared with 54 patients who received platinum-based chemotherapies. Patients treated with TKI had a median OS of 8.3 months compared to 11.9 months for patients treated with platinum-based chemotherapy (p = 0.86). After a robust doubly adjustment on tumor number and size, vascular invasion, ALBI, MELD, and cirrhosis, the type of treatment did not impact OS (HR = 0.92, 95% CI: 0.27-3.15, p = 0.88) or progression-free survival (HR = 1.24, 95% CI: 0.44-3.49, p = 0.67). CONCLUSIONS First-line systemic treatments with TKIs or platinum-based chemotherapies have similar efficacy in patients with unresectable/metastatic cHCC-CCA. The ALBI score predicts OS.
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Affiliation(s)
- Elia Gigante
- Service d'Hépatologie, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bobigny, France et Centre de recherche sur l'inflammation, Inserm, Université de Paris, INSERM UMR 1149, De l'inflammation au cancer, Paris, France
| | - Christian Hobeika
- Service de Chirurgie Digestive, Hépato-Bilio-Pancréatique et Transplantation Hépatique, Hôpital de la Pitié Salpêtrière, AP-HP, Paris, France
| | - Brigitte Le Bail
- Service d'Anatomo-Pathologie, Hôpital Pellegrin, CHU Bordeaux, Bordeaux, France
| | - Valérie Paradis
- Service d'Anatomo-Pathologie, Hôpital Beaujon, AP-HP, Clichy, France et Centre de recherche sur l'inflammation, Inserm, Université de Paris, INSERM UMR 1149, De l'inflammation au cancer, Paris, France
| | - David Tougeron
- Service d'Hépato-gastroentérologie, CHU de Poitiers et Université de Poitiers, Poitiers, France
| | - Marie Lequoy
- Service d'Hépatologie, Hôpital Saint-Antoine, AP-HP, Paris, France
| | - Mohamed Bouattour
- Unité Oncologie Hépatique, Service d'Hépatologie, Hôpital Beaujon, AP-HP, Paris, France
| | - Jean-Frederic Blanc
- Service d'Hépato-gastroentérologie et d'Oncologie digestive, Hôpital Haut-Lévêque, CHU Bordeaux, Pessac: INSERM U1053, Université de Bordeaux, Bordeaux, France
| | - Nathalie Ganne-Carrié
- Service d'Hépatologie, Hôpital Avicenne, AP-HP, Université Sorbonne Paris Nord, Bobigny, Paris, France,Centre de Recherche des Cordeliers, Université de Paris, INSERM UMR 1138, Paris, France
| | - Henri Tran
- Service d'Hépatologie, Hôpital Avicenne, AP-HP, Université Sorbonne Paris Nord, Bobigny, Paris, France,Centre de Recherche des Cordeliers, Université de Paris, INSERM UMR 1138, Paris, France
| | | | - Manon Allaire
- Service d'Hépatologie, Hôpital de la Pitié Salpêtrière, AP-HP, Paris, France
| | | | | | - Paul Vigneron
- Service d'Hépatologie, Hôpital Mondor, AP-HP, Paris, France
| | - Maxime Ronot
- Centre de recherche sur l'inflammation, Inserm, Université de Paris, INSERM UMR 1149, De l'inflammation au cancer, Paris, France,Service de Radiologie, Hôpital Beaujon, AP-HP, Paris, France
| | - Laure Elkrief
- Service d'Hépatologie HC, UMUH 1, CHRU Tours, Tours, France
| | - Gontran Verset
- Department of Gastroenterology and Digestive Oncology, Erasme Hospital, Brussels, Belgium
| | - Eric Trepo
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium
| | - Aziz Zaanan
- Service Hépato-gastro-entérologie et Oncologie digestive, Hôpital Européen Georges-Pompidou, Université de Paris, AP-HP centre, Paris, France
| | - Marianne Ziol
- Service d'Anatomo-Pathologie, Hôpital Avicenne, AP-HP, Université Sorbonne Paris Nord, Bobigny, France
| | - Massih Ningarhari
- Service des Maladies de l'appareil digestif et nutrition–Hépatologie, CHRU de Lille–Hôpital Claude Huriez, Lille, France
| | - Julien Calderaro
- Service d'Anatomo-Pathologie, Hôpital Mondor, AP-HP, Paris, France
| | - Julien Edeline
- Service d'Oncologie, Centre Eugène Marquis, Rennes, France
| | - Jean-Charles Nault
- Service d'Hépatologie, Hôpital Avicenne, AP-HP, Université Sorbonne Paris Nord, Bobigny, Paris, France,Centre de Recherche des Cordeliers, Université de Paris, INSERM UMR 1138, Paris, France,*Jean-Charles Nault,
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Li Z, Kwon SM, Li D, Li L, Peng X, Zhang J, Sueyoshi T, Raufman JP, Negishi M, Wang XW, Wang H. Human constitutive androstane receptor represses liver cancer development and hepatoma cell proliferation by inhibiting erythropoietin signaling. J Biol Chem 2022; 298:101885. [PMID: 35367211 PMCID: PMC9052153 DOI: 10.1016/j.jbc.2022.101885] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/22/2022] [Accepted: 03/24/2022] [Indexed: 12/13/2022] Open
Abstract
The constitutive androstane receptor (CAR) is a nuclear receptor that plays a crucial role in regulating xenobiotic metabolism and detoxification, energy homeostasis, and cell proliferation by modulating the transcription of numerous target genes. CAR activation has been established as the mode of action by which phenobarbital-like nongenotoxic carcinogens promote liver tumor formation in rodents. This paradigm, however, appears to be unrelated to the function of human CAR (hCAR) in hepatocellular carcinoma (HCC), which remains poorly understood. Here, we show that hCAR expression is significantly lower in HCC than that in adjacent nontumor tissues and, importantly, reduced hCAR expression is associated with a worse HCC prognosis. We also show overexpression of hCAR in human hepatoma cells (HepG2 and Hep3B) profoundly suppressed cell proliferation, cell cycle progression, soft-agar colony formation, and the growth of xenografts in nude mice. RNA-Seq analysis revealed that the expression of erythropoietin (EPO), a pleiotropic growth factor, was markedly repressed by hCAR in hepatoma cells. Addition of recombinant EPO in HepG2 cells partially rescued hCAR-suppressed cell viability. Mechanistically, we showed that overexpressing hCAR repressed mitogenic EPO-EPO receptor signaling through dephosphorylation of signal transducer and activator of transcription 3, AKT, and extracellular signal-regulated kinase 1/2. Furthermore, we found that hCAR downregulates EPO expression by repressing the expression and activity of hepatocyte nuclear factor 4 alpha, a key transcription factor regulating EPO expression. Collectively, our results suggest that hCAR plays a tumor suppressive role in HCC development, which differs from that of rodent CAR and offers insight into the hCAR-hepatocyte nuclear factor 4 alpha-EPO axis in human liver tumorigenesis.
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Affiliation(s)
- Zhihui Li
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland, USA
| | - So Mee Kwon
- Laboratory of Human Carcinogenesis, and Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Daochuan Li
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland, USA
| | - Linhao Li
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland, USA
| | - Xiwei Peng
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland, USA
| | - Junran Zhang
- Department of Radiation Oncology, The Ohio State University James Comprehensive Cancer Center and College of Medicine, Ohio, USA
| | - Tatsuya Sueyoshi
- Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA
| | - Jean-Pierre Raufman
- Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, Maryland, USA; Office of Research and Development, Biomedical Laboratory Research and Development, VA Maryland Healthcare System, Baltimore, Maryland, USA
| | - Masahiko Negishi
- Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA
| | - Xin Wei Wang
- Laboratory of Human Carcinogenesis, and Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Hongbing Wang
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland, USA.
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Preoperative application of systemic inflammatory biomarkers combined with MR imaging features in predicting microvascular invasion of hepatocellular carcinoma. Abdom Radiol (NY) 2022; 47:1806-1816. [PMID: 35267069 DOI: 10.1007/s00261-022-03473-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 02/21/2022] [Accepted: 02/21/2022] [Indexed: 02/07/2023]
Abstract
PURPOSE To investigate whether systemic inflammatory biomarkers compared with the imaging features interpreted by radiologists can offer complementary value for predicting the risk of microvascular invasion (MVI) in patients with hepatocellular carcinoma (HCC). METHODS A total of 156 patients with histologically confirmed HCC between Jan 2018 and Dec 2020 were retrospectively enrolled in the primary cohort. Preoperative clinical-inflammatory biomarkers and MR imaging of the patients were recorded and then evaluated as an inflammatory score (Inflam-score) and imaging feature score (Radio-score). Six Inflam-scores and 12 Radio-scores were determined from each patient by univariate analysis. Logistic regression was performed to select risk factors for MVI and establish a predictive nomogram. Decision curve analysis was applied to estimate the incremental value of the Inflam-score to the Radio-score for predicting MVI. RESULTS Four Radio-scores and 2 Inflam-scores, namely, larger tumor size, non-smooth tumor margin, presence of satellite nodules, presence of peritumoral enhance, higher neutrophil-lymphocyte ratio (NLR), and lower prognostic nutritional index (PNI), were significantly associated with MVI (p < 0.05). An MVI risk prediction nomogram was then constructed with an area under the curve (AUC) of 0.868 (95% CI 0.806-0.931). Adding Inflam-scores to Radio-scores improved the sensitivity of the model from 60.9 to 80.4% in receiver operating characteristic (ROC) curve analysis and led to a net benefit in decision curve analysis. CONCLUSION Systemic inflammatory biomarkers are complementary tools that provide additional benefit to conventional imaging estimation for predicting MVI in HCC patients.
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Terai K, Ishigaki K, Kagawa Y, Okada K, Yoshida O, Sakurai N, Heishima T, Asano K. Clinical, diagnostic, and pathologic features and surgical outcomes of combined hepatocellular-cholangiocarcinoma in dogs: 14 cases (2009-2021). J Am Vet Med Assoc 2022; 260:1668-1674. [PMID: 35482569 DOI: 10.2460/javma.21.12.0514] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To describe the clinical, diagnostic, and pathological features and postoperative prognosis of canine combined hepatocellular-cholangiocarcinoma (cHCC-CCA). ANIMALS 14 privately owned dogs that underwent surgical treatment. PROCEDURES The medical records, including signalment, clinical signs, blood test, urine analysis, computed tomography (CT) findings, intraoperative findings, and pathological findings, were retrospectively reviewed in the dogs with cHCC-CCA. RESULTS Of 306 dogs that underwent surgical removal of hepatic masses, 14 dogs (4.6%) were pathologically confirmed to have cHCC-CCA. Median age and body weight were 11.3 years and 7.3 kg, respectively. There were no specific clinicopathological findings for cHCC-CCA. CT revealed a massive hepatic mass in all dogs and the inclusion of cyst-like lesions within the mass in 13 dogs. Intrahepatic metastases were found at time of surgery in 2 dogs (14.3%). Of the residual 12 dogs, 1 dog showed postoperative formation of intrahepatic nodules suggestive of metastases and another had intrahepatic and pulmonary nodules and a forelimb skin mass, suggesting postoperative metastases. The median survival time of the patients with cHCC-CCA was 700 days (range, 10 to 869 days) after surgery. CLINICAL RELEVANCE To the authors' knowledge, this is the first study to describe the clinical, diagnostic, and pathological features and postoperative prognosis of canine cHCC-CCA. The clinical and diagnostic features of canine cHCC-CCA might be more similar to those of HCC rather than to those of CCA, but the preoperative diagnosis differentiating between HCC and cHCC-CCA was challenging. Our study suggests that the postoperative prognosis of canine patients with cHCC-CCA is similar to that of dogs with HCC.
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Affiliation(s)
- Kazuyuki Terai
- 1Laboratory of Veterinary Surgery, Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, Japan
| | - Kumiko Ishigaki
- 1Laboratory of Veterinary Surgery, Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, Japan
| | - Yumiko Kagawa
- 2North Lab, 2-8-35, Hondori, Shiroisi-ku, Sapporo, Hokkaido 003-027, Japan
| | - Kazuki Okada
- 2North Lab, 2-8-35, Hondori, Shiroisi-ku, Sapporo, Hokkaido 003-027, Japan
| | - Orie Yoshida
- 1Laboratory of Veterinary Surgery, Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, Japan
| | - Naoki Sakurai
- 1Laboratory of Veterinary Surgery, Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, Japan
| | - Tatsuya Heishima
- 1Laboratory of Veterinary Surgery, Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, Japan
| | - Kazushi Asano
- 1Laboratory of Veterinary Surgery, Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, Japan
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Combined Hepatocellular-Cholangiocarcinoma: What the Multidisciplinary Team Should Know. Diagnostics (Basel) 2022; 12:diagnostics12040890. [PMID: 35453938 PMCID: PMC9026907 DOI: 10.3390/diagnostics12040890] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/01/2022] [Accepted: 04/01/2022] [Indexed: 12/10/2022] Open
Abstract
Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare type of primary liver malignancy. Among the risk factors, hepatitis B and hepatitis C virus infections, cirrhosis, and male gender are widely reported. The clinical appearance of cHCC-CCA is similar to that of HCC and iCCA and it is usually silent until advanced states, causing a delay of diagnosis. Diagnosis is mainly based on histology from biopsies or surgical specimens. Correct pre-surgical diagnosis during imaging studies is very problematic and is due to the heterogeneous characteristics of the lesion in imaging, with overlapping features of HCC and CCA. The predominant histological subtype within the lesion establishes the predominant imaging findings. Therefore, in this scenario, the radiological findings characteristic of HCC show an overlap with those of CCA. Since cHCC-CCAs are prevalent in patients at high risk of HCC and there is a risk that these may mimic HCC, it is currently difficult to see a non-invasive diagnosis of HCC. Surgery is the only curative treatment of HCC-CCA. The role of liver transplantation (LT) in the treatment of cHCC-CCA remains controversial, as is the role of ablative or systemic therapies in the treatment of this tumour. These lesions still remain challenging, both in diagnosis and in the treatment phase. Therefore, a pre-treatment imaging diagnosis is essential, as well as the identification of prognostic factors that could stratify the risk of recurrence and the most adequate therapy according to patient characteristics.
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Song Y, Wang S, Cheng X. LINC01006 regulates the proliferation, migration and invasion of hepatocellular carcinoma cells through regulating miR-433-3p/CBX3 axis. Ann Hepatol 2022; 25:100343. [PMID: 33781916 DOI: 10.1016/j.aohep.2021.100343] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 02/18/2021] [Accepted: 02/19/2021] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES LINC01006 has been verified to be correlated with several cancer types, whereas its biological function in hepatocellular carcinoma (HCC) is still elusive. This study aimed to elucidate the specific regulatory mechanism of LINC01006 in the tumorigenesis of HCC. MATERIALS AND METHODS The expression of LINC01006, miR-433-3p and CBX3 in HCC tissues and cells was assessed by qRT-PCR or Western blot. MTT, wound-healing, and transwell assays were used to evaluate the effects of LINC01006 on cell viability, migration, and invasion in vitro. A mouse xenograft model was established for in vivo assays. The relations among LINC01006, miR-433-3p, and CBX3 were analyzed by MS2-RNA immunoprecipitation (RIP) and Dual-luciferase reporter (DLR) assays. RESULTS The expression of LINC01006 was up-regulated in HCC tissues and cells. LINC01006 knockdown inhibited the viability, wound healing rate, and invasive cell number of HeP3B and SK-HeP-1 cells, and decreased the tumor volume and weight in a mouse xenograft model. MiR-433-3p was a target of LINC01006, and LINC01006 overexpression inhibited the viability, wound healing rate, and invasive cell number of HeP3B and SK-HeP-1 cells. In addition, CBX3 was a target of miR-433-3p, which was negatively regulated by miR-433-3p. CBX3 overexpression and miR-433-3p inhibition reversed the inhibiting effects of LINC01006 knockdown on the viability, migration, and invasion of HeP3B cells. CONCLUSIONS Silencing of LINC01006 inhibited the viability, migration, and invasion of HCC cells through regulating miR-433-3p/CBX3 axis.
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Affiliation(s)
- Yaobo Song
- Department of Oncology, Yantai Mountain Hospital, No. 91, Jiefang Road, Zhifu District, Yantai City, Shandong Province, 264000, China
| | - Shuang Wang
- The First Department of Oncology, Tai'an City Central Hospital, No. 29, Longtan Road, Tai'an City, Shandong Province, 271000, China
| | - Xiangming Cheng
- Department of Hematology and Oncology, Jinxiang People's Hospital, No. 117, East Jinfeng Road, Jinxiang County, Jining City, Shandong Province, 272200, China.
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c-Met up-regulates the expression of PD-L1 through MAPK/NF-κBp65 pathway. J Mol Med (Berl) 2022; 100:585-598. [PMID: 35122106 DOI: 10.1007/s00109-022-02179-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 01/11/2022] [Accepted: 01/24/2022] [Indexed: 12/29/2022]
Abstract
Sorafenib acquired drug resistance during the treatment of hepatocellular carcinoma (HCC) reduces the efficacy of the drug. The immune escape effect induced by PD-L1 is largely associated with drug resistance of HCC. However, the regulated mechanism of PD-L1 is unclear. This research aimed to clarify the control mechanism of PD-L1. c-Met was found abnormally highly expressed in Huh-7SR with high PD-L1 expression. In addition, c-Met, as the upstream target molecule of PD-L1, promoted the proliferation and migration of HCC in vitro and in vivo. We also found that c-Met activated the MAPK signaling pathway and the downstream NF-κBp65 transcription factor, which interacts with the proximal region of the PD-L1 promoter to promote PD-L1 expression. In conclusion, c-Met regulates the transcription of PD-L1 through the MAPK/NF-κBp65 pathway, thereby promoting the progress of HCC. The role of c-Met and PD-L1 in HCC needs to be further studied, but it is a potential target for the treatment of HCC. KEY MESSAGES: In the study, it was found that c-Met is also abnormally highly expressed in Huh-7SR with high PD-L1 expression and can promote the development of HCC in vitro and in vivo. PD-L1 and c-Met expression levels are positively correlated. In the follow-up mechanism study, we found that c-Met activated the MAPK signaling pathway and subsequently activated the downstream NF-κBp65 transcription factor, which interacts with the proximal region of the PD-L1 promoter to promote PD-L1 expression. Our study found that c-Met regulates the transcription of PD-L1 through the MAPK/NF-κBp65 pathway, thereby promoting the progress of HCC.
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Yan J, Huang YJ, Huang QY, Liu PX, Wang CS. Transcriptional activation of S100A2 expression by HIF-1α via binding to the hypomethylated hypoxia response elements in HCC cells. Mol Carcinog 2022; 61:494-507. [PMID: 35107180 DOI: 10.1002/mc.23393] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 01/05/2022] [Accepted: 01/13/2022] [Indexed: 12/16/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers. Dysregulation of S100A2 has recently been found in many cancers including HCC. However, its regulatory mechanism in HCC remains poorly understood, especially in hypoxia. In this study, we found that S100A2 is upregulated and correlated with the clinicopathological features of HCC patients. Moreover, the elevated S100A2 showed worse overall survival. Functionally, S100A2 inhibition decreased the proliferation and migration of HepG2 cells. Interestingly, we found that HIF-1α directly binds to hypoxia response elements (HREs) of the S100A2 promoter region. S100A2 expression could be induced in an HIF-1α-dependent manner under hypoxia. Furthermore, S100A2 silencing significantly suppressed HCC cell proliferation and invasion under hypoxia. Mechanistically, pyrosequencing results showed that the hypomethylation status of CpG located in the HRE at the S100A2 promoter was correlated with S100A2 induction. Additionally, HIF-1α- mediated S100A2 activation was associated with TET2-related epigenetic inactivation. TET2 was enriched in the HRE of the S100A2 promoter in HepG2 cells. Finally, S100A2 methylation-related genes and pathways were analyzed. We found that the methylation of S100A2 is correlated with ANXA2, PPP1R15A, and FOS, which include in a hypoxia-related gene set from the GSEA database. Moreover, some EMT-related genes are associated with the methylation of S100A2 in HCC. Conclusively, our study thus uncovered a novel mechanism showing that hypoxia/HIF-1α signaling associated with DNA methylation enhances S100A2 expression in HCC. S100A2 may be useful as a target for facilitating novel diagnostic and therapeutic strategies in liver cancer.
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Affiliation(s)
- Jia Yan
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Inner Mongolia University, Hohhot, Inner Mongolia, China.,College of Life Science, Inner Mongolia University, Hohhot, Inner Mongolia, China
| | - Ya Jun Huang
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Inner Mongolia University, Hohhot, Inner Mongolia, China
| | - Qing Yu Huang
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Inner Mongolia University, Hohhot, Inner Mongolia, China
| | - Peng Xia Liu
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Inner Mongolia University, Hohhot, Inner Mongolia, China.,College of Life Science, Inner Mongolia University, Hohhot, Inner Mongolia, China
| | - Chang Shan Wang
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Inner Mongolia University, Hohhot, Inner Mongolia, China.,College of Life Science, Inner Mongolia University, Hohhot, Inner Mongolia, China
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Zhang WY, Zhan HL, Li MK, Wu GD, Liu Z, Wu LF. Long noncoding RNA Gas5 induces cell apoptosis and inhibits tumor growth via activating the CHOP-dependent endoplasmic reticulum stress pathway in human hepatoblastoma HepG2 cells. J Cell Biochem 2022; 123:231-247. [PMID: 34636091 DOI: 10.1002/jcb.30159] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 09/24/2021] [Accepted: 09/28/2021] [Indexed: 02/05/2023]
Abstract
In recent years, long noncoding RNAs (lncRNAs) have been demonstrated to be important tumor-associated regulatory factors. LncRNA growth arrest-specific transcript 5 (Gas5) acts as an anti-oncogene in most cancers. Whether Gas5 acts as an oncogene or anti-oncogene in hepatocellular carcinoma (HCC) remains unclear. In the present study, the expression and role of Gas5 in HCC were investigated in vitro and in vivo. Lower expression levels of Gas5 were determined in HCC tissues and cells by quantitative reverse transcription-polymerase chain reaction. Overexpressed Gas 5 lentiviral vectors were constructed to analyze their influence on cell viability, migration, invasion, and apoptosis. Fluorescence in situ hybridization was used to identify the subcellular localization of Gas5. Protein complexes that bound to Gas5 were isolated from HepG2 cells through pull-down experiments and analyzed by mass spectrometry. A series of novel Gas5-interacting proteins were identified and bioinformatics analysis was carried out. These included ribosomal proteins, proteins involved in protein folding, sorting, and transportation in the ER, some nucleases and protein enzymes involved in gene transcription, translation, and other proteins with various functions.78 kDa glucose-regulated protein (GRP78) was identified as a direct target of Gas5 by Rip-qPCR and Western blot analysis assay. Gas5 inhibited HepG2 cell growth and induced cell apoptosis via upregulating CHOP to activate the ER stress signaling pathway. Further studies indicated that the knockdown of CHOP by shRNA partially reversed Gas5-mediated apoptosis in HepG2 cells. Magnetic resonance imaging showed that the ectopic expression of Gas5 inhibited the growth of HCC in nude mice. These findings suggest that Gas5 functions as a tumor suppressor and induces apoptosis through activation of ER stress by targeting the CHOP signal pathway in HCC.
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Affiliation(s)
- Wei-Yi Zhang
- Department of Gastroenterology, Second Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Hao-Lian Zhan
- Department of Gastroenterology, Second Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Ming-Kai Li
- Department of Gastroenterology, Second Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Guan-Di Wu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong Province, China
| | - Zhe Liu
- Department of Gastroenterology, Second Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Ling-Fei Wu
- Department of Gastroenterology, Second Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong Province, China
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Identification of MAD2L1 as a Potential Biomarker in Hepatocellular Carcinoma via Comprehensive Bioinformatics Analysis. BIOMED RESEARCH INTERNATIONAL 2022; 2022:9868022. [PMID: 35132379 PMCID: PMC8817109 DOI: 10.1155/2022/9868022] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/19/2021] [Accepted: 01/15/2022] [Indexed: 11/17/2022]
Abstract
Background Hepatocellular carcinoma (HCC) is widely acknowledged as a malignant tumor with rapid progression, high recurrence rate, and poor prognosis. At present, there is a paucity of reliable biomarkers at the clinical level to guide the management of HCC and improve patient outcomes. Our research is aimed at assessing the prognostic value of MAD2L1 in HCC. Methods Four datasets, GSE121248, GSE101685, GSE85598, and GSE62232, were selected from the GEO database to analyze differentially expressed genes (DEGs) between HCC and normal liver tissues. After functional analysis, we constructed a protein-protein interaction network (PPI) for DEGs and identified core genes in this network with high connectivity with other genes. We assessed the relationship between core genes and the pathogenesis and prognosis of HCC. Finally, we explored the gene regulatory signaling mechanisms involved in HCC pathogenesis. Results 145 DEGs were screened from the intersection of the four GEO datasets. MAD2L1 was associated with most genes according to the PPI network and was selected as a candidate gene for further study. Survival analysis suggested that high MAD2L1 expression in HCC correlated with a worse prognosis. In addition, real-time quantitative PCR (RT-qPCR), western blot (WB), and immunohistochemistry (IHC) findings suggested that the expression of MAD2L1 was abnormally increased in HCC tissues and cells compared to paraneoplastic tissues and normal hepatocytes. Conclusion We found that high MAD2L1 expression in HCC was significantly associated with overall patient survival and clinical features. We also explored the potential biological properties of this gene.
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Igelström E, Campbell M, Craig P, Katikireddi SV. Cochrane's risk of bias tool for non-randomized studies (ROBINS-I) is frequently misapplied: A methodological systematic review. J Clin Epidemiol 2021; 140:22-32. [PMID: 34437948 PMCID: PMC8809341 DOI: 10.1016/j.jclinepi.2021.08.022] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 08/16/2021] [Accepted: 08/18/2021] [Indexed: 12/20/2022]
Abstract
OBJECTIVES We aimed to review how 'Risk of Bias In Non-randomized Studies-of Interventions' (ROBINS-I), a Cochrane risk of bias assessment tool, has been used in recent systematic reviews. STUDY DESIGN AND SETTING Database and citation searches were conducted in March 2020 to identify recently published reviews using ROBINS-I. Reported ROBINS-I assessments and data on how ROBINS-I was used were extracted from each review. Methodological quality of reviews was assessed using AMSTAR 2 ('A MeaSurement Tool to Assess systematic Reviews'). RESULTS Of 181 hits, 124 reviews were included. Risk of bias was serious/critical in 54% of assessments on average, most commonly due to confounding. Quality of reviews was mostly low, and modifications and incorrect use of ROBINS-I were common, with 20% reviews modifying the rating scale, 20% understating overall risk of bias, and 19% including critical-risk of bias studies in evidence synthesis. Poorly conducted reviews were more likely to report low/moderate risk of bias (predicted probability 57% [95% CI: 47-67] in critically low-quality reviews, 31% [19-46] in high/moderate-quality reviews). CONCLUSION Low-quality reviews frequently apply ROBINS-I incorrectly, and may thus inappropriately include or give too much weight to uncertain evidence. Readers should be aware that such problems can lead to incorrect conclusions in reviews.
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Affiliation(s)
- Erik Igelström
- MRC/CSO Social and Public Health Sciences Unit, University of Glasgow, Berkeley Square 99 Berkeley Street, Glasgow, G3 7HR.
| | - Mhairi Campbell
- MRC/CSO Social and Public Health Sciences Unit, University of Glasgow, Berkeley Square 99 Berkeley Street, Glasgow, G3 7HR
| | - Peter Craig
- MRC/CSO Social and Public Health Sciences Unit, University of Glasgow, Berkeley Square 99 Berkeley Street, Glasgow, G3 7HR
| | - Srinivasa Vittal Katikireddi
- MRC/CSO Social and Public Health Sciences Unit, University of Glasgow, Berkeley Square 99 Berkeley Street, Glasgow, G3 7HR
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Rodriguez S, Skeet K, Mehmetoglu-Gurbuz T, Goldfarb M, Karri S, Rocha J, Shahinian M, Yazadi A, Poudel S, Subramani R. Phytochemicals as an Alternative or Integrative Option, in Conjunction with Conventional Treatments for Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:cancers13225753. [PMID: 34830907 PMCID: PMC8616323 DOI: 10.3390/cancers13225753] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 11/10/2021] [Accepted: 11/15/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is globally ranked as the sixth most diagnosed cancer, and the second most deadly cancer. To worsen matters, there are only limited therapeutic options currently available; therefore, it is necessary to find a reservoir from which new HCC treatments may be acquired. The field of phytomedicine may be the solution to this problem, as it offers an abundance of plant-derived molecules, which show capabilities of being effective against HCC proliferation, invasion, migration, and metastasis. In our review, we collect and analyze current evidence regarding these promising phytochemical effects on HCC, and delve into their potential as future chemotherapies. Additionally, information on the signaling behind these numerous phytochemicals is provided, in an attempt to understand their mechanisms. This review makes accessible the current body of knowledge pertaining to phytochemicals as HCC treatments, in order to serve as a reference and inspiration for further research into this subject. Abstract Hepatocellular carcinoma (HCC) is the most abundant form of liver cancer. It accounts for 75–85% of liver cancer cases and, though it ranks globally as the sixth most common cancer, it ranks second in cancer-related mortality. Deaths from HCC are usually due to metastatic spread of the cancer. Unfortunately, there are many challenges and limitations with the latest HCC therapies and medications, making it difficult for patients to receive life-prolonging care. As there is clearly a high demand for alternative therapy options for HCC, it is prudent to turn to plants for the solution, as their phytochemicals have long been used and revered for their many medicinal purposes. This review explores the promising phytochemical compounds identified from pre-clinical and clinical trials being used either independently or in conjunction with already existing cancer therapy treatments. The phytochemicals discussed in this review were classified into several categories: lipids, polyphenols, alkaloids, polysaccharides, whole extracts, and phytochemical combinations. Almost 80% of the compounds failed to progress into clinical studies due to lack of information regarding the toxicity to normal cells and bioavailability. Although large obstacles remain, phytochemicals can be used either as an alternative or integrative therapy in conjunction with existing HCC chemotherapies. In conclusion, phytochemicals have great potential as treatment options for hepatocellular carcinoma.
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Affiliation(s)
- Sheryl Rodriguez
- Center of Emphasis in Cancer Research, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA; (S.R.); (T.M.-G.); (S.P.)
| | - Kristy Skeet
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA; (K.S.); (J.R.); (M.S.); (A.Y.)
| | - Tugba Mehmetoglu-Gurbuz
- Center of Emphasis in Cancer Research, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA; (S.R.); (T.M.-G.); (S.P.)
| | - Madeline Goldfarb
- Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA; (M.G.); (S.K.)
| | - Shri Karri
- Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA; (M.G.); (S.K.)
| | - Jackelyn Rocha
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA; (K.S.); (J.R.); (M.S.); (A.Y.)
| | - Mark Shahinian
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA; (K.S.); (J.R.); (M.S.); (A.Y.)
| | - Abdallah Yazadi
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA; (K.S.); (J.R.); (M.S.); (A.Y.)
| | - Seeta Poudel
- Center of Emphasis in Cancer Research, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA; (S.R.); (T.M.-G.); (S.P.)
| | - Ramadevi Subramani
- Center of Emphasis in Cancer Research, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA; (S.R.); (T.M.-G.); (S.P.)
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA; (K.S.); (J.R.); (M.S.); (A.Y.)
- Correspondence: ; Tel.: +1-915-215-6851
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Lang SA, Bednarsch J, Czigany Z, Joechle K, Kroh A, Amygdalos I, Strnad P, Bruns T, Heise D, Ulmer F, Neumann UP. Liver transplantation in malignant disease. World J Clin Oncol 2021; 12:623-645. [PMID: 34513597 PMCID: PMC8394155 DOI: 10.5306/wjco.v12.i8.623] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 06/15/2021] [Accepted: 07/23/2021] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation for malignant disease has gained increasing attention as part of transplant oncology. Following the implementation of the Milan criteria, hepatocellular carcinoma (HCC) was the first generally accepted indication for transplantation in patients with cancer. Subsequently, more liberal criteria for HCC have been developed, and research on this topic is still ongoing. The evident success of liver transplantation for HCC has led to the attempt to extend its indication to other malignancies. Regarding perihilar cholangiocarcinoma, more and more evidence supports the use of liver transplantation, especially after neoadjuvant therapy. In addition, some data also show a benefit for selected patients with very early stage intrahepatic cholangiocarcinoma. Hepatic epithelioid hemangioendothelioma is a very rare but nonetheless established indication for liver transplantation in primary liver cancer. In contrast, patients with hepatic angiosarcoma are currently not considered to be optimal candidates. In secondary liver tumors, neuroendocrine cancer liver metastases are an accepted but comparability rare indication for liver transplantation. Recently, some evidence has been published supporting the use of liver transplantation even for colorectal liver metastases. This review summarizes the current evidence for liver transplantation for primary and secondary liver cancer.
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Affiliation(s)
- Sven Arke Lang
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Jan Bednarsch
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Zoltan Czigany
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Katharina Joechle
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Andreas Kroh
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Iakovos Amygdalos
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Pavel Strnad
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Tony Bruns
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Daniel Heise
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Florian Ulmer
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Ulf Peter Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
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Rare variants of primary liver cancer: Fibrolamellar, combined, and sarcomatoid hepatocellular carcinomas. Eur J Med Genet 2021; 64:104313. [PMID: 34418585 DOI: 10.1016/j.ejmg.2021.104313] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 06/21/2021] [Accepted: 07/22/2021] [Indexed: 01/07/2023]
Abstract
Hepatocellular carcinoma (HCC) constitutes 80% of all primary liver cancers. Based on key developments in the understanding of its carcinogenesis and the advancement of treatment options, detailed algorithms and practice guidelines have been published to guide the clinical management of HCC. Furthermore, several subclasses of HCC have been described based on molecular profiles and linked to pathological characteristics, clinical features, and disease aggressiveness. Most recently, the combination of the checkpoint inhibitor atezolizumab plus bevacizumab has significantly increased treatment response in the first line systemic treatment of HCC. Unfortunately, rare HCC variants, in particular fibrolamellar liver cancer (FLC), combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CCA), and sarcomatoid hepatocellular carcinoma (sHCC), were excluded from phase III studies. Therefore, data for decision-making and treatment allocation for these distinct entities, representing 1-5% of all primary liver cancers, is scarce. Moreover, most of the knowledge available for these rare HCC variants is based on registry data and retrospective studies. In this position paper, we briefly summarize the current clinical knowledge regarding FLC, cHCC-CCA, and sHCC. Based on our summary, we propose future clinical research activities within the framework of the European Reference Network on Hepatological Diseases (ERN RARE-LIVER).
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Ruan W, Yang Y, Yu Q, Huang T, Wang Y, Hua L, Zeng Z, Pan R. FUT11 is a target gene of HIF1α that promotes the progression of hepatocellular carcinoma. Cell Biol Int 2021; 45:2275-2286. [PMID: 34288238 DOI: 10.1002/cbin.11675] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 06/29/2021] [Accepted: 07/19/2021] [Indexed: 01/16/2023]
Abstract
Hypoxia promotes the progression of hepatocellular carcinoma. However, the hypoxia regulatory network in hepatocellular carcinoma is known to be limited. Thus, this study aimed to identify the crucial hypoxia-associated genes and to explore their effects and molecular mechanisms in hepatocellular carcinoma cells. FUT11 was first identified as a crucial hypoxia-associated gene through bioinformatics analysis. High FUT11 mRNA levels were positively correlated with poor clinical parameters. FUT11 knockdown under normoxia and hypoxia both decreased hepatocellular carcinoma cell proliferation, colony formation, migration, and invasion. HIF1α binds to the promoter of FUT11 and increases its transcription and co-expression with FUT11 in hepatocellular carcinoma tissues. Overexpression of FUT11 in HIF1α knockdown cells reversed the inhibitory effects of HIF1α suppression on hepatocellular carcinoma cell proliferation and mobility under hypoxia. Therefore, our findings indicate that FUT11 is a key target gene of HIF1α, which can promote the proliferation and mobility of hepatocellular carcinoma cells. FUT11 may be a novel and effective target for blocking the hypoxia response of hepatocellular carcinoma cells.
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Affiliation(s)
- Wanyuan Ruan
- School of Clinical Medicine, Hubei University of Science and Technology, Xianning, China.,Department of Infection, The Second Affiliated Hospital of Hubei University of Science and Technology, Xianning, China
| | - Yushi Yang
- School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China.,Department of Pathology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Qionghua Yu
- School of Clinical Medicine, Hubei University of Science and Technology, Xianning, China.,Department of Infection, The Second Affiliated Hospital of Hubei University of Science and Technology, Xianning, China
| | - Tiejun Huang
- School of Clinical Medicine, Hubei University of Science and Technology, Xianning, China.,Department of Infection, The Second Affiliated Hospital of Hubei University of Science and Technology, Xianning, China
| | - Yaofen Wang
- School of Clinical Medicine, Hubei University of Science and Technology, Xianning, China.,Department of Infection, The Second Affiliated Hospital of Hubei University of Science and Technology, Xianning, China
| | - Li Hua
- School of Clinical Medicine, Hubei University of Science and Technology, Xianning, China
| | - Zhirui Zeng
- School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China
| | - Runsang Pan
- Department of Orthopedics, Guiyang Maternal and Child Health-care Hospital, Guiyang, Guizhou, China
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