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Yin X, Gu HW, Ning D, Li YS, Tang HB. Testosterone Exacerbates the Formation of Liver Cancer Induced by Environmental N-Nitrosamines Exposure: Potential Mechanisms and Implications for Human Health. Onco Targets Ther 2024; 17:395-409. [PMID: 38774818 PMCID: PMC11107913 DOI: 10.2147/ott.s456746] [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: 12/26/2023] [Accepted: 05/11/2024] [Indexed: 05/24/2024] Open
Abstract
Background Humans are frequently exposed to N-nitrosamines through various sources, including diet, cigarette smoking, contaminated water, the atmosphere, and endogenous nitrosation. Exposure to these carcinogens may also contribute to the gender-specific incidence of liver cancer, which is significantly higher in males than in females, possibly due to the influence of endogenous hormones such as testosterone. However, the effect of testosterone on N-nitrosamine-induced liver cancer and its underlying mechanism remains unclear. Purpose To investigate the effect of testosterone on the development of liver cancer induced by N-nitrosamines exposure. Patients and Methods Histopathological and immunohistochemical staining techniques were employed to analyze the expression levels and nuclear localizations of key signaling molecules, including androgen receptor (AR), β-catenin, and HMGB1, in both tumor and non-tumor regions of liver samples obtained from human patients and mice. Results The findings demonstrated a strong correlation between AR and β-catenin in the nuclear region of tumor areas. AR also showed a significant correlation with HMGB1 in the cytoplasmic region of non-tumor areas in both human and mice samples. The study further analyzed the expression levels and patterns of these three proteins during the progression of liver tumors. Conclusion This study confirms that AR has the ability to modulate the expression levels and patterns of β-catenin and HMGB1 in vivo, thereby exacerbating the progression of liver cancer induced by environmental N-nitrosamines exposure. Importantly, the effect of testosterone on the formation of liver cancer induced by environmental N-nitrosamine exposure intensifies this progression. These findings have important implications for drug safety in clinical practice and emphasize the significance of reducing N-nitrosamines exposure through conscious choices regarding diet and lifestyle to ensure environmental safety.
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Affiliation(s)
- Xin Yin
- Lab of Hepatopharmacology and Ethnopharmacology, School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, Hubei, People’s Republic of China
| | - Hong-Wei Gu
- Pharmacy Department, Mental Health Center of Wuhan, Wuhan, Hubei, People’s Republic of China
| | - Dan Ning
- Lab of Hepatopharmacology and Ethnopharmacology, School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, Hubei, People’s Republic of China
| | - Yu-Sang Li
- Lab of Hepatopharmacology and Ethnopharmacology, School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, Hubei, People’s Republic of China
| | - He-Bin Tang
- Lab of Hepatopharmacology and Ethnopharmacology, School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, Hubei, People’s Republic of China
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2
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Qiao W, Li J, Xiong Y, Zheng J, Jin R, Hu C. GALAD score as a prognostic model for recurrence of hepatocellular carcinoma after local ablation. J Cancer Res Clin Oncol 2024; 150:241. [PMID: 38713414 PMCID: PMC11076334 DOI: 10.1007/s00432-024-05760-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: 03/09/2024] [Accepted: 04/22/2024] [Indexed: 05/08/2024]
Abstract
BACKGROUND Currently, the high recurrence rate still forms severe challenges in hepatocellular carcinoma (HCC) treatment. The GALAD score, including age, gender, alpha-fetoprotein (AFP), lens culinaris agglutinin-reactive AFP (AFP-L3), and des-gamma-carboxyprothrombin (DCP) was developed as a diagnostic model. However, evidence is still lacking to confirm the capability of the GALAD score to predict the recurrence of HCC. METHODS This study included 390 HCC patients after local ablation at Beijing You'an Hospital from January 1, 2018, to December 31, 2022. Firstly, the area under the receiver operating characteristic (ROC) curve (AUC) was calculated to assess the predictive capability of the GALAD score. Then, the Kaplan-Meier (KM) curve and log-rank test were used to compare the prognosis between two groups classified by GALAD score. Finally, a nomogram for high-risk patients was established by Lasso-Cox regression. It was assessed by ROC curves, calibration curves, and decision curve analysis (DCA). RESULTS The ROC curve (AUC: 0.749) and KM curve showed the GALAD score had good predictive ability and could clearly stratify patients into two groups through the risk of recurrence. Prognostic factors selected by Lasso-Cox regression contained tumor number, tumor size, and globulin. The nomogram for high-risk patients showed reliable discrimination, calibration, and clinical utility. CONCLUSION This research displayed that the GALAD score is an effective model for predicting the recurrence of HCC. Meanwhile, we found the poor prognosis of the high-risk group and created a nomogram for these patients.
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Affiliation(s)
- Wenying Qiao
- Interventional Therapy Center for Oncology, Beijing You'an Hospital, Capital Medical University, 8 Xitoutiao, Youanmenwai Street, Fengtai District, Beijing, People's Republic of China
- Beijing Di'tan Hospital, Capital Medical University, 8 Jingshun East Street, Chaoyang District, Beijing, People's Republic of China
- Changping Laboratory, Beijing, People's Republic of China
| | - Jiashuo Li
- Beijing Di'tan Hospital, Capital Medical University, 8 Jingshun East Street, Chaoyang District, Beijing, People's Republic of China
| | - Yiqi Xiong
- Interventional Therapy Center for Oncology, Beijing You'an Hospital, Capital Medical University, 8 Xitoutiao, Youanmenwai Street, Fengtai District, Beijing, People's Republic of China
| | - Jiasheng Zheng
- Interventional Therapy Center for Oncology, Beijing You'an Hospital, Capital Medical University, 8 Xitoutiao, Youanmenwai Street, Fengtai District, Beijing, People's Republic of China.
| | - Ronghua Jin
- Beijing Di'tan Hospital, Capital Medical University, 8 Jingshun East Street, Chaoyang District, Beijing, People's Republic of China.
- Changping Laboratory, Beijing, People's Republic of China.
| | - Caixia Hu
- Interventional Therapy Center for Oncology, Beijing You'an Hospital, Capital Medical University, 8 Xitoutiao, Youanmenwai Street, Fengtai District, Beijing, People's Republic of China.
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Abdolahi M, Ghaedi Talkhounche P, Derakhshan Nazari MH, Hosseininia HS, Khoshdel-Rad N, Ebrahimi Sadrabadi A. Functional Enrichment Analysis of Tumor Microenvironment-Driven Molecular Alterations That Facilitate Epithelial-to-Mesenchymal Transition and Distant Metastasis. Bioinform Biol Insights 2024; 18:11779322241227722. [PMID: 38318286 PMCID: PMC10840405 DOI: 10.1177/11779322241227722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 01/04/2024] [Indexed: 02/07/2024] Open
Abstract
Nowadays, hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths, and identifying the effective factors in causing this disease can play an important role in its prevention and treatment. Tumors provide effective agents for invasion and metastasis to other organs by establishing appropriate communication between cancer cells and the microenvironment. Epithelial-to-mesenchymal transition (EMT) can be mentioned as one of the effective phenomena in tumor invasion and metastasis. Several factors are involved in inducing this phenomenon in the tumor microenvironment, which helps the tumor survive and migrate to other places. It can be effective to identify these factors in the use of appropriate treatment strategies and greater patient survival. This study investigated the molecular differences between tumor border cells and tumor core cells or internal tumor cells in HCC for specific EMT genes. Expression of NOTCH1, ID1, and LST1 genes showed a significant increase at the HCC tumor border. Targeting these genes can be considered as a useful therapeutic strategy to prevent distant metastasis in HCC patients.
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Affiliation(s)
- Mahnaz Abdolahi
- Department of Immunology, Faculty of Medicine, Shahid Beheshti University, Tehran, Iran
| | - Parnian Ghaedi Talkhounche
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Mohammad Hossein Derakhshan Nazari
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Haniyeh Sadat Hosseininia
- Department of Cellular and Molecular Biology, Faculty of Advanced Medical Science, Islamic Azad University of Medical Sciences, Tehran, Iran
- Cytotech & Bioinformatics Research Group, Bioinformatics Department, Tehran, Iran
| | - Niloofar Khoshdel-Rad
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Amin Ebrahimi Sadrabadi
- Cytotech & Bioinformatics Research Group, Bioinformatics Department, Tehran, Iran
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACER, Tehran, Iran
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Yang A, Huang H, Xie J, Tian Y, Wang L, Liu D, Wei X, Tan P, Chai X, Zha X, Tu P, Hu Z. Interfering with the AKT/mTOR/STAT3/ID1 signaling axis with usenamine A restrains the proliferative and invasive potential of human hepatocellular carcinoma cells. Chin Med 2024; 19:4. [PMID: 38183094 PMCID: PMC10770941 DOI: 10.1186/s13020-023-00875-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Accepted: 12/29/2023] [Indexed: 01/07/2024] Open
Abstract
BACKGROUND Usenamine A, a novel natural compound initially isolated from the lichen Usnea longissima, has exhibited promising efficacy against hepatoma in prior investigation. Nevertheless, the underlying mechanisms responsible for its antihepatoma effects remain unclear. Furthermore, the role of the AKT/mechanistic target of the rapamycin (mTOR)/signal transducer and activator of transcription 3 (STAT3)/inhibitor of differentiation/DNA binding 1 (ID1) signaling axis in hepatocellular carcinoma (HCC), and the potential anti-HCC effects of drugs targeting this pathway are not well understood. METHODS CCK-8 assay was used to investigate the effects of usenamine A on the proliferation of human HCC cells. Moreover, the effects of usenamine A on the invasion ability of human HCC cells were evaluated by transwell assay. In addition, expression profiling analysis, quantitative real-time PCR, immunoblotting, immunohistochemistry (IHC) analysis, RNAi, immunoprecipitation, and chromatin immunoprecipitation (ChIP) assay were used to explore the effects of usenamine A on the newly identified AKT/mTOR/STAT3/ID1 signaling axis in human HCC cells. RESULTS Usenamine A inhibited the proliferation and invasion of human HCC cell lines (HepG2 and SK-HEP-1). Through the analysis of gene expression profiling, we identified that usenamine A suppressed the expression of ID1 in human HCC cells. Furthermore, immunoprecipitation experiments revealed that usenamine A facilitated the degradation of the ID1 protein via the ubiquitin-proteasome pathway. Moreover, usenamine A inhibited the activity of STAT3 in human HCC cells. ChIP analysis demonstrated that STAT3 positively regulated ID1 expression at the transcriptional level in human HCC cells. The STAT3/ID1 axis played a role in mediating the anti-proliferative and anti-invasive impacts of usenamine A on human HCC cells. Additionally, usenamine A suppressed the STAT3/ID1 axis through AKT/mTOR signaling in human HCC cells. CONCLUSION Usenamine A displayed robust anti-HCC potential, partly attributed to its capacity to downregulate the AKT/mTOR/STAT3/ID1 signaling pathway and promote ubiquitin-proteasome-mediated ID1 degradation. Usenamine A has the potential to be developed as a therapeutic agent for HCC cases characterized by abnormal AKT/mTOR/STAT3/ID1 signaling, and targeting the AKT/mTOR/STAT3 signaling pathway may be a viable option for treating patients with HCC exhibiting elevated ID1 expression.
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Affiliation(s)
- Ailin Yang
- Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North 3rd Ring East Road, Chaoyang District, Beijing, 100029, People's Republic of China
- School of Pharmacy, Binzhou Medical University, Yantai, 264003, China
| | - Huiming Huang
- Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North 3rd Ring East Road, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Jinxin Xie
- Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North 3rd Ring East Road, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Yingying Tian
- Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North 3rd Ring East Road, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Longyan Wang
- Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North 3rd Ring East Road, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Dongxiao Liu
- Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North 3rd Ring East Road, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Xuejiao Wei
- Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North 3rd Ring East Road, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Peng Tan
- Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North 3rd Ring East Road, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Xingyun Chai
- Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North 3rd Ring East Road, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Xiaojun Zha
- Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, 230032, China
| | - Pengfei Tu
- Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North 3rd Ring East Road, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Zhongdong Hu
- Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North 3rd Ring East Road, Chaoyang District, Beijing, 100029, People's Republic of China.
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Oh RK, Hwang S, Song GW, Ahn CS, Moon DB, Ha TY, Jung DH, Park GC, Yoon YI, Kang WH. Donor sex and donor-recipient sex disparity do not affect hepatocellular carcinoma recurrence after living donor liver transplantation. Ann Surg Treat Res 2023; 105:133-140. [PMID: 37693289 PMCID: PMC10485355 DOI: 10.4174/astr.2023.105.3.133] [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: 05/30/2023] [Revised: 07/11/2023] [Accepted: 08/01/2023] [Indexed: 09/12/2023] Open
Abstract
Purpose Studies have yielded contradictory results on whether donor sex and donor-recipient sex disparity affect hepatocellular carcinoma (HCC) recurrence after living donor liver transplantation (LDLT). The present study assessed whether donor sex or donor-recipient sex disparity affects HCC recurrence after LDLT at a high-volume center. Methods This study included 772 HCC patients who underwent LDLT between January 2006 and December 2015 at Asan Medical Center. Patients were divided into 4 groups based on the sex of the donor and recipient: male-to-male (n = 490, 63.5%), male-to-female (n = 75, 9.7%), female-to-male (n = 170, 22.0%), and female-to-female (n = 37, 4.8%). Results Disease-free survival (DFS; P = 0.372) and overall survival (OS; P = 0.591) did not differ significantly among the 4 groups. DFS also did not differ significantly between LDLT recipients with male and female donors (P = 0.792) or between male and female recipients (P = 0.084). After patient matching with an α-FP/des-γ-carboxy prothrombin/tumor volume score cutoff of 5logs, donor-recipient sex disparity did not significantly affect DFS (P = 0.598) or OS (P = 0.777). There were also no differences in DFS in matched LDLT recipients with male and female donors (P = 0.312) or between male and female recipients (P = 0.374). Conclusion Neither donor sex nor donor-recipient sex disparity significantly affected posttransplant HCC recurrence.
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Affiliation(s)
- Rak Kyun Oh
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Shin Hwang
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Gi-Won Song
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chul-Soo Ahn
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Deok-Bog Moon
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Tae-Yong Ha
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Dong-Hwan Jung
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Gil-Chun Park
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Young-In Yoon
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Woo-Hyoung Kang
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Sun Y, Xiong Y, Wang Q, Qiao W, Zhang H, Zhang Y. Development and validation of a nomogram to predict the recurrence of hepatocellular carcinoma patients with dynamic changes in AFP undergoing locoregional treatments. Front Oncol 2023; 13:1206345. [PMID: 37700838 PMCID: PMC10494718 DOI: 10.3389/fonc.2023.1206345] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Accepted: 08/14/2023] [Indexed: 09/14/2023] Open
Abstract
Background Serum alpha-fetoprotein (AFP) is an important clinical indicator for screening, diagnosis, and prognosis of primary hepatocellular carcinoma (HCC). Our team's previous study showed that patients with negative AFP at baseline and positive AFP at relapse had a worse prognosis (N-P). Therefore, the aim of our study was to develop and validate a nomogram for this group of patients. Methods A total of 513 patients with HCC who received locoregional treatments at Beijing You'an Hospital, Capital Medical University, from January 2012 to December 2019 were prospectively enrolled. Patients admitted from 2012 to 2015 were assigned to the training cohort (n = 335), while 2016 to 2019 were in the validation cohort (n =183). The clinical and pathological features of patients were collected, and independent risk factors were identified using univariate and multivariate Cox regression analysis as a basis for developing a nomogram. The performance of the nomogram was evaluated by C-index, receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA) curves in the training and validation cohorts. Results The content of the nomogram includes gender, tumor number, tumor size, lymphocyte, direct bilirubin (DBIL), gamma-glutamyl transferase (GGT), and prealbumin. The C-index (0.717 and 0.752) and 1-, 3-, and 5-year AUCs (0.721, 0.825, 0.845, and 0.740, 0.868, 0.837) of the training and validation cohorts proved the good predictive performance of the nomogram. Calibration curves and DCA curves suggested accuracy and net clinical benefit rates. The nomogram enabled to classify of patients with dynamic changes in AFP into three groups according to the risk of recurrence: low risk, intermediate risk, and high risk. There was a statistically significant difference in RFS between the three groups in the training and validation cohorts (P<0.001). Conclusion The nomogram developed and validated in this study had good predictive power for patients with dynamic changes in AFP.
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Affiliation(s)
- Yu Sun
- Interventional Therapy Center for Oncology, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Yiqi Xiong
- Interventional Therapy Center for Oncology, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Qi Wang
- Interventional Therapy Center for Oncology, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Wenying Qiao
- Interventional Therapy Center for Oncology, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Honghai Zhang
- Interventional Therapy Center for Oncology, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Yonghong Zhang
- Interventional Therapy Center for Oncology, Beijing You’an Hospital, Capital Medical University, Beijing, China
- Research Center for Biomedical Resources, Beijing You’an Hospital, Capital Medical University, Beijing, China
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Kersten V, Seitz T, Sommer J, Thasler WE, Bosserhoff A, Hellerbrand C. Bone Morphogenetic Protein 13 Has Protumorigenic Effects on Hepatocellular Carcinoma Cells In Vitro. Int J Mol Sci 2023; 24:11059. [PMID: 37446238 DOI: 10.3390/ijms241311059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 06/29/2023] [Accepted: 07/01/2023] [Indexed: 07/15/2023] Open
Abstract
Activated hepatic stellate cells (HSCs) play a key role in hepatic fibrosis and, thus, build the "soil" for hepatocarcinogenesis. Furthermore, HSCs are known to promote the progression of hepatocellular carcinoma (HCC), but the molecular mechanisms are only incompletely understood. Recently, we newly described the expression of bone morphogenetic protein 13 (BMP13) by HSCs in fibrotic liver tissue. In addition, BMP13 has mostly been studied in the context of cartilage and bone repair, but not in liver disease or cancer. Thus, we aimed to analyze the expression and function of BMP13 in HCC. Expression analyses revealed high BMP13-expression in activated human HSCs, but not in human HCC-cell-lines. Furthermore, analysis of human HCC tissues showed a significant correlation between BMP13 and α-smooth muscle actin (α-SMA), and immunofluorescence staining confirmed the co-localization of BMP13 and α-SMA, indicating activated HSCs as the cellular source of BMP13 in HCC. Stimulation of HCC cells with recombinant BMP13 increased the expression of the inhibitors of differentiation 1 (ID1) and 2 (ID2), which are known targets of BMP-signaling and cell-cycle promotors. In line with this, BMP13-stimulation caused an induced SMAD 1/5/9 and extracellular signal-regulated kinase (ERK) phosphorylation, as well as reduced expression of cyclin-dependent kinase inhibitors 1A (CDKN1A) and 2A (CDKN2A). Furthermore, stimulation with recombinant BMP13 led to increased proliferation and colony size formation of HCC cells in clonogenicity assays. The protumorigenic effects of BMP13 on HCC cells were almost completely abrogated by the small molecule dorsomorphin 1 (DMH1), which selectively blocks the intracellular kinase domain of ALK2 and ALK3, indicating that BMP13 acts via these BMP type I receptors on HCC cells. In summary, this study newly identifies stroma-derived BMP13 as a potential new tumor promotor in HCC and indicates this secreted growth-factor as a possible novel therapeutic target in HCC.
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Affiliation(s)
- Vanessa Kersten
- Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg, D-91054 Erlangen, Germany
| | - Tatjana Seitz
- Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg, D-91054 Erlangen, Germany
| | - Judith Sommer
- Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg, D-91054 Erlangen, Germany
| | - Wolfgang E Thasler
- Human Tissue and Cell Research-Services GmbH, Am Klopferspitz 19, D-82152 Planegg, Germany
| | - Anja Bosserhoff
- Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg, D-91054 Erlangen, Germany
- Comprehensive Cancer Center (CCC) Erlangen-EMN, D-91054 Erlangen, Germany
| | - Claus Hellerbrand
- Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg, D-91054 Erlangen, Germany
- Comprehensive Cancer Center (CCC) Erlangen-EMN, D-91054 Erlangen, Germany
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Zhang L, Wu J, Wu Q, Zhang X, Lin S, Ran W, Zhu L, Tang C, Wang X. Sex steroid axes in determining male predominance in hepatocellular carcinoma. Cancer Lett 2023; 555:216037. [PMID: 36563929 DOI: 10.1016/j.canlet.2022.216037] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 11/23/2022] [Accepted: 12/05/2022] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death. The mechanisms for male propensity in HCC incidence, prognosis and treatment responses are complicated and remain inconclusive. Sex-biased molecular signatures in carcinogenesis, viral infections and immune responses have been studied predominantly within the context of sex hormones effects. This review integrates current knowledge on the mechanisms through which the hormones regulate HCC development in sexually dimorphic fashion. Firstly, the androgen/androgen receptor (AR) accelerate cell proliferation and virus infection, especially during the initial stage of HCC, while estrogen/estrogen receptor (ER) function in an opposite way to induce cell apoptosis and immune responses. Interestingly, the controversial effects of AR in late stage of HCC metastasis are summarized and the reasons are attributed to inconsistent cancer grading or experimental models between the studies. In addition, the new insights into these intricate cellular and molecular mechanisms underlying sexual dimorphism are fully discussed. A detailed understanding of sex hormones-associated regulation to male predominance in HCC may help to develop personalized therapeutic strategies in high-risk populations.
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Affiliation(s)
- Lei Zhang
- Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - JinFeng Wu
- Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - QiuMei Wu
- Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - XiangJuan Zhang
- Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - ShuaiCai Lin
- Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - WanLi Ran
- Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Li Zhu
- Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - ChengYan Tang
- Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Xing Wang
- Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China.
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Zhang F, Hu K, Liu W, Quan B, Li M, Lu S, Chen R, Ren Z, Yin X. Oxaliplatin-Resistant Hepatocellular Carcinoma Drives Immune Evasion Through PD-L1 Up-Regulation and PMN-Singular Recruitment. Cell Mol Gastroenterol Hepatol 2023; 15:573-591. [PMID: 36513250 PMCID: PMC9868681 DOI: 10.1016/j.jcmgh.2022.12.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 12/06/2022] [Accepted: 12/06/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Previously, we showed the inhibitor of differentiation or DNA binding 1 (ID1)/Myc signaling is highly expressed in oxaliplatin-resistant hepatocellular carcinoma (HCC). This study sought to investigate the role of ID1/Myc signaling on immune evasion in oxaliplatin-resistant HCC. METHODS The oxaliplatin (OXA)-resistant HCC cell lines (Hepa 1-6-OXA, 97H-OXA, and 3B-OXA) were established and their oxaliplatin tolerance was confirmed in vitro and in vivo. The relationship between ID1/Myc and programmed death-ligand 1 (PD-L1) up-regulation and polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) accumulation was explored. The underlying mechanism in which ID1/Myc signaling regulated PD-L1 expression and PMN-MDSC accumulation was investigated in vitro and vivo. RESULTS Increased ID1/Myc expression was identified in oxaliplatin-resistant HCC and correlated with PD-L1 up-regulation and PMN-MDSC accumulation. The knockdown of Myc sensitized oxaliplatin-resistant HCC cells to oxaliplatin and resulted in a decrease of PMN-MDSCs and an increase of interferon-γ+ CD8+ T cells in a tumor microenvironment. Polymerase chain reaction array, enzyme-linked immunosorbent assay, and MDSC Transwell migration assay indicated that oxaliplatin-resistant HCC cells recruited PMN-MDSCs through chemokine (C-C motif) ligand 5 (CCL5). The dual luciferase reporter assay and chromatin immunoprecipitation assay indicated that Myc could directly increase the transcriptions of PD-L1 and CCL5. Furthermore, anti-PD-L1 antibody combined with CCL5 blockade showed significant antitumor effects in oxaliplatin-resistant HCC. CONCLUSIONS ID1/Myc signaling drives immune evasion in oxaliplatin-resistant HCC via PD-L1 up-regulation and PMN-MDSC recruitment. Blocking the ID1/Myc-induced immune tolerance represents a promising treatment target to conquer chemoresistance in HCC.
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Affiliation(s)
- Feng Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Keshu Hu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wenfeng Liu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Bing Quan
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Miao Li
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shenxin Lu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Rongxin Chen
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhenggang Ren
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xin Yin
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
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10
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Lu Z, Yang D, Qin S, Mo C, Zhang L, Ou Y, Li S. Testis-specific protein Y-encoded 1 regulates androgen receptor expression through the MAPK/ERK pathway in male hepatocellular carcinoma. Saudi Med J 2022; 43:1087-1095. [PMID: 36261201 PMCID: PMC9994500 DOI: 10.15537/smj.2022.43.10.20220455] [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: 06/09/2022] [Accepted: 09/13/2022] [Indexed: 06/16/2023] Open
Abstract
OBJECTIVES To analyze the mechanism of testis-specific protein Y-encoded 1 (TSPY1) in male hepatocellular carcinoma (HCC). METHODS This experimental study was carried out at Guangxi Medical University's First Affiliated Hospital, Guangxi, China, between January 2016 and December 2019. The expression of TSPY1, androgen receptor (AR), messenger ribonucleic acids (mRNAs), and proteins were detected by qRT-PCR and Western blotting. The co-localization and interaction of TSPY1 and AR were observed by immunofluorescence assay and co-immunoprecipitation. Hepatocellular carcinoma cells overexpressing and silencing TSPY1 were constructed, and the expression and phosphorylation levels of TSPY1, AR, and mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) signaling pathway-related key molecules ERK1/2, p38, and JNK were also detected. RESULTS The expression levels of TSPY1, AR mRNAs, and proteins were highly positively correlated in HCC cells in different metastatic potentials with a high correlation coefficient of R=0.929 and R=0.884. Testis-specific protein Y-encoded 1 and AR were then co-localized in the nucleus of HCC cells, and TSPY1 and AR can interact with each other. In addition, the expression of AR and phosphorylation of ERK1/2 were enhanced in TSPY1 overexpressed Huh7 cells. They were reduced in HCCLM3 cells with TSPY1 knockdown expression. In addition, in response to blocking MAPK/ERK signaling activity, AR was reduced in expression. CONCLUSION These findings suggested that there was a positive correlation between TSPY1 expression and AR in male HCC cells, and high TSPY1 expression stimulates AR expression, MAPK/ERK signaling pathway may be involved in its mechanism.
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Affiliation(s)
- Zhaolu Lu
- From the Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Guangxi, China.
| | - Dongmei Yang
- From the Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Guangxi, China.
| | - Shanzi Qin
- From the Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Guangxi, China.
| | - Cuiju Mo
- From the Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Guangxi, China.
| | - Linyan Zhang
- From the Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Guangxi, China.
| | - Yingying Ou
- From the Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Guangxi, China.
| | - Shan Li
- From the Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Guangxi, China.
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11
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Calaf GM, Crispin LA, Muñoz JP, Aguayo F, Bleak TC. Muscarinic Receptors Associated with Cancer. Cancers (Basel) 2022; 14:cancers14092322. [PMID: 35565451 PMCID: PMC9100020 DOI: 10.3390/cancers14092322] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 04/26/2022] [Accepted: 04/30/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary Recently, cancer research has described the presence of the cholinergic machinery, specifically muscarinic receptors, in a wide variety of cancers due to their activation and signaling pathways associated with tumor progression and metastasis, providing a wide overview of their contribution to different cancer formation and development for new antitumor targets. This review focused on determining the molecular signatures associated with muscarinic receptors in breast and other cancers and the need for pharmacological, molecular, biochemical, technological, and clinical approaches to improve new therapeutic targets. Abstract Cancer has been considered the pathology of the century and factors such as the environment may play an important etiological role. The ability of muscarinic agonists to stimulate growth and muscarinic receptor antagonists to inhibit tumor growth has been demonstrated for breast, melanoma, lung, gastric, colon, pancreatic, ovarian, prostate, and brain cancer. This work aimed to study the correlation between epidermal growth factor receptors and cholinergic muscarinic receptors, the survival differences adjusted by the stage clinical factor, and the association between gene expression and immune infiltration level in breast, lung, stomach, colon, liver, prostate, and glioblastoma human cancers. Thus, targeting cholinergic muscarinic receptors appears to be an attractive therapeutic alternative due to the complex signaling pathways involved.
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Affiliation(s)
- Gloria M. Calaf
- Instituto de Alta Investigación, Universidad de Tarapacá, Arica 1000000, Chile; (L.A.C.); (J.P.M.); (T.C.B.)
- Correspondence:
| | - Leodan A. Crispin
- Instituto de Alta Investigación, Universidad de Tarapacá, Arica 1000000, Chile; (L.A.C.); (J.P.M.); (T.C.B.)
| | - Juan P. Muñoz
- Instituto de Alta Investigación, Universidad de Tarapacá, Arica 1000000, Chile; (L.A.C.); (J.P.M.); (T.C.B.)
| | - Francisco Aguayo
- Laboratorio de Oncovirología, Programa de Virología, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago 8380000, Chile;
| | - Tammy C. Bleak
- Instituto de Alta Investigación, Universidad de Tarapacá, Arica 1000000, Chile; (L.A.C.); (J.P.M.); (T.C.B.)
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12
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Taura K, Shimamura T, Akamatsu N, Umeshita K, Fujiyoshi M, Abe H, Morita S, Uemoto S, Eguchi S, Furukawa H, Takada Y, Egawa H, Ohdan H, Hatano E. No impact of donor sex on the recurrence of hepatocellular carcinoma after liver transplantation. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2022; 29:570-584. [PMID: 35279950 DOI: 10.1002/jhbp.1134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 12/28/2021] [Accepted: 01/23/2022] [Indexed: 11/12/2022]
Abstract
BACKGROUND/PURPOSE We aimed to verify a recent theory that female donors reduced the risk of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT). METHODS A total of 1118 recipients registered in the Japanese Liver Transplantation Society database were evaluated for HCC, of whom 446 received a graft from female donors (F-D group) and 672 from male donors (M-D group). RESULTS Between the groups, donor age, recipient age and sex, positivity of hepatitis viruses, and graft type were different, whereas tumor-related factors were all comparable. The 5-year overall recurrence rates were 14% and 16% in the F-D and M-D groups, respectively (P = 0.59). The 5-year graft recurrence rate was also comparable between the groups (4% and 6%, respectively, P = 0.17). Neither univariate nor multivariate analysis identified donor sex as a significant risk factor for recurrence. Propensity score matching showed similar 5-year overall recurrence rates (15% in the F-D group and 14% in the M-D group, P = 0.63) and graft recurrence rates (5% and 5%, respectively, P = 0.94) between the groups. CONCLUSION Donor sex did not affect post-LT recurrence of HCC in the Japanese cohort and should not be considered in the process of donor selection or organ allocation.
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Affiliation(s)
- Kojiro Taura
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tsuyoshi Shimamura
- Division of Organ Transplantation, Hokkaido University Hospital, Sapporo, Japan
| | - Nobuhisa Akamatsu
- Artificial Organ and Transplantation Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Koji Umeshita
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Masato Fujiyoshi
- Division of Organ Transplantation, Hokkaido University Hospital, Sapporo, Japan
| | - Hiroyasu Abe
- Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan
| | - Satoshi Morita
- Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan
| | | | - Susumu Eguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Hiroyuki Furukawa
- Division of Gastroenterological Surgery, Department of Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Yasutsugu Takada
- Department of Hepato-Pancreatic-Biliary and Breast Surgery, Ehime University Graduate School of Medicine, Shitsukawa, Japan
| | - Hiroto Egawa
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Etsuro Hatano
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
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13
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Zhou HC, Liu CX, Pan WD, Shang LR, Zheng JL, Huang BY, Chen JY, Zheng L, Fang JH, Zhuang SM. Dual and opposing roles of the androgen receptor in VETC-dependent and invasion-dependent metastasis of hepatocellular carcinoma. J Hepatol 2021; 75:900-911. [PMID: 34004215 DOI: 10.1016/j.jhep.2021.04.053] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 04/26/2021] [Accepted: 04/29/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Contradictory roles of the androgen receptor (AR) in hepatocellular carcinoma (HCC) metastasis have been reported. We have shown that VETC (vessels encapsulating tumor clusters) mediates invasion-independent metastasis, whereas VETC- HCCs metastasize in an invasion-dependent manner. Herein, we aimed to reveal the roles of AR in HCC metastasis. METHODS Mouse xenograft models, clinical samples, and cell models were used. RESULTS AR expression was significantly lower in HCCs with a VETC pattern, portal vein tumor thrombus, endothelium-coated microemboli or high recurrence rates. Overexpressing AR in VETC+ hepatoma cells suppressed VETC formation and intrahepatic metastasis but promoted pulmonary metastasis of mouse xenografts. AR decreased the transcription of Angiopoietin-2 (Angpt2), a factor essential for VETC formation, by binding to the Angpt2 promoter. The roles of AR in inhibiting VETC formation and intrahepatic metastasis were attenuated by restoring Angpt2 expression, suggesting that AR may repress VETC-dependent intrahepatic metastasis by inhibiting Angpt2 expression and VETC formation. On the other hand, AR upregulated Rac1 expression, promoted lamellipodia formation and increased cell migration/invasion. A Rac1 inhibitor abrogated the AR-mediated promotion of migration/invasion and pulmonary metastasis of VETC+ hepatoma cells, but did not affect the AR-mediated inhibition of intrahepatic metastasis. Furthermore, an AR inhibitor decreased Rac1 expression and attenuated both intrahepatic and pulmonary metastasis of VETC- xenografts, an effect which was abrogated by restoring Rac1 expression. These data indicate that AR may facilitate the lung metastasis of VETC+ HCCs and both the liver/lung metastases of VETC- HCCs by upregulating Rac1 expression and then promoting migration/invasion. CONCLUSION AR plays dual and opposing roles in VETC-dependent and invasion-dependent metastasis, which highlights the complex functions of AR and the importance of individualized cancer therapy. LAY SUMMARY In this study, we uncovered the dual and opposing roles of the androgen receptor in VETC (vessels encapsulating tumor clusters)-dependent and invasion-dependent metastasis of hepatocellular carcinoma (HCC). We elucidated the underlying mechanisms of these processes, which provided novel insights into the complex regulatory network of the androgen receptor in HCC metastasis and may have important implications for precision medicine.
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Affiliation(s)
- Hui-Chao Zhou
- Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
| | - Chu-Xing Liu
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China
| | - Wei-Dong Pan
- Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
| | - Li-Ru Shang
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China
| | - Jia-Lin Zheng
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China
| | - Bi-Yu Huang
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China
| | - Jie-Ying Chen
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China
| | - Limin Zheng
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China
| | - Jian-Hong Fang
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China.
| | - Shi-Mei Zhuang
- Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China; MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China.
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14
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Zhang N, Zhang S, Wu W, Lu W, Jiang M, Zheng N, Huang J, Wang L, Liu H, Zheng M, Wang J. Regorafenib inhibits migration, invasion, and vasculogenic mimicry of hepatocellular carcinoma via targeting ID1-mediated EMT. Mol Carcinog 2021; 60:151-163. [PMID: 33428809 DOI: 10.1002/mc.23279] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 12/22/2020] [Accepted: 12/28/2020] [Indexed: 12/20/2022]
Abstract
Regorafenib is approved for patients with unresectable hepatocellular carcinoma (HCC) following sorafenib. However, the effect of regorafenib on HCC metastasis and its mechanism are poorly understood. Here, our data showed that regorafenib significantly restrained the migration, invasion and vasculogenic mimicry (VM) of HCC cells, and downregulated the expression of epithelial-to-mesenchymal transition (EMT)/VM-related molecules. Using RNA-seq and cellular thermal shift assays, we found that inhibitor of differentiation 1 (ID1) was a key target of regorafenib. In HCC tissues, the protein expression of ID1 was positively correlated with EMT and VM formation (CD34- /PAS+ ). Functionally, ID1 knockdown inhibited HCC cell migration, invasion, metastasis, and VM formation in vitro and in vivo, with upregulation of E-cadherin and downregulation of Snail and VE-cadherin. Moreover, Snail overexpression promoted the migration, invasion, and VM formation of ID1 knockdown cells. Snail knockdown reduced the migration, invasion, and VM formation of ID1 overexpression cells. Finally, regorafenib suppressed VM formation and decreased the expression of ID1, VE-cadherin and Snail in HCC PDX model. In conclusion, we manifested that regorafenib distinctly inhibited EMT in HCC cells via targeting ID1, leading to the suppression of cell migration, invasion and VM formation. These findings suggest that regorafenib may be developed as a suitable therapeutic agent for HCC metastasis.
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Affiliation(s)
- Nan Zhang
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, China
| | - Shaoqin Zhang
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, China
| | - Wenda Wu
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, China
| | - Wenxian Lu
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, China
| | - Mingting Jiang
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, China
| | - Ning Zheng
- Department of Pharmacology, Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, The School of Pharmacy, Fujian Medical University, Fujian, China
| | - Jing Huang
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, China
| | - Long Wang
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, China
| | - Hekun Liu
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, China
| | - Min Zheng
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, China
| | - Jichuang Wang
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, China
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15
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Zhu P, Feng R, Lu X, Liao Y, Du Z, Zhai W, Chen K. Diagnostic and prognostic values of AKR1C3 and AKR1D1 in hepatocellular carcinoma. Aging (Albany NY) 2021; 13:4138-4156. [PMID: 33493134 PMCID: PMC7906155 DOI: 10.18632/aging.202380] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 10/31/2020] [Indexed: 12/29/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common histological type of primary liver cancer and the majority of patients are diagnosed at an advanced stage and have a poor prognosis. AKR1C3 (Aldo-keto reductase family 1 member C3) and AKR1D1 (Aldo-keto reductase family 1 member D1) catalyze the conversion of aldehydes and ketones to alcohols and play crucial roles in multiple cancers. However, the functions of AKR1C3 and AKR1D1 in HCC remain unclear. In our study, data from the public databases were selected as training and validation sets, then 76 HCC patients in our center were chosen as a test set. Bioinformatics methods suggested AKR1C3 was overexpressed in HCC and AKR1D1 was down-regulated. The receiver operating characteristic curve (ROC) analysis was performed and the area under curve (AUC) values of AKR1C3 and AKR1D1 were above 0.7 (0.948, 0.836, respectively). Also, the high expression of AKR1C3 and low expression of AKR1D1 predicted poor prognosis and short median survival time. Then, the knockdown of AKR1C3 and overexpression of AKR1D1 in HCC cells were achieved with lentivirus. And both decreased cell proliferation, restrained cell viability, and inhibited tumorigenesis. Moreover, the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted and the results showed that AKR1C3 and AKR1D1 might participate in the MAPK/ERK and androgen receptor (AR) signaling pathway. Furthermore, the AR and phosphorylated ERK1/2 were significantly reduced after the suppression of AKR1C3 or overexpression of AKR1D1. Collectively, AKR1C3 and AKR1D1 might serve as candidate diagnostic and prognostic biomarkers for HCC and provide potential targets for HCC treatment.
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Affiliation(s)
- Pengfei Zhu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Henan 450052, P.R. China
| | - Ruo Feng
- Department of Histology and Embryology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450052, Henan, P.R. China
| | - Xu Lu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Henan 450052, P.R. China
| | - Yuan Liao
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Henan 450052, P.R. China
| | - Zhicheng Du
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Henan 450052, P.R. China
| | - Wenlong Zhai
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Henan 450052, P.R. China
| | - Kunlun Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Henan 450052, P.R. China
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16
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The androgen receptor expression and its activity have different relationships with prognosis in hepatocellular carcinoma. Sci Rep 2020; 10:22046. [PMID: 33328560 PMCID: PMC7744520 DOI: 10.1038/s41598-020-79177-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 12/02/2020] [Indexed: 01/01/2023] Open
Abstract
The role of the Androgen Receptor (AR) expression and its activity in the prognosis of hepatocellular carcinoma (HCC) remains inconclusive. The aim of this study is to analyze the role of the AR expression and its activity as prognostic biomarkers in HCC. Three-hundred and thirty-seven patients from The Cancer Genome Atlas (TCGA) (107 females; 59.42 years [SD = 13.0]) were included. To infer AR activity, the expression-profile of previously validated androgen responsive genes (ARGs) was included. AR activity was shown by the AR-Score-21 (21 ARGs) and AR-Score-13 (13 ARGs) that were computed based on the expression of the selected ARGs. Those ARGs whose expression was significantly different between histological grades were used for computing two new AR-Scores. HCC patients with higher AR expression showed a higher median overall survival (OS). AR-Score 21 and AR-Score-13 did not show any association with prognosis. Six of the 21 ARGs of the AR-Score-21 and 7 of the 13 ARGs of the AR-Score-13 showed a significant different expression profile among histological grades. Based on these differences, another two AR-Scores were computed (AR-Score-6 and AR-Score-7). They showed the relative increase of upregulated to downregulated ARGs in high-grade HCC. Higher AR activity inferred by these AR-Scores was associated with worse outcomes. The expression of AR is associated with a better prognosis in HCC. However, the activity of the AR seems to be qualitatively different among histological grades. The AR activity inferred by the shifted ARGs is associated with a worse prognosis in HCC patients.
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17
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Soleymani Fard S, Yazdanbod M, Sotoudeh M, Bashash D, Mahmoodzadeh H, Saliminejad K, Mousavi SA, Ghaffari SH, Alimoghaddam K. Prognostic and Therapeutic Significance of Androgen Receptor in Patients with Gastric Cancer. Onco Targets Ther 2020; 13:9821-9837. [PMID: 33061460 PMCID: PMC7537849 DOI: 10.2147/ott.s265364] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 08/29/2020] [Indexed: 01/02/2023] Open
Abstract
Purpose The clinical studies carried out in the last few decades unequivocally introduced activated androgen receptor (AR) as a pathogenic feature of human malignancies which not only endows cancer cells with survival advantage, but also may be exploited for anticancer interventions. Patients and Methods In this study, we have investigated the expression profile of AR and EMT-related genes in fresh gastric cancer (GC), adjacent nontumor and normal gastric tissues, as well as the effect and molecular mechanisms of AR inhibition in GC cell lines. Results Amongst 60 GC patients, 66.7% overexpressed AR that was remarkably correlated with the overexpression of Snail, β-catenin, Twist1, and STAT3. AR overexpression was also remarkably associated with unfavorable outcome (HR=3.478, P=0.001); however, multivariate Cox regression analysis indicated that it was not an independent prognostic factor (HR=2.089, P=0.056). This study has investigated simultaneous assessment of AR and EMT-related genes expression and indicated that concurrent overexpression of AR and Snail is an independent unfavorable factor for GC overall survival after adjustment with other variables (HR=2.382, P=0.021). Interestingly, the inhibition of AR signaling by potent AR antagonist enzalutamide suppressed cell growth, migration and invasion of GC cells via regulation of apoptosis-, cell cycle-, and EMT-related gene expressions. Conclusion Our findings have clinical importance proposing AR as an important prognostic factor involved in GC progression and metastasis, and submit AR inhibition as an appealing therapeutic approach for GC patients, either as a single agent or in a combined-modal strategy.
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Affiliation(s)
- Shahrzad Soleymani Fard
- Hematology, Oncology and Stem Cell Transplantation Research Institute, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Masoud Sotoudeh
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Habibollah Mahmoodzadeh
- Department of Surgical Oncology, Cancer Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Kioomars Saliminejad
- Hematology, Oncology and Stem Cell Transplantation Research Institute, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Asadollah Mousavi
- Hematology, Oncology and Stem Cell Transplantation Research Institute, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed H Ghaffari
- Hematology, Oncology and Stem Cell Transplantation Research Institute, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Kamran Alimoghaddam
- Hematology, Oncology and Stem Cell Transplantation Research Institute, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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18
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Zhou Q, Li Z, Song L, Mu D, Wang J, Tian L, Liao Y. Whole-exome mutational landscape of metastasis in patient-derived hepatocellular carcinoma cells. Genes Dis 2020; 7:380-391. [PMID: 32884992 PMCID: PMC7452411 DOI: 10.1016/j.gendis.2020.05.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 04/29/2020] [Accepted: 05/09/2020] [Indexed: 02/06/2023] Open
Abstract
In order to explore the genomic basis for liver cancer metastasis, whole-exome sequencing (WES) was performed on patient-derived hepatocellular carcinoma (HCC) cell lines with differential metastatic potentials and analyzed their clonal evolution relationships. An evolutionary tree based on genomic single nucleotide polymorphism (SNP) was constructed in MegaX software. The WES data showed that the average percentage of heterogeneous mutations in each HCC cell lines was 16.55% (range, 15.38%–18.17%). C: G > T: A and T: A > C: G somatic transitions were the two most frequent substitutions. In these metastatic HCC cell lines, non-silent gene mutations were found in 21.88% of known driver genes and 10 classical signaling pathways. The protein interaction network was constructed by STRING, and hub genes were found in the shared trunk mutation genes and the heterogeneous branch mutations respectively. In cBioPortal database, some of the selected hub genes were found to be associated with poor overall survival (OS) of HCC patients. Among the mutated HCC driver genes, a novel KEAP1 mutation with a homozygous frameshift truncation at the c-terminal Nrf2 binding region was detected and verified in MHCC97-H and HCC97LM3 cells. In conclusion, WES data demonstrate that HCC cell lines from tumor biopsy specimens of the same patient have obtained different metastatic potentials through repeated selection in rodents in vivo, and they do indeed have a genetic relationship at the genomic level.
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Key Words
- BTB, Broad-complex, Tramtrack, and Bric-a-brac
- CDS, coding for amino acids in protein
- CNC, cap’n’collar
- CTR, C-terminal region
- CUL3, Cullin3
- Clonal evolution
- DGR, DC domain harboring six Kelch-repeat domain
- Encyclopedia of genes and genomes (KEGG)
- FA, fatty acid
- GO, Gene Ontology
- Gene ontology (GO)
- Genome-wide association
- HCC, hepatocellular carcinoma
- Hepatocellular carcinoma
- IVR, intervening region
- KEGG, Kyoto Encyclopedia of Genes and Genomes
- Metastatic potentiality
- NTR, N-terminal region
- OS, overall survival
- SNP, single nucleotide polymorphism
- Somatic gene mutation
- WES, whole exome sequencing
- Whole exome sequencing
- bZIP, basic-region leucine zipper
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Affiliation(s)
- Qian Zhou
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing, China.,Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, China.,Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Zuli Li
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing, China.,Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, China.,Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Linlan Song
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing, China.,Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, China.,Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Di Mu
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing, China.,Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, China.,Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Jin Wang
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing, China.,Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, China.,Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Li Tian
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing, China.,Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, China.,Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Yong Liao
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing, China.,Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, China.,Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
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19
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Wang Q, Ma L, Li J, Yuan C, Sun J, Li K, Qin L, Zang C, Zhao Y, Zhao Y, Zhang Y. A Novel Scoring System for Patients with Recurrence of Hepatocellular Carcinoma After Undergoing Minimal Invasive Therapies. Cancer Manag Res 2020; 11:10641-10649. [PMID: 31908536 PMCID: PMC6930388 DOI: 10.2147/cmar.s224711] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 12/08/2019] [Indexed: 12/24/2022] Open
Abstract
Background The higher recurrence rate of hepatocellular carcinoma (HCC) needs to be urgently controlled. However, definitive markers are lacking for patients with recurrence of HCC after undergoing minimal invasive therapies-local ablation combined with transcatheter arterial chemoembolization (TACE). Materials and methods Demographic and clinicopathological data of 234 subjects receiving combined therapies as the initial treatment were retrospectively analyzed. Univariate and multivariate Cox regression analysis was used to assess independent risk factors of recurrence. Selected variables were divided into low-, intermediate-, and high-risk groups of recurrence according to the scores assigned to them based on their respective hazard ratio (HR) values. The area under the curve (AUC) was used to evaluate the predictive value of the scoring system. Cumulative recurrence-free survival (RFS) and overall survival rates were calculated by the Kaplan-Meier estimator. Finally, a correlation analysis was performed on demographic and clinical data among the three groups. Results The AUC of predicting 1-, 2-, and 3-year recurrence rates was 0.680, 0.728, and 0.709, respectively. The cumulative RFS rate in the low-risk group at 1, 2, and 3 years after undergoing combined treatments was 4%, 12.2%, and 30.6%, while that in the intermediate-risk group and high-risk group was 23.4%, 51.6%, 60.0%, and 47.3%, 78.2%, 83.6%, respectively. Gamma-glutamyltransferase (γ-GT), blood urea nitrogen (BUN), and total cholesterol (TC) levels among the three groups were statistically different. Conclusion The scoring system of the present study for patients with the recurrence of HCC after undergoing TACE combined with local ablation may help physicians make a reasonable clinical decision, providing ideal management for diagnosis and treatment.
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Affiliation(s)
- Qi Wang
- Research Center for Biomedical Resources, Beijing You'an Hospital, Capital Medical University, Beijing 100069, People's Republic of China
| | - Liang Ma
- Interventional Therapy Center for Oncology, Beijing You'an Hospital, Capital Medical University, Beijing 100069, People's Republic of China
| | - Jianjun Li
- Interventional Therapy Center for Oncology, Beijing You'an Hospital, Capital Medical University, Beijing 100069, People's Republic of China
| | - Chunwang Yuan
- Interventional Therapy Center for Oncology, Beijing You'an Hospital, Capital Medical University, Beijing 100069, People's Republic of China
| | - Jianping Sun
- Research Center for Biomedical Resources, Beijing You'an Hospital, Capital Medical University, Beijing 100069, People's Republic of China
| | - Kang Li
- Research Center for Biomedical Resources, Beijing You'an Hospital, Capital Medical University, Beijing 100069, People's Republic of China
| | - Ling Qin
- Research Center for Biomedical Resources, Beijing You'an Hospital, Capital Medical University, Beijing 100069, People's Republic of China
| | - Chaoran Zang
- Research Center for Biomedical Resources, Beijing You'an Hospital, Capital Medical University, Beijing 100069, People's Republic of China
| | - Yanan Zhao
- Research Center for Biomedical Resources, Beijing You'an Hospital, Capital Medical University, Beijing 100069, People's Republic of China
| | - Yan Zhao
- Clinical Detection Center, Beijing You'an Hospital, Capital Medical University, Beijing 100069, People's Republic of China
| | - Yonghong Zhang
- Research Center for Biomedical Resources, Beijing You'an Hospital, Capital Medical University, Beijing 100069, People's Republic of China.,Interventional Therapy Center for Oncology, Beijing You'an Hospital, Capital Medical University, Beijing 100069, People's Republic of China
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20
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Zhao Z, Bo Z, Gong W, Guo Y. Inhibitor of Differentiation 1 (Id1) in Cancer and Cancer Therapy. Int J Med Sci 2020; 17:995-1005. [PMID: 32410828 PMCID: PMC7211148 DOI: 10.7150/ijms.42805] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 03/20/2020] [Indexed: 02/07/2023] Open
Abstract
The inhibitor of DNA binding (Id) proteins are regulators of cell cycle and cell differentiation. Of all Id family proteins, Id1 is mostly linked to tumorigenesis, cellular senescence as well as cell proliferation and survival. Id1 is a stem cell-like gene more than a classical oncogene. Id1 is overexpressed in numerous types of cancers and exerts its promotion effect to these tumors through different pathways. Briefly, Id1 was found significantly correlated with EMT-related proteins, K-Ras signaling, EGFR signaling, BMP signaling, PI3K/Akt signaling, WNT and SHH signaling, c-Myc signaling, STAT3 signaling, RK1/2 MAPK/Egr1 pathway and TGF-β pathway, etc. Id1 has potent effect on facilitating tumorous angiogenesis and metastasis. Moreover, high expression of Id1 plays a facilitating role in the development of drug resistance, including chemoresistance, radiation resistance and resistance to drugs targeting angiogenesis. However, controversial results were also obtained. Overall, Id1 represent a promising target of anti-tumor therapeutics based on its potent promotion effect to cancer. Numerous drugs were found exerting their anti-tumor function through Id1-related signaling pathways, such as fucoidan, berberine, tetramethylpyrazine, crizotinib, cannabidiol and vinblastine.
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Affiliation(s)
- Zhengxiao Zhao
- Department of Oncology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310006, China
| | - Zhiyuan Bo
- The Second Department of Biliary Tract Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China
| | - Weiyi Gong
- The Department of Integrative Medicine, Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai 200040, PR China
| | - Yong Guo
- Department of Oncology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310006, China
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21
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Dauki AM, Blachly JS, Kautto EA, Ezzat S, Abdel-Rahman MH, Coss CC. Transcriptionally Active Androgen Receptor Splice Variants Promote Hepatocellular Carcinoma Progression. Cancer Res 2019; 80:561-575. [PMID: 31685543 DOI: 10.1158/0008-5472.can-19-1117] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 08/20/2019] [Accepted: 10/28/2019] [Indexed: 12/29/2022]
Abstract
Owing to the marked sexual dimorphism of hepatocellular carcinoma (HCC), sex hormone receptor signaling has been implicated in numerous aspects of liver cancer pathogenesis. We sought to reconcile the clear contribution of androgen receptor (AR) activity that has been established in preclinical models of HCC with the clinical failure of AR antagonists in patients with advanced HCC by evaluating potential resistance mechanisms to AR-targeted therapy. The AR locus was interrogated for resistance-causing genomic modifications using publicly available primary HCC datasets (1,019 samples). Analysis of HCC tumor and cell line RNA-seq data revealed enriched expression of constitutively active, treatment-refractory AR splice variants (AR-SV). HCC cell lines expressed C-terminal-truncated AR-SV; 28 primary HCC samples abundantly expressed AR-SV. Low molecular weight AR species were nuclear localized and constitutively active. Furthermore, AR/AR-SV signaling promoted AR-mediated HCC cell progression and conferred resistance to AR antagonists. Ligand-dependent and -independent AR signaling mediated HCC epithelial-to-mesenchymal transition by regulating the transcription factor SLUG. These data suggest that AR-SV expression in HCC drives HCC progression and resistance to traditional AR antagonists. Novel therapeutic approaches that successfully target AR-SVs may be therapeutically beneficial for HCC. SIGNIFICANCE: Treatment-refractory, constitutively active androgen receptor splice variants promote hepatocellular carcinoma progression by regulating the epithelial-to-mesenchymal transition pathway.
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Affiliation(s)
- Anees M Dauki
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio
| | - James S Blachly
- Division of Hematology, College of Medicine, The Ohio State University, Columbus, Ohio.,Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, Ohio
| | - Esko A Kautto
- Division of Hematology, College of Medicine, The Ohio State University, Columbus, Ohio.,Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio.,Biomedical Sciences Graduate Program, The Ohio State University, Columbus, Ohio
| | - Sameera Ezzat
- Department of Public Health, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt.,National Liver Institute Sustainable Sciences Institute Collaborative Research Center, Menoufia University, Shebin El-kom, Egypt
| | - Mohamed H Abdel-Rahman
- National Liver Institute Sustainable Sciences Institute Collaborative Research Center, Menoufia University, Shebin El-kom, Egypt.,Department of Ophthalmology, College of Medicine, The Ohio State University, Columbus, Ohio.,Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.,Pathology Department, National Liver Institute, Menoufia University, Shebin El-kom, Egypt
| | - Christopher C Coss
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio. .,Drug Development Institute, OSU Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
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22
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Ke J, Wu R, Chen Y, Abba ML. Inhibitor of DNA binding proteins: implications in human cancer progression and metastasis. Am J Transl Res 2018; 10:3887-3910. [PMID: 30662638 PMCID: PMC6325517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Accepted: 11/29/2018] [Indexed: 06/09/2023]
Abstract
Inhibitor of DNA binding (ID) proteins are a class of helix-loop-helix (HLH) transcription regulatory factors that act as dominant-negative antagonists of other basic HLH proteins through the formation of non-functional heterodimers. These proteins have been shown to play critical roles in a wide range of tumor-associated processes, including cell differentiation, cell cycle progression, migration and invasion, epithelial-mesenchymal transition, angiogenesis, stemness, chemoresistance, tumorigenesis, and metastasis. The aberrant expression of ID proteins has not only been detected in many types of human cancers, but is also associated with advanced tumor stages and poor clinical outcome. In this review, we provide an overview of the key biological functions of ID proteins including affiliated signaling pathways. We also describe the regulation of ID proteins in cancer progression and metastasis, and elaborate on expression profiles in cancer and the implications for prognosis. Lastly, we outline strategies for the therapeutic targeting of ID proteins as a promising and effective approach for anticancer therapy.
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Affiliation(s)
- Jing Ke
- Department of Liver Disease, The Fourth Affiliated Hospital of Anhui Medical UniversityHefei 230022, China
- Center for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, University of HeidelbergMannheim 68167, Germany
| | - Ruolin Wu
- Department of Hepatopancreatobiliary Surgery and Organ Transplantation Center, Department of General Surgery, First Affiliated Hospital of Anhui Medical University218 Jixi Avenue, Hefei 230022, Anhui, China
- Center for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, University of HeidelbergMannheim 68167, Germany
| | - Yong Chen
- Department of Medical Oncology, Subei People’s HospitalYangzhou, Jiangsu 225000, China
| | - Mohammed L Abba
- Department of Hematology and Oncology, University Hospital Mannheim, Medical Faculty Mannheim, University of HeidelbergMannheim, Germany
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23
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Risk of Post-transplant Hepatocellular Carcinoma Recurrence Is Higher in Recipients of Livers From Male Than Female Living Donors. Ann Surg 2018. [DOI: 10.1097/sla.0000000000002318] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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24
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Wei X, Yu L, Jin X, Song L, Lv Y, Han Y. Identification of open chromosomal regions and key genes in prostate cancer via integrated analysis of DNase‑seq and RNA‑seq data. Mol Med Rep 2018; 18:2245-2252. [PMID: 29956775 DOI: 10.3892/mmr.2018.9193] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 01/11/2018] [Indexed: 11/06/2022] Open
Abstract
Prostate cancer is a type of adenocarcinoma arising from the peripheral zone of the prostate gland, and metastasized prostate cancer is incurable with the current available therapies. The present study aimed to identify open chromosomal regions and differentially expressed genes (DEGs) associated with prostate cancer development. The DNase sequencing data (GSE33216) and RNA sequencing data (GSE22260) were downloaded from the Gene Expression Omnibus database. DNase I hypersensitive sites were detected and analyzed. Subsequently, DEGs were identified and their potential functions were enriched. Finally, upstream regulatory elements of DEGs were predicted. In LNCaP cells, following androgen receptor activation, 244 upregulated and 486 downregulated open chromosomal regions were identified. However, only 1% of the open chromosomal regions were dynamically altered. The 41 genes with upregulated open chromosomal signals within their promoter regions were primarily enriched in biological processes. Additionally, 211 upregulated and 150 downregulated DEGs were identified in prostate cancer, including eight transcription factors (TFs). Finally, nine regulatory elements associated with prostate cancer were predicted. In particular, inhibitor of DNA binding 1 HLH protein (ID1) was the only significantly upregulated TF which exhibited motif enrichment in the promoter regions of upregulated genes. CCCTC‑binding factor (CTCF) and ELK1 ETS transcription factor (ELK1), enriched in the open promoter regions of downregulated genes, were potential upstream regulatory elements. Furthermore, reverse transcription‑quantitative polymerase chain reaction analysis confirmed that ID1 expression was significantly upregulated in LNCaP cells and 5α‑dihydrotestosterone (DHT)‑treated LNCaP cells compared with that in BPH1 cells, while CTCF and ELK1 expression was significantly downregulated in LNCaP cells and DHT‑treated LNCaP cells. In conclusion, ID1, CTCF and ELK1 may be associated with prostate cancer, and may be potential therapeutic targets for the treatment of this disease.
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Affiliation(s)
- Xin Wei
- Department of Urology, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Lili Yu
- Department of Radiology, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Xuefei Jin
- Department of Urology, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Lide Song
- Department of Pathology, Zhuji People's Hospital, Zhuji, Zhejiang 311800, P.R. China
| | - Yanting Lv
- Department of Pathology, Zhuji People's Hospital, Zhuji, Zhejiang 311800, P.R. China
| | - Yuping Han
- Department of Urology, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
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25
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Kim E, Kim D, Lee JS, Yoe J, Park J, Kim CJ, Jeong D, Kim S, Lee Y. Capicua suppresses hepatocellular carcinoma progression by controlling the ETV4-MMP1 axis. Hepatology 2018; 67:2287-2301. [PMID: 29251790 DOI: 10.1002/hep.29738] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 12/12/2017] [Accepted: 12/13/2017] [Indexed: 12/24/2022]
Abstract
UNLABELLED Hepatocellular carcinoma (HCC) is developed by multiple steps accompanying progressive alterations of gene expression, which leads to increased cell proliferation and malignancy. Although environmental factors and intracellular signaling pathways that are critical for HCC progression have been identified, gene expression changes and the related genetic factors contributing to HCC pathogenesis are still insufficiently understood. In this study, we identify a transcriptional repressor, Capicua (CIC), as a suppressor of HCC progression and a potential therapeutic target. Expression of CIC is posttranscriptionally reduced in HCC cells. CIC levels are correlated with survival rates in patients with HCC. CIC overexpression suppresses HCC cell proliferation and invasion, whereas loss of CIC exerts opposite effects in vivo as well as in vitro. Levels of polyoma enhancer activator 3 (PEA3) group genes, the best-known CIC target genes, are correlated with lethality in patients with HCC. Among the PEA3 group genes, ETS translocation variant 4 (ETV4) is the most significantly up-regulated in CIC-deficient HCC cells, consequently promoting HCC progression. Furthermore, it induces expression of matrix metalloproteinase 1 (MMP1), the MMP gene highly relevant to HCC progression, in HCC cells; and knockdown of MMP1 completely blocks the CIC deficiency-induced HCC cell proliferation and invasion. CONCLUSION Our study demonstrates that the CIC-ETV4-MMP1 axis is a regulatory module controlling HCC progression. (Hepatology 2018;67:2287-2301).
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Affiliation(s)
- Eunjeong Kim
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea
| | - Donghyo Kim
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea
| | - Jeon-Soo Lee
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea
| | - Jeehyun Yoe
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea
| | - Jongmin Park
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea
| | - Chang-Jin Kim
- Department of Pathology, College of Medicine, Soonchunhyang University, Cheonan, Chungnam, Republic of Korea
| | - Dongjun Jeong
- Department of Pathology, College of Medicine, Soonchunhyang University, Cheonan, Chungnam, Republic of Korea.,Soonchunhyang Medical Science Research Institute, College of Medicine, Soonchunhyang University, Cheonan, Chungnam, Republic of Korea
| | - Sanguk Kim
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea.,Division of Integrative Bioscience and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea
| | - Yoontae Lee
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea.,Division of Integrative Bioscience and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea
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26
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Zheng B, Zhu YJ, Wang HY, Chen L. Gender disparity in hepatocellular carcinoma (HCC): multiple underlying mechanisms. SCIENCE CHINA-LIFE SCIENCES 2017; 60:575-584. [PMID: 28547581 DOI: 10.1007/s11427-016-9043-9] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2016] [Accepted: 02/20/2017] [Indexed: 02/07/2023]
Abstract
On the global scale, hepatitis B virus (HBV) infection is the main cause of hepatocellular carcinoma (HCC) especially in regions of Asia where HBV infection is endemic. Epidemiological studies show that the incidence of inflammation-driven HCC in males is three times as high as in females. Recent studies suggest that sex hormones have a crucial role in the pathogenesis and development of HBV-induced HCC. We found that the estrogen/androgen signaling pathway is associated with decreased/increased transcription and replication of HBV genes and can promote the development of HBV infections by up/downregulating HBV RNA transcription and inflammatory cytokines levels, which in turn slow down the progression of HBV-induced HCC. Additionally, sex hormones can also affect HBV-related HCC by inducing epigenetic changes. The evidence that both morphology and function of the human liver are affected by sex hormones was found over 60 years ago. However, the underlying molecular mechanism largely remains to be elucidated. This review focuses mainly on the molecular mechanisms behind the sex difference in HCC associated with HBV and other factors. In addition, several potential treatment and therapeutic strategies for inflammation-driven HCC will be introduced in this review.
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Affiliation(s)
- Bo Zheng
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, 200438, China.,National Center for Liver Cancer, Shanghai, 201805, China
| | - Yan-Jing Zhu
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, 200438, China.,National Center for Liver Cancer, Shanghai, 201805, China
| | - Hong-Yang Wang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, 200438, China. .,National Center for Liver Cancer, Shanghai, 201805, China. .,State Key Laboratory of Oncogenes and related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
| | - Lei Chen
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, 200438, China. .,National Center for Liver Cancer, Shanghai, 201805, China.
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27
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Ali MA, Lacin S, Abdel-Wahab R, Uemura M, Hassan M, Rashid A, Duda DG, Kaseb AO. Nonalcoholic steatohepatitis-related hepatocellular carcinoma: is there a role for the androgen receptor pathway? Onco Targets Ther 2017; 10:1403-1412. [PMID: 28424556 PMCID: PMC5344425 DOI: 10.2147/ott.s111681] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The epidemic of insulin resistance, obesity, and metabolic syndrome has led to the emergence of nonalcoholic steatohepatitis (NASH) as the most common cause of liver disease in the US. Patients with NASH are at an increased risk for hepatic disease-related morbidity and death, and chronic inflammation in NASH patients can lead to hepatocellular carcinoma (HCC). The prevalence of HCC is higher in males than in females, and genetic studies have identified androgen and androgen receptors (ARs) as partially responsible for the gender disparity in the development of liver disease and HCC. Although many factors are known to play important roles in the progression of inflammation in NASH patients, the role of androgen and AR in the progression of NASH to HCC has been understudied. This review summarizes the evidence for a potential role of androgen and the AR pathway in the development of NASH-related HCC and in the treatment of HCC. It has been proposed that AR plays a role in the progression of HCC: inhibitory roles in early stages of hepatocarcinogenesis and tumor-promoting roles in advanced stages. AR can be activated by several pathways, even in the absence of androgen. While AR has been explored as a potential therapeutic target in HCC, several clinical trials have failed to demonstrate a clinical benefit of antiandrogen drugs in HCC. This review discusses the potential reason for these observations and discuss the potential future trials design in this important setting.
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Affiliation(s)
- Mahmoud A Ali
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sahin Lacin
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Reham Abdel-Wahab
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Department of Clinical Oncology, Assiut University, Assiut, Egypt
| | - Mark Uemura
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Manal Hassan
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Asif Rashid
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Dan G Duda
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Ahmed O Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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AR-Signaling in Human Malignancies: Prostate Cancer and Beyond. Cancers (Basel) 2017; 9:cancers9010007. [PMID: 28085048 PMCID: PMC5295778 DOI: 10.3390/cancers9010007] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 01/04/2017] [Accepted: 01/05/2017] [Indexed: 12/11/2022] Open
Abstract
In the 1940s Charles Huggins reported remarkable palliative benefits following surgical castration in men with advanced prostate cancer, and since then the androgen receptor (AR) has remained the main therapeutic target in this disease. Over the past couple of decades, our understanding of AR-signaling biology has dramatically improved, and it has become apparent that the AR can modulate a number of other well-described oncogenic signaling pathways. Not surprisingly, mounting preclinical and epidemiologic data now supports a role for AR-signaling in promoting the growth and progression of several cancers other than prostate, and early phase clinical trials have documented preliminary signs of efficacy when AR-signaling inhibitors are used in several of these malignancies. In this article, we provide an overview of the evidence supporting the use of AR-directed therapies in prostate as well as other cancers, with an emphasis on the rationale for targeting AR-signaling across tumor types.
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Esmaeili M, Jennek S, Ludwig S, Klitzsch A, Kraft F, Melle C, Baniahmad A. The tumor suppressor ING1b is a novel corepressor for the androgen receptor and induces cellular senescence in prostate cancer cells. J Mol Cell Biol 2016; 8:207-20. [PMID: 26993046 DOI: 10.1093/jmcb/mjw007] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 12/10/2015] [Indexed: 12/28/2022] Open
Abstract
The androgen receptor (AR) signaling is critical for prostate cancer (PCa) progression to the castration-resistant stage with poor clinical outcome. Altered function of AR-interacting factors may contribute to castration-resistant PCa (CRPCa). Inhibitor of growth 1 (ING1) is a tumor suppressor that regulates various cellular processes including cell proliferation. Interestingly, ING1 expression is upregulated in senescent primary human prostate cells; however, its role in AR signaling in PCa was unknown. Using a proteomic approach by surface-enhanced laser desorption ionization-mass spectrometry (SELDI-MS) combined with immunological techniques, we provide here evidence that ING1b interacts in vivo with the AR. The interaction was confirmed by co-immunoprecipitation, in vitro GST-pull-down, and quantitative intracellular colocalization analyses. Functionally, ING1b inhibits AR-responsive promoters and endogenous key AR target genes in the human PCa LNCaP cells. Conversely, ING1b knockout (KO) mouse embryonic fibroblasts (MEFs) exhibit enhanced AR activity, suggesting that the interaction with ING1b represses the AR-mediated transcription. Also, data suggest that ING1b expression is downregulated in CRPCa cells compared with androgen-dependent LNCaP cells. Interestingly, its ectopic expression induces cellular senescence and reduces cell migration in both androgen-dependent and CRPCa cells. Intriguingly, ING1b can also inhibit androgen-induced growth in LNCaP cells in a similar manner as AR antagonists. Moreover, ING1b upregulates different cell cycle inhibitors including p27(KIP1), which is a novel target for ING1b. Taken together, our findings reveal a novel corepressor function of ING1b on various AR functions, thereby inhibiting PCa cell growth.
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Affiliation(s)
- Mohsen Esmaeili
- Institute of Human Genetics, Jena University Hospital, Jena, Germany
| | - Susanne Jennek
- Institute of Human Genetics, Jena University Hospital, Jena, Germany
| | - Susann Ludwig
- Institute of Human Genetics, Jena University Hospital, Jena, Germany
| | | | - Florian Kraft
- Institute of Human Genetics, Jena University Hospital, Jena, Germany
| | - Christian Melle
- Biomolecular Photonics Group, Jena University Hospital, Jena, Germany
| | - Aria Baniahmad
- Institute of Human Genetics, Jena University Hospital, Jena, Germany
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Kanda T, Yokosuka O. The androgen receptor as an emerging target in hepatocellular carcinoma. J Hepatocell Carcinoma 2015; 2:91-9. [PMID: 27508198 PMCID: PMC4918288 DOI: 10.2147/jhc.s48956] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the male-dominant liver diseases with poor prognosis, although treatments for HCC have been progressing in the past decades. Androgen receptor (AR) is a member of the nuclear receptor superfamily. Previous studies reported that AR was expressed in human HCC and non-HCC tissues. AR is activated both ligand-dependently and ligand-independently. The latter is associated with a mitogen-activated protein kinase–, v-akt murine thymoma viral oncogene homolog 1–, or signal-transducer and activator of transcription–signaling pathway, which has been implicated in the development of HCC. It has been reported that more than 200 RNA expression levels are altered by androgen treatment. In the liver, androgen-responsive genes are cytochrome P450s, transforming growth factor β, vascular endothelial growth factor, and glucose-regulated protein 78 kDa, which are also associated with human hepatocarcinogenesis. Recent studies also revealed that AR plays a role in cell migration and metastasis. It is possible that cross-talk among AR-signaling, endoplasmic reticulum stress, and innate immune response is important for human hepatocarcinogenesis and HCC development. This review shows that AR could play a potential role in human HCC and represent one of the important target molecules for the treatment of HCC.
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Affiliation(s)
- Tatsuo Kanda
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan
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31
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Tian YE, Xie XU, Lin Y, Tan G, Zhong WU. Androgen receptor in hepatocarcinogenesis: Recent developments and perspectives. Oncol Lett 2015; 9:1983-1988. [PMID: 26136999 DOI: 10.3892/ol.2015.3025] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Accepted: 02/13/2015] [Indexed: 02/06/2023] Open
Abstract
Previous studies have indicated that males are at a higher risk of developing hepatocellular carcinoma (HCC) compared with females. Identifying the factors that cause this gender-specific difference in the incidence of HCC has long been considered important for revealing the molecular mechanisms involved in hepatocarcinogenesis. Given the unprecedented tools that are now available for molecular research, genetic studies have established that the androgen receptor (AR) may be partly responsible for gender disparity in HCC. AR has a dual role, promoting HCC initiation and development, as well as suppressing HCC metastasis. The present review provides an overview of the involvement of AR signaling in HCC. The review highlighted important studies, examples of the direct AR transcriptional target genes involved in HCC and novel theories concerning the conventional concept, suggesting that targeting the AR, rather than the androgen, may provide an improved therapeutic approach for the treatment of HCC.
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Affiliation(s)
- Y E Tian
- Department of Emergency Medicine, Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan 646000, P.R. China
| | - X U Xie
- Department of General Surgery, First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Yao Lin
- Department of Urology, Anhui Provincial Hospital, Hefei, Anhui 230001, P.R. China
| | - Guang Tan
- Department of General Surgery, First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - W U Zhong
- Department of Emergency Medicine, Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan 646000, P.R. China
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32
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Yang D, Hanna DL, Usher J, LoCoco J, Chaudhari P, Lenz HJ, Setiawan VW, El-Khoueiry A. Impact of sex on the survival of patients with hepatocellular carcinoma: a Surveillance, Epidemiology, and End Results analysis. Cancer 2014; 120:3707-16. [PMID: 25081299 DOI: 10.1002/cncr.28912] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Revised: 04/07/2014] [Accepted: 04/23/2014] [Indexed: 11/10/2022]
Abstract
BACKGROUND Men are 4 to 8 times more likely to develop hepatocellular carcinoma (HCC) than women. Preclinical models have suggested a role for sex hormones in the development of HCC. In the current study, the authors investigated the impact of age, sex, race, and ethnicity on the survival of patients with HCC using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS Patients diagnosed with HCC from 1988 through 2010 were identified from the SEER registry. Hazard ratios (HR) for overall survival (OS) were derived using the Cox regression model adjusted for race, year of diagnosis, marital status, treatment, birthplace, tumor differentiation, and tumor size. RESULTS A total of 39,345 patients were identified; 76% were men and 34% were women (50% white, 12% African American, 21% Asian, 16% Hispanic, and 1% Native American). The median age at the time of diagnosis was 61 years for men and 67 years for women. Approximately 84% of patients had liver-limited disease and 16% had metastatic disease. Treatment information was available for patients diagnosed after 1998 (34,674 patients): 11% received liver-directed therapy, 11% underwent surgical resection, and 7% underwent liver transplantation. The HR for the OS of women versus men was 0.83 (95% confidence interval [95% CI], 0.77-0.88) for patients aged <55 years. The protective effect of sex on OS was found to be greatest in patients aged 18 to 44 years (HR, 0.75; 95% CI, 0.65-0.86 [P<.001]), especially those with surgically resected tumors (HR, 0.68; 95% CI, 0.54-0.86 [P = .001]) and those who were African American (HR, 0.85; 95% CI, 0.78-0.92 [P<.001]). There was no survival difference between sexes noted among Hispanics or patients aged >65 years. CONCLUSIONS Sex appears to be associated with survival in patients with HCC. The role of androgens and estrogens in the development and progression of HCC warrants further investigation.
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Affiliation(s)
- Dongyun Yang
- Department of Preventive Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
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33
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Kanda T, Jiang X, Yokosuka O. Androgen receptor signaling in hepatocellular carcinoma and pancreatic cancers. World J Gastroenterol 2014; 20:9229-9236. [PMID: 25071315 PMCID: PMC4110552 DOI: 10.3748/wjg.v20.i28.9229] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Revised: 03/07/2014] [Accepted: 04/30/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) and pancreatic cancer remain difficult to treat, and despite the ongoing development of new treatments, the overall survival rate has only modestly improved over the past decade. Liver and pancreatic progenitors commonly develop from endoderm cells in the embryonic foregut. A previous study showed that HCC and pancreatic cancer cell lines variably express androgen receptor (AR), and these cancers and the surrounding tissues also express AR. AR is a ligand-dependent transcription factor that belongs to the nuclear receptor superfamily. Androgen response element is present in regulatory elements on the AR-responsive target genes, such as transforming growth factor beta-1 (TGF beta-1) and vascular endothelial growth factor (VEGF). It is well known that the activation of AR is associated with human carcinogenesis in prostate cancer as well as HCC and pancreatic cancer and that GRP78, TGF beta, and VEGF all play important roles in carcinogenesis and cancer development in these cancers. HCC is a male-dominant cancer irrespective of its etiology. Previous work has reported that vertebrae forkhead box A 1/2 are involved in estrogen receptors and/or AR signaling pathways, which may contribute to the gender differences observed with HCC. Our recent work also showed that AR has a critical role in pancreatic cancer development, despite pancreatic cancer not being a male dominant cancer. Aryl hydrocarbon (or dioxin) receptor is also involved in both HCC and pancreatic cancer through the formation of complex with AR. It is possible that AR might be involved in their carcinogenesis through major histocompatibility complex class I chain-related gene A/B. This review article describes AR and its role in HCC and pancreatic cancer and suggests that more specific AR signaling-inhibitors may be useful in the treatment of these "difficult to treat" cancers.
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Yu XL, Jing T, Zhao H, Li PJ, Xu WH, Shang FF. Curcumin Inhibits Expression of Inhibitor of DNA Binding 1 in PC3 Cells and Xenografts. Asian Pac J Cancer Prev 2014; 15:1465-70. [DOI: 10.7314/apjcp.2014.15.3.1465] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Abstract
The family of inhibitor of differentiation (Id) proteins is a group of evolutionarily conserved molecules, which play important regulatory roles in organisms ranging from Drosophila to humans. Id proteins are small polypeptides harboring a helix-loop-helix (HLH) motif, which are best known to mediate dimerization with other basic HLH proteins, primarily E proteins. Because Id proteins do not possess the basic amino acids adjacent to the HLH motif necessary for DNA binding, Id proteins inhibit the function of E protein homodimers, as well as heterodimers between E proteins and tissue-specific bHLH proteins. However, Id proteins have also been shown to have E protein-independent functions. The Id genes are broadly but differentially expressed in a variety of cell types. Transcription of the Id genes is controlled by transcription factors such as C/EBPβ and Egr as well as by signaling pathways triggered by different stimuli, which include bone morphogenic proteins, cytokines, and ligands of T cell receptors. In general, Id proteins are capable of inhibiting the differentiation of progenitors of different cell types, promoting cell-cycle progression, delaying cellular senescence, and facilitating cell migration. These properties of Id proteins enable them to play significant roles in stem cell maintenance, vasculogenesis, tumorigenesis and metastasis, the development of the immune system, and energy metabolism. In this review, we intend to highlight the current understanding of the function of Id proteins and discuss gaps in our knowledge about the mechanisms whereby Id proteins exert their diverse effects in multiple cellular processes.
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Affiliation(s)
- Flora Ling
- Immunobiology Cancer Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Bin Kang
- Immunobiology Cancer Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Xiao-Hong Sun
- Immunobiology Cancer Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
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36
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Nie H, Cao Q, Zhu L, Gong Y, Gu J, He Z. Acetylcholine acts on androgen receptor to promote the migration and invasion but inhibit the apoptosis of human hepatocarcinoma. PLoS One 2013; 8:e61678. [PMID: 23620780 PMCID: PMC3631145 DOI: 10.1371/journal.pone.0061678] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2013] [Accepted: 03/13/2013] [Indexed: 12/22/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most fatal cancers. In almost all populations, males have a higher HCC rate than females. Here we sought to explore the roles and mechanisms of acetylcholine (Ach) and androgen receptor (AR) on regulating the fate determinations of HCC. Ach activated AR and promoted its expression in HCC cells. Ach enhanced HCC cell migration and invasion but inhibited their apoptosis. Ach had no obvious effects on the migration, invasion, or apoptosis in AR-negative HCC cells. Elevation of migration and invasion induced by Ach was eliminated in AR-knockdown HCC cells. In contrast, Ach stimulated the migration and invasion but suppressed apoptosis in AR over-expressed HCC cells. Additionally, AR agonist R1881 promoted the migration and invasion but reduced the apoptosis of SNU-449 cells, whereas AR antagonist casodex inhibited the migration and invasion but stimulated the apoptosis of SNU-449 cells. STAT3 and AKT phosphorylation was activated by Ach in HCC cells. Collectively, these data suggest that Ach activates STAT3 and AKT pathways and acts on AR to promote the migration and invasion but inhibit the apoptosis of HCC cells. This study thus provides novel insights into carcinogenesis of liver cancer by local interaction between neurotransmitter Ach and hormone receptor AR in HCC.
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MESH Headings
- Acetylcholine/pharmacology
- Androgen Antagonists/pharmacology
- Androgens/pharmacology
- Anilides/pharmacology
- Apoptosis/drug effects
- Carcinoma, Hepatocellular/enzymology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Cell Line, Tumor
- Cell Movement/drug effects
- Female
- Gene Expression Regulation, Neoplastic/drug effects
- Humans
- Liver Neoplasms/enzymology
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Male
- Mecamylamine/pharmacology
- Metribolone/pharmacology
- Neoplasm Invasiveness
- Nitriles/pharmacology
- Phosphorylation/drug effects
- Proto-Oncogene Proteins c-akt/metabolism
- RNA, Small Interfering/metabolism
- Receptors, Androgen/genetics
- Receptors, Androgen/metabolism
- Receptors, Cholinergic/metabolism
- STAT3 Transcription Factor/metabolism
- Signal Transduction/drug effects
- Tosyl Compounds/pharmacology
- Transcription, Genetic/drug effects
- Up-Regulation/drug effects
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Affiliation(s)
- Huizhen Nie
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qingzhen Cao
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei Zhu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuehua Gong
- Stem Cell Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jianren Gu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zuping He
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Stem Cell Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- * E-mail:
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37
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Ao J, Meng J, Zhu L, Nie H, Yang C, Li J, Gu J, Lin Q, Long W, Dong X, Li C. Activation of androgen receptor induces ID1 and promotes hepatocellular carcinoma cell migration and invasion. Mol Oncol 2012; 6:507-15. [PMID: 22819717 DOI: 10.1016/j.molonc.2012.06.005] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2012] [Revised: 06/25/2012] [Accepted: 06/28/2012] [Indexed: 02/07/2023] Open
Abstract
Androgen receptor (AR) activity is associated with cancer development and progression. In hepatocellular carcinoma (HCC), AR contributes to HCC incidence, but the role of AR in HCC cell migration and invasion remains largely unknown. In this study, we found that AR was expressed at high levels in a subgroup of HCC cell lines with high metastatic potential. Experiments using lentiviral overexpression or small hairpin RNA knockdown of AR as well as activation of AR by its ligand indicated that AR activation promoted HCC cell migration and invasion. We also found that AR activation enhanced the expression of a metastasis-promoting gene, ID1, which led to increased HCC cell migration and invasion. An AR antagonist was able to block this process, suggesting that AR activation in AR-positive HCC may be therapeutically inhibited as a potential intervention strategy.
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Affiliation(s)
- Junping Ao
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200032, China
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