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Dobrowolska K, Pawłowska M, Zarębska-Michaluk D, Rzymski P, Janczewska E, Tudrujek-Zdunek M, Berak H, Mazur W, Klapaczyński J, Lorenc B, Janocha-Litwin J, Parfieniuk-Kowerda A, Dybowska D, Piekarska A, Krygier R, Dobracka B, Jaroszewicz J, Flisiak R. Direct-acting antivirals in women of reproductive age infected with hepatitis C virus. J Viral Hepat 2024; 31:309-319. [PMID: 38483035 DOI: 10.1111/jvh.13936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 02/16/2024] [Accepted: 03/03/2024] [Indexed: 05/18/2024]
Abstract
Eliminating hepatitis C virus (HCV) infection in the population of women of reproductive age is important not only for the health of women themselves but also for the health of newborns. This study aimed to evaluate the implementation of this goal by analysing the effectiveness of contemporary therapy in a large cohort from everyday clinical practice along with identifying factors reducing therapeutic success. The analysed population consisted of 7861 patients, including 3388 women aged 15-49, treated in 2015-2022 in 26 hepatology centres. Data were collected retrospectively using a nationwide EpiTer-2 database. Females were significantly less often infected with HCV genotype 3 compared to males (11.2% vs. 15.7%) and less frequently showed comorbidities (40.5% vs. 44.2%) and comedications (37.2% vs. 45.2%). Hepatocellular carcinoma, liver transplantation, HIV and HBV coinfections were reported significantly less frequently in women. Regardless of the treatment type, females significantly more often reached sustained virologic response (98.8%) compared to males (96.8%). Regardless of gender, genotype 3 and cirrhosis were independent factors increasing the risk of treatment failure. Women more commonly reported adverse events, but death occurred significantly more frequently in men (0.3% vs. 0.1%), usually related to underlying advanced liver disease. We have demonstrated excellent effectiveness and safety profiles for treating HCV infection in women. This gives hope for the micro-elimination of HCV infections in women, translating into a reduced risk of severe disease in both women and their children.
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Affiliation(s)
| | - Małgorzata Pawłowska
- Department of Infectious Diseases and Hepatology, Faculty of Medicine, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
| | | | - Piotr Rzymski
- Department of Environmental Medicine, Poznań University of Medical Sciences, Poznań, Poland
| | - Ewa Janczewska
- Department of Basic Medical Sciences, School of Public Health in Bytom, Medical University of Silesia, Katowice, Poland
| | | | - Hanna Berak
- Outpatient Clinic, Hospital for Infectious Diseases in Warsaw, Warsaw, Poland
| | - Włodzimierz Mazur
- Clinical Department of Infectious Diseases in Chorzów, Medical University of Silesia, Katowice, Poland
| | - Jakub Klapaczyński
- Department of Internal Medicine and Hepatology, The National Institute of Medicine of the Ministry of Interior and Administration, Warszawa, Poland
| | - Beata Lorenc
- Pomeranian Center of Infectious Diseases, Medical University, Gdańsk, Poland
| | - Justyna Janocha-Litwin
- Department of Infectious Diseases and Hepatology, Wrocław Medical University, Wrocław, Poland
| | - Anna Parfieniuk-Kowerda
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok, Poland
| | - Dorota Dybowska
- Department of Infectious Diseases and Hepatology, Faculty of Medicine, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
| | - Anna Piekarska
- Department of Infectious Diseases and Hepatology, Medical University of Łódź, Łódź, Poland
| | - Rafał Krygier
- Outpatients Hepatology Department, State University of Applied Sciences, Konin, Poland
| | | | - Jerzy Jaroszewicz
- Department of Infectious Diseases and Hepatology, Medical University of Silesia in Katowice, Bytom, Poland
| | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok, Poland
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Matsushima-Nishiwaki R, Yamada N, Hattori Y, Hosokawa Y, Tachi J, Hori T, Kozawa O. SERMs (selective estrogen receptor modulator), acting as estrogen receptor β agonists in hepatocellular carcinoma cells, inhibit the transforming growth factor-α-induced migration via specific inhibition of AKT signaling pathway. PLoS One 2022; 17:e0262485. [PMID: 35007301 PMCID: PMC8746762 DOI: 10.1371/journal.pone.0262485] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 12/27/2021] [Indexed: 01/18/2023] Open
Abstract
Selective estrogen receptor modulator (SERM) interacts with estrogen receptors and acts as both an agonist or an antagonist, depending on the target tissue. SERM is widely used as a safer hormone replacement therapeutic medicine for postmenopausal osteoporosis. Regarding hepatocellular carcinoma (HCC), accumulating evidence indicates gender differences in the development, and that men are at higher morbidity risk than premenopausal women, suggesting that estrogen protects against HCC. However, it remains unclear whether SERM affects the HCC progression. Previously, we have shown that transforming growth factor (TGF)-α promotes the migration of HCC cells via p38 mitogen-activated protein kinases (MAPK), c-Jun N-terminal kinase and AKT. In the present study, we investigated whether SERM such as tamoxifen, raloxifene and bazedoxifene, affects the HCC cell migration using human HCC-derived HuH7 cells. Raloxifene and bazedoxifene but not tamoxifen, significantly suppressed the TGF-α-induced HuH7 cell migration. ERB041 and DPN, estrogen receptor (ER) β agonists, inhibited the TGF-α-induced cell migration whereas PPT, an ERα agonist, did not show the suppressive effect on the cell migration. ERB041 attenuated the TGF-α-induced phosphorylation of AKT without affecting the phosphorylation of p38 MAPK and c-Jun N-terminal kinase. Raloxifene and bazedoxifene also inhibited the phosphorylation of AKT by TGF-α. Furthermore, PHTPP, an ERβ antagonist, significantly reversed the suppression by both raloxifene and bazedoxifene of the TGF-α-induced cell migration. Taken together, our results strongly indicate that raloxifene and bazedoxifene, SERMs, suppress the TGF-α-induced migration of HCC cells through ERβ-mediated inhibition of the AKT signaling pathway.
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Affiliation(s)
| | - Noriko Yamada
- Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Yuria Hattori
- Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Yui Hosokawa
- Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Junko Tachi
- Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Takamitsu Hori
- Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Osamu Kozawa
- Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
- * E-mail:
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3
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O’Brien MH, Pitot HC, Chung SH, Lambert PF, Drinkwater NR, Bilger A. Estrogen Receptor-α Suppresses Liver Carcinogenesis and Establishes Sex-Specific Gene Expression. Cancers (Basel) 2021; 13:2355. [PMID: 34068249 PMCID: PMC8153146 DOI: 10.3390/cancers13102355] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 05/10/2021] [Indexed: 02/06/2023] Open
Abstract
Estrogen protects females from hepatocellular carcinoma (HCC). To determine whether this protection is mediated by classic estrogen receptors, we tested HCC susceptibility in estrogen receptor-deficient mice. In contrast to a previous study, we found that diethylnitrosamine induces hepatocarcinogenesis to a significantly greater extent when females lack Esr1, which encodes Estrogen Receptor-α. Relative to wild-type littermates, Esr1 knockout females developed 9-fold more tumors. Deficiency of Esr2, which encodes Estrogen Receptor-β, did not affect liver carcinogenesis in females. Using microarrays and QPCR to examine estrogen receptor effects on hepatic gene expression patterns, we found that germline Esr1 deficiency resulted in the masculinization of gene expression in the female liver. Six of the most dysregulated genes have previously been implicated in HCC. In contrast, Esr1 deletion specifically in hepatocytes of Esr1 conditional null female mice (in which Cre was expressed from the albumin promoter) resulted in the maintenance of female-specific liver gene expression. Wild-type adult females lacking ovarian estrogen due to ovariectomy, which is known to make females susceptible to HCC, also maintained female-specific expression in the liver of females. These studies indicate that Esr1 mediates liver cancer risk, and its control of sex-specific liver gene expression involves cells other than hepatocytes.
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Affiliation(s)
- Mara H. O’Brien
- Department of Craniofacial Sciences, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA;
| | - Henry C. Pitot
- McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin—Madison, 1111 Highland Ave, Madison, WI 53705, USA; (H.C.P.); (P.F.L.); (N.R.D.)
| | - Sang-Hyuk Chung
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA;
| | - Paul F. Lambert
- McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin—Madison, 1111 Highland Ave, Madison, WI 53705, USA; (H.C.P.); (P.F.L.); (N.R.D.)
| | - Norman R. Drinkwater
- McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin—Madison, 1111 Highland Ave, Madison, WI 53705, USA; (H.C.P.); (P.F.L.); (N.R.D.)
| | - Andrea Bilger
- McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin—Madison, 1111 Highland Ave, Madison, WI 53705, USA; (H.C.P.); (P.F.L.); (N.R.D.)
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Guo Y, Wu G, Yi J, Yang Q, Jiang W, Lin S, Yang X, Cai X, Mao L. Anti-Hepatocellular Carcinoma Effect and Molecular Mechanism of the Estrogen Signaling Pathway. Front Oncol 2021; 11:763539. [PMID: 35096574 PMCID: PMC8789654 DOI: 10.3389/fonc.2021.763539] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 12/14/2021] [Indexed: 12/18/2022] Open
Abstract
There are significant gender differences in the incidence and mortality of hepatocellular carcinoma (HCC). Compared with men, the incidence and mortality of HCC in women are relatively low. The estrogen signaling pathway, composed of estrogen and estrogen receptors, has been postulated to have a protective effect on the occurrence and development of HCC. There have been multiple studies that have supported anti-HCC effects of the estrogen signaling pathways, including direct and indirect pathways such as genomic pathways, rapid transduction pathways, non-coding RNA, tumor microenvironment, estrogen metabolites, and inhibition of hepatitis infection and replication. Based on the evidence of an anti-HCC effect of the estrogen signaling pathway, a number of strategies have been investigated to determine the potential therapeutic effect. These have included estrogen replacement therapy, targeting the estrogen receptor, key molecules, inflammatory mediators, and regulatory pathways of the estrogen signaling pathway. In this review, we have systematically summarized the latest developments in the complex functions and molecular mechanisms of the estrogen signaling pathway in liver cancer. Furthermore, we have highlighted the potential targets of treatment strategies based on the estrogen signaling pathway in the treatment of liver cancer and the principal obstacles currently encountered for future investigation.
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Affiliation(s)
- Yusheng Guo
- Scientific Research Center, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Guohui Wu
- Scientific Research Center, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Junrong Yi
- Scientific Research Center, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Qin Yang
- Nephrology Department, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Wengong Jiang
- Nephrology Department, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Shaoqiang Lin
- Scientific Research Center, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Xiaorong Yang
- Clinical Laboratory, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- *Correspondence: Liufeng Mao, ; Xiangsheng Cai, ; Xiaorong Yang,
| | - Xiangsheng Cai
- Center for Medical Experiments, University of Chinese Academy of Science-Shenzhen Hospital, Shenzhen, China
- *Correspondence: Liufeng Mao, ; Xiangsheng Cai, ; Xiaorong Yang,
| | - Liufeng Mao
- Scientific Research Center, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- *Correspondence: Liufeng Mao, ; Xiangsheng Cai, ; Xiaorong Yang,
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5
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Zhao J, Sun Y, Lin H, Chou F, Xiao Y, Jin R, Cai X, Chang C. Olaparib and enzalutamide synergistically suppress HCC progression via the AR-mediated miR-146a-5p/BRCA1 signaling. FASEB J 2020; 34:5877-5891. [PMID: 32134529 DOI: 10.1096/fj.201903045rr] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 02/23/2020] [Accepted: 02/25/2020] [Indexed: 12/26/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of most common cancers worldwide, however, the treatment for advanced HCC remains unsatisfactory. We focused on the function of the androgen receptor (AR) in HCC and tried to find new treatment strategy based on antiandrogen enzalutamide (Enz). Here, we found that olaparib, a FDA-approved PARP inhibitor, could enhance the cytotoxicity in HCC cells with a lower BRCA1 expression, and suppressing the AR with either Enz or AR-shRNA could further increase the olaparib sensitivity to better suppress the HCC cell growth via a synergistic mechanism that may involve suppressing the expression of BRCA1 and other DNA damage response (DDR) genes. Mechanism studies revealed that Enz/AR signaling might transcriptionally regulate the miR-146a-5p expression via binding to the Androgen Response Elements on its 5' promoter region, which could then lead to suppress the homologous recombination-related BRCA1 expression via direct binding to the mRNA 3'UTR. Preclinical studies using an in vivo mouse model also demonstrated that combining Enz plus olaparib led to better suppression of the HCC progression. Together, these in vitro/in vivo data suggest that combining Enz and olaparib may help in the development of a novel therapy to better suppress the HCC progression.
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Affiliation(s)
- Jie Zhao
- Department of General Surgery, Innovation Center for Minimally Invasive Technique and Device, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Urology, Innovation Center for Minimally Invasive Technique and Device, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,George Whipple Lab for Cancer Research, Departments of Pathology and Urology and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Yin Sun
- George Whipple Lab for Cancer Research, Departments of Pathology and Urology and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Hui Lin
- Department of General Surgery, Innovation Center for Minimally Invasive Technique and Device, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Urology, Innovation Center for Minimally Invasive Technique and Device, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Fuju Chou
- George Whipple Lab for Cancer Research, Departments of Pathology and Urology and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Yao Xiao
- George Whipple Lab for Cancer Research, Departments of Pathology and Urology and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Ren'an Jin
- Department of General Surgery, Innovation Center for Minimally Invasive Technique and Device, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Urology, Innovation Center for Minimally Invasive Technique and Device, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,George Whipple Lab for Cancer Research, Departments of Pathology and Urology and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Xiujun Cai
- Department of General Surgery, Innovation Center for Minimally Invasive Technique and Device, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Urology, Innovation Center for Minimally Invasive Technique and Device, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Chawnshang Chang
- George Whipple Lab for Cancer Research, Departments of Pathology and Urology and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.,Sex Hormone Research Center, China Medical University/Hospital, Taichung, Taiwan
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Genetic Predisposition to Hepatocarcinogenesis in Inbred and Outbred Mouse Lines Selected for High or Low Inflammatory Response. J Immunol Res 2019; 2019:5298792. [PMID: 31049358 PMCID: PMC6462334 DOI: 10.1155/2019/5298792] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 01/24/2019] [Indexed: 11/18/2022] Open
Abstract
AIRmax and AIRmin mouse strains phenotypically selected for high and low acute inflammatory responsiveness (AIR) are, respectively, susceptible or resistant to developing hepatocellular carcinoma (HCC) induced by the chemical carcinogens urethane and diethylnitrosamine (DEN). Early production of TNF-α, IL-1β, and IL-6 in the liver after DEN treatment correlated with tumor development in AIRmax mice. Transcriptome analysis of livers from untreated AIRmax and AIRmin mice showed specific gene expression profiles in each line, which might play a role in their differential susceptibility to HCC. Linkage analysis with SNP markers in F2 (AIRmax×AIRmin) intercross mice revealed two quantitative trait loci (QTL) in chromosomes 2 and 9, which are significantly associated with the number and progression of urethane-induced liver tumors. An independent linkage analysis with an intercross population from A/J and C57BL/6J inbred mice mapped regions in chromosomes 1 and 7 associated with the progression of urethane-induced liver tumors, evidencing the heterogeneity of HCC genetic control.
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7
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Zheng D, Williams C, Vold JA, Nguyen JH, Harnois DM, Bagaria SP, McLaughlin SA, Li Z. Regulation of sex hormone receptors in sexual dimorphism of human cancers. Cancer Lett 2018; 438:24-31. [PMID: 30223066 PMCID: PMC6287770 DOI: 10.1016/j.canlet.2018.09.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 08/24/2018] [Accepted: 09/03/2018] [Indexed: 02/07/2023]
Abstract
Gender differences in the incidences of cancers have been found in almost all human cancers. However, the mechanisms that underlie gender disparities in most human cancer types have been under-investigated. Here, we provide a comprehensive overview of potential mechanisms underlying sexual dimorphism of each cancer regarding sex hormone signaling. Fully addressing the mechanisms of sexual dimorphism in human cancers will greatly benefit current development of precision medicine. Our discussions of potential mechanisms underlying sexual dimorphism in each cancer will be instructive for future cancer research on gender disparities.
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Affiliation(s)
- Daoshan Zheng
- Department of Cancer Biology, 4500 San Pablo Road, Jacksonville, FL, 32224, USA
| | - Cecilia Williams
- Department of Biosciences and Nutrition, KTH Royal Institute of Technology, Karolinska Institutet, Science for Life Laboratory, Stockholm, Sweden
| | - Jeremy A Vold
- Mayo Cancer Registry, 4500 San Pablo Road, Jacksonville, FL, 32224, USA
| | - Justin H Nguyen
- Department of Surgery, and Mayo Clinic Cancer Center, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA
| | - Denise M Harnois
- Department of Surgery, and Mayo Clinic Cancer Center, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA
| | - Sanjay P Bagaria
- Department of Surgery, and Mayo Clinic Cancer Center, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA
| | - Sarah A McLaughlin
- Department of Surgery, and Mayo Clinic Cancer Center, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA
| | - Zhaoyu Li
- Department of Cancer Biology, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
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8
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Iyer JK, Kalra M, Kaul A, Payton ME, Kaul R. Estrogen receptor expression in chronic hepatitis C and hepatocellular carcinoma pathogenesis. World J Gastroenterol 2017; 23:6802-6816. [PMID: 29085224 PMCID: PMC5645614 DOI: 10.3748/wjg.v23.i37.6802] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Revised: 05/12/2017] [Accepted: 07/22/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate gender-specific liver estrogen receptor (ER) expression in normal subjects and patients with hepatitis C virus (HCV)-related cirrhosis and hepatocellular carcinoma (HCC). METHODS Liver tissues from normal donors and patients diagnosed with HCV-related cirrhosis and HCV-related HCC were obtained from the NIH Liver Tissue and Cell Distribution System. The expression of ER subtypes, ERα and ERβ, were evaluated by Western blotting and real-time RT-PCR. The subcellular distribution of ERα and ERβ was further determined in nuclear and cytoplasmic tissue lysates along with the expression of inflammatory [activated NF-κB and IκB-kinase (IKK)] and oncogenic (cyclin D1) markers by Western blotting and immunohistochemistry. The expression of ERα and ERβ was correlated with the expression of activated NF-κB, activated IKK and cyclin D1 by Spearman's correlation. RESULTS Both ER subtypes were expressed in normal livers but male livers showed significantly higher expression of ERα than females (P < 0.05). We observed significantly higher mRNA expression of ERα in HCV-related HCC liver tissues as compared to normals (P < 0.05) and ERβ in livers of HCV-related cirrhosis and HCV-related HCC subjects (P < 0.05). At the protein level, there was a significantly higher expression of nuclear ERα in livers of HCV-related HCC patients and nuclear ERβ in HCV-related cirrhosis patients as compared to normals (P < 0.05). Furthermore, we observed a significantly higher expression of phosphorylated NF-κB and cyclin D1 in diseased livers (P < 0.05). There was a positive correlation between the expression of nuclear ER subtypes and nuclear cyclin D1 and a negative correlation between cytoplasmic ER subtypes and cytoplasmic phosphorylated IKK in HCV-related HCC livers. These findings suggest that dysregulated expression of ER subtypes following chronic HCV-infection may contribute to the progression of HCV-related cirrhosis to HCV-related HCC. CONCLUSION Gender differences were observed in ERα expression in normal livers. Alterations in ER subtype expression observed in diseased livers may influence gender-related disparity in HCV-related pathogenesis.
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Affiliation(s)
- Janaki K Iyer
- Department of Biochemistry and Microbiology, Oklahoma State University-Center for Health Sciences, Tulsa, OK 74107, United States
- (Current Affiliation) Department of Natural Sciences, Northeastern State University, Tahlequah, OK 74464, United States
| | - Mamta Kalra
- Immatics US Inc, Houston, TX 77077, United States
| | - Anil Kaul
- Health Care Administration, Oklahoma State University-Center for Health Sciences, Tulsa, OK 74107, United States
| | - Mark E Payton
- Department of Statistics, Oklahoma State University, Stillwater, OK 74078, United States
| | - Rashmi Kaul
- Department of Biochemistry and Microbiology, Oklahoma State University-Center for Health Sciences, Tulsa, OK 74107, United States
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9
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Activation of liver stromal cells is associated with male-biased liver tumor initiation in xmrk and Myc transgenic zebrafish. Sci Rep 2017; 7:10315. [PMID: 28871112 PMCID: PMC5583234 DOI: 10.1038/s41598-017-10529-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 08/09/2017] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is more prevalent in men than in women. Previously we have found that some stromal cells, including hepatic stellate cells (HSCs), neutrophils and macrophages, play crucial roles in promoting sex disparity in krasV12-induced zebrafish HCC. The activation of HSCs is mediated by serotonin while activation of neutrophils and macrophages is mediated by cortisol. To ensure that these findings are also applicable to other oncogene induced tumors, stromal cell activation was compared between male and female fish during liver tumorigenesis initiated by xmrk or Myc oncogene. Consistently, we observed male-biased liver tumorigenesis in the xmrk and Myc models. In both models, there was a higher rate of HSC activation accompanied with a higher level of serotonin in male liver tumors. For tumor-infiltrated neutrophils and macrophages, significantly higher densities in male liver tumors were observed in both xmrk and Myc models. However, the male-biased increase of cortisol was observed only in xmrk- but not apparently in Myc expressing liver tumors. Overall, these observations are consistent with the observations in the kras liver tumor model, indicating that the serotonin- and cortisol-mediated pathways also play roles in sex disparity of liver tumors caused by other molecular pathways.
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10
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Cocciadiferro L, Miceli V, Granata OM, Carruba G. Merlin, the product of NF2 gene, is associated with aromatase expression and estrogen formation in human liver tissues and liver cancer cells. J Steroid Biochem Mol Biol 2017; 172:222-230. [PMID: 27289045 DOI: 10.1016/j.jsbmb.2016.05.023] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Revised: 05/29/2016] [Accepted: 05/31/2016] [Indexed: 02/07/2023]
Abstract
The product of neurofibromatosis type 2 (NF2) gene, also known as Merlin/neurofibromin 2, homeostatically regulates liver stem cells by controlling abundance and signaling of epidermal growth factor receptor (EGFR), with a mechanism independent of the Hippo pathway. We have reported that locally elevated estrogen formation, driven by abnormally high expression and function of aromatase, may be implicated in development and progression of human hepatocellular carcinoma (HCC) through activation of a rapid signaling pathway mediated by amphiregulin (AREG) and EGFR. We have recently presented a model by which the aromatase-estrogen-amphiregulin-EGFR axis is activated in response to tissue injury and/or inflammatory disease, with its alteration eventually leading to development of major human tumors (liver, breast, prostate) and other chronic diseases (diabetes, obesity, Alzheimer's and heart disease). In this study, we investigated NF2 expression in liver cancer cells and tissues in relation to aromatase expression/function, estrogen receptor (ER) status and amphiregulin. Our data indicate that NF2 expression is associated with aromatase and AREG expression, being elevated in HCC tissues and HepG2 cells, intermediate in cirrhotic tissues and Huh7 cells, and lower in nontumoral liver and HA22T cells. In addition, NF2 expression is inversely related to wild type hERα66 and proportional to the expression of the membrane-associated hERα36 splice variant, as measured by exon-specific RT-PCR analysis, both in vivo and in vitro. Furthermore, incubation with estradiol induced a significant decrease of NF2 expression in both HA22T and Huh7 cells (over 54% and 22%, respectively), while no change could be observed in HepG2 cells, this effect being inversely related to aromatase expression and activity in HCC cell lines. Based on the above combined evidence, we hypothesize that NF2 behaves as a protein sensing tissue damage and aromatase-driven local estrogen formation, eventually leading to regulation of stem cells differentiation and tissue repair.
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Affiliation(s)
- Letizia Cocciadiferro
- Unit of Research & Internationalization, ARNAS-Civico Di Cristina Benfratelli (ARNAS-CDB), Piazzale N. Leotta 2, 90127 Palermo, Italy.
| | - Vitale Miceli
- Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Via Tricomi 5, 90127 Palermo, Italy.
| | - Orazia M Granata
- Unit of Clinical Pathology, "G. Di Cristina" Children Hospital, ARNAS-CDB, Via dei Benedettini 1, 90127 Palermo, Italy.
| | - Giuseppe Carruba
- Unit of Research & Internationalization, ARNAS-Civico Di Cristina Benfratelli (ARNAS-CDB), Piazzale N. Leotta 2, 90127 Palermo, Italy.
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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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12
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Yan C, Yang Q, Gong Z. Tumor-Associated Neutrophils and Macrophages Promote Gender Disparity in Hepatocellular Carcinoma in Zebrafish. Cancer Res 2017; 77:1395-1407. [PMID: 28202512 DOI: 10.1158/0008-5472.can-16-2200] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 12/12/2016] [Accepted: 12/26/2016] [Indexed: 11/16/2022]
Abstract
Hepatocellular carcinoma (HCC) occurs more frequently and aggressively in men than women, but the mechanistic basis of this gender disparity is obscure. Chronic inflammation is a major etiologic factor in HCC, so we investigated the role of cortisol in gender discrepancy in a zebrafish model of HCC. Inducible expression of oncogenic KrasV12 in hepatocytes of transgenic zebrafish resulted in accelerated liver tumor progression in males. These tumors were more heavily infiltrated with tumor-associated neutrophils (TAN) and tumor-associated macrophages (TAM) versus females, and they both showed protumor gene expression and promoted tumor progression. Interestingly, the adrenal hormone cortisol was predominantly produced in males to induce Tgfb1 expression, which functioned as an attractant for TAN and TAM. Inhibition of cortisol signaling in males, or increase of cortisol level in females, decreased or increased the numbers of TAN and TAM, respectively, accompanied by corresponding changes in protumor molecular expression. Higher levels of cortisol, TGFB1, and TAN/TAM infiltration in males were also confirmed in human pre-HCC and HCC samples, features that positively correlated in human patients. These results identify increased cortisol production and TAN/TAM infiltration as primary factors in the gender disparity of HCC development in both fish and human. Cancer Res; 77(6); 1395-407. ©2017 AACR.
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Affiliation(s)
- Chuan Yan
- Department of Biological Sciences, National University of Singapore, Singapore
- National University of Singapore Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore
| | - Qiqi Yang
- Department of Biological Sciences, National University of Singapore, Singapore
| | - Zhiyuan Gong
- Department of Biological Sciences, National University of Singapore, Singapore.
- National University of Singapore Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore
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13
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Alkhalili E, Greenbaum A, Luo L, Rodriguez R, Caldwell K, Estrada OM, O'Neill J, Nir I, Morris KT. Viral hepatitis status does not affect survival in patients with hepatocellular carcinoma. Ann Gastroenterol 2017; 30:101-105. [PMID: 28042245 PMCID: PMC5198233 DOI: 10.20524/aog.2016.0097] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 09/29/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND There have been few studies on the impact of viral etiology on the prognosis in patients with hepatocellular carcinoma (HCC). The aim of this study was to evaluate the clinical characteristics and survival of patients with viral hepatitis-associated HCC (V-HCC), compared to patients with HCC of non-hepatitis B, non-hepatitis C (NBNC-HCC) etiology. METHODS We performed a retrospective analysis of all patients with HCC treated at our comprehensive cancer center from 2000 through 2014. Patients were divided into two groups according to their viral hepatitis status. Presentation patterns, treatments, and survival data were analyzed. RESULTS We evaluated 366 patients: 233 patients (63.7%) had V-HCC while 133 (36.3%) patients had NBNC-HCC. V-HCC patients were younger (P<0.0001) and more likely to be male (P=0.001). Decompensated cirrhosis was more prevalent in V-HCC patients (P=0.01). There was no difference in the resectability rate or disease stage. In patients with resectable disease, those with V-HCC were less likely to undergo hepatectomy (23.7% vs. 38%; P=0.04) for more advanced liver disease. The estimated median survival for V-HCC was 13 months compared to 16 months in NBNC-HCC patients (P=0.57). On multivariate analysis, disease stage (P<0.0001) and Child-Pugh class (P<0.0001) were independent factors affecting survival, but viral status was not (P=0.75). CONCLUSION Despite presenting with more advanced cirrhosis and being less likely to undergo surgery, V-HCC patients had similar survival to patients with NBNC-HCC.
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Affiliation(s)
- Eyas Alkhalili
- Department of Surgery, School of Medicine, University of New Mexico, New Mexico, USA
| | - Alissa Greenbaum
- Department of Surgery, School of Medicine, University of New Mexico, New Mexico, USA
| | - Li Luo
- Department of Surgery, School of Medicine, University of New Mexico, New Mexico, USA
| | - Rodrigo Rodriguez
- Department of Surgery, School of Medicine, University of New Mexico, New Mexico, USA
| | - Katharine Caldwell
- Department of Surgery, School of Medicine, University of New Mexico, New Mexico, USA
| | - Oscar Munoz Estrada
- Department of Surgery, School of Medicine, University of New Mexico, New Mexico, USA
| | - Jacqueline O'Neill
- Department of Surgery, School of Medicine, University of New Mexico, New Mexico, USA
| | - Itzhak Nir
- Department of Surgery, School of Medicine, University of New Mexico, New Mexico, USA
| | - Katherine T Morris
- Department of Surgery, School of Medicine, University of New Mexico, New Mexico, USA
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14
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Seike M. Endocrine Disease and Liver. THE LIVER IN SYSTEMIC DISEASES 2016:251-270. [DOI: 10.1007/978-4-431-55790-6_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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15
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Zhao Y, Li Z. Interplay of estrogen receptors and FOXA factors in the liver cancer. Mol Cell Endocrinol 2015; 418 Pt 3:334-9. [PMID: 25661537 PMCID: PMC4524798 DOI: 10.1016/j.mce.2015.01.043] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Revised: 01/29/2015] [Accepted: 01/30/2015] [Indexed: 12/15/2022]
Abstract
Liver cancer is the fifth most common cancer in human with male dominance. Sexual dimorphism of liver cancer is conserved from rodents to humans, which was firstly found in mice in late 1930s and female mice were resistant to liver cancer. Sex hormones were found to affect the incidence of liver cancer in rodents. Estrogen receptor alpha (ERα)-mediated estrogen signaling or androgen receptor-mediated androgen signaling prevents or promotes the growth of rodent liver tumors, respectively. Forkhead box protein A (Foxa) factors, Foxa1 and Foxa2, also known as pioneer transcription factors in liver specification, are essential for both estrogen and androgen signaling by acting as central regulators of sexual dimorphism in liver cancer. This review mainly focuses on the interplay between ERα and FOXA factors in liver cancer, and summarizes recent breakthrough studies in elucidating the mechanisms of sexual dimorphism in liver cancer.
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Affiliation(s)
- Yongbing Zhao
- Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
| | - Zhaoyu Li
- Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
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16
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Ikeda M, Mitsunaga S, Ohno I, Hashimoto Y, Takahashi H, Watanabe K, Umemoto K, Okusaka T. Systemic Chemotherapy for Advanced Hepatocellular Carcinoma: Past, Present, and Future. Diseases 2015; 3:360-381. [PMID: 28943630 PMCID: PMC5548259 DOI: 10.3390/diseases3040360] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2015] [Revised: 11/19/2015] [Accepted: 11/19/2015] [Indexed: 12/18/2022] Open
Abstract
Systemic chemotherapy is one of the most important treatment modalities for advanced hepatocellular carcinoma (HCC). Before the introduction of sorafenib, cytotoxic agents, hormonal therapies, or many combinations of these were the mainly used modalities for systemic chemotherapy of advanced HCC. However, such regimens were of only limited value in clinical practice, because some randomized controlled studies comparing promising regimens with no treatment or doxorubicin alone failed to show any overall survival advantage. In two pivotal phase III placebo-controlled studies, the SHARP trial and the Asia-Pacific trial, sorafenib was demonstrated to significantly delay the time to progression and the overall survival time in patients with advanced HCC. Therefore, sorafenib therapy has come to be acknowledged as a standard therapy for advanced HCC worldwide. After the introduction of sorafenib, a number of phase III trials of various molecular-targeted agents vs. sorafenib as first-line chemotherapy and of various molecular-targeted agents vs. placebo as second-line chemotherapy have been conducted to determine if any of these agents could offer a survival benefit, however, none of the agents examined so far has been demonstrated to provide any survival benefit over sorafenib or placebo. Recently, favorable treatment efficacies have been reported in some clinical trials of molecular-targeted agents in the biomarker-enriched population. Development of individualized cancer treatments using molecular-targeted agents based on the results of genome-sequencing is aggressively ongoing. Furthermore, immune-oncologic agents, such as anti-CTLA-4 antibody and anti-PD-1/PD-L1 antibody, have been reported to provide promising outcomes. Thus, various novel systemic chemotherapeutic agents are currently under development, and further improvements in the treatment outcomes are expected.
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Affiliation(s)
- Masafumi Ikeda
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan.
| | - Shuichi Mitsunaga
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan.
| | - Izumi Ohno
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan.
| | - Yusuke Hashimoto
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan.
| | - Hideaki Takahashi
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan.
| | - Kazuo Watanabe
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan.
| | - Kumiko Umemoto
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan.
| | - Takuji Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan.
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17
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Chen KW, Ou TM, Hsu CW, Horng CT, Lee CC, Tsai YY, Tsai CC, Liou YS, Yang CC, Hsueh CW, Kuo WH. Current systemic treatment of hepatocellular carcinoma: A review of the literature. World J Hepatol 2015; 7:1412-20. [PMID: 26052386 PMCID: PMC4450204 DOI: 10.4254/wjh.v7.i10.1412] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Revised: 11/29/2014] [Accepted: 03/30/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common form of human cancer worldwide and the third most common cause of cancer-related deaths. The strategies of various treatments for HCC depend on the stage of tumor, the status of patient's performance and the reserved hepatic function. The Barcelona Clinic Liver Cancer (BCLC) staging system is currently used most for patients with HCC. For example, for patients with BCLC stage 0 (very early stage) and stage A (early stage) HCC, the curable treatment modalities, including resection, transplantation and radiofrequency ablation, are taken into consideration. If the patients are in BCLC stage B (intermediate stage) and stage C (advanced stage) HCC, they may need the palliative transarterial chemoembolization and even the target medication of sorafenib. In addition, symptomatic treatment is always recommended for patients with BCLC stage D (end stage) HCC. In this review, we will attempt to summarize the historical perspective and the current developments of systemic therapies in BCLC stage B and C in HCC.
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Affiliation(s)
- Kai-Wen Chen
- Kai-Wen Chen, Department of Internal Medicine, Hualien Armed Forces General Hospital, Hualien 97144, Taiwan
| | - Tzu-Ming Ou
- Kai-Wen Chen, Department of Internal Medicine, Hualien Armed Forces General Hospital, Hualien 97144, Taiwan
| | - Chin-Wen Hsu
- Kai-Wen Chen, Department of Internal Medicine, Hualien Armed Forces General Hospital, Hualien 97144, Taiwan
| | - Chi-Ting Horng
- Kai-Wen Chen, Department of Internal Medicine, Hualien Armed Forces General Hospital, Hualien 97144, Taiwan
| | - Ching-Chang Lee
- Kai-Wen Chen, Department of Internal Medicine, Hualien Armed Forces General Hospital, Hualien 97144, Taiwan
| | - Yuh-Yuan Tsai
- Kai-Wen Chen, Department of Internal Medicine, Hualien Armed Forces General Hospital, Hualien 97144, Taiwan
| | - Chi-Chang Tsai
- Kai-Wen Chen, Department of Internal Medicine, Hualien Armed Forces General Hospital, Hualien 97144, Taiwan
| | - Yi-Sheng Liou
- Kai-Wen Chen, Department of Internal Medicine, Hualien Armed Forces General Hospital, Hualien 97144, Taiwan
| | - Chen-Chieh Yang
- Kai-Wen Chen, Department of Internal Medicine, Hualien Armed Forces General Hospital, Hualien 97144, Taiwan
| | - Chao-Wen Hsueh
- Kai-Wen Chen, Department of Internal Medicine, Hualien Armed Forces General Hospital, Hualien 97144, Taiwan
| | - Wu-Hsien Kuo
- Kai-Wen Chen, Department of Internal Medicine, Hualien Armed Forces General Hospital, Hualien 97144, Taiwan
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18
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Solbach P, Potthoff A, Raatschen HJ, Soudah B, Lehmann U, Schneider A, Gebel MJ, Manns MP, Vogel A. Testosterone-receptor positive hepatocellular carcinoma in a 29-year old bodybuilder with a history of anabolic androgenic steroid abuse: a case report. BMC Gastroenterol 2015; 15:60. [PMID: 25986067 PMCID: PMC4461943 DOI: 10.1186/s12876-015-0288-0] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Accepted: 05/08/2015] [Indexed: 12/21/2022] Open
Abstract
Background Continuous use of anabolic androgenic steroid in high-doses is associated with substantial health risks, including hepatocellular adenoma. Malignant transformation from hepatocellular adenoma to hepatocellular carcinoma after anabolic androgenic steroid abuse has been rarely reported. The morphological distinction of adenoma from well-differentiated hepatocellular carcinoma is challenging and requires elaborated imaging techniques and histology. Case presentation We report about a 29-year old male professional bodybuilder who presented with mid-epigastric pain at the emergency unit. Ultrasound showed a severe hepatomegaly with multiple lesions. Contrast-enhanced ultrasound revealed a heterogeneous pattern with signs of hepatocellular carcinoma. CT scan of the abdomen confirmed multiple hypervascular lesions and central areas of necrosis without contrast enhancement. Subsequent diagnostics included fine needle aspiration (FNA) of suspicious lesions and mini-laparoscopy to establish the diagnosis of a β-catenin and testosterone-receptor positive hepatocellular carcinoma embedded in multiple adenomas. The patient was subsequently treated by liver transplantation and remains tumor-free 27 month after surgery. Conclusion Hepatocellular carcinoma occurring in association with anabolic androgenic steroid abuse should sensitize physicians and especially professional bodybuilders for the harmful use of high doses of steroids.
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Affiliation(s)
- Philipp Solbach
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule, OE 6810 Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
| | - Andrej Potthoff
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule, OE 6810 Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
| | - Hans-Jürgen Raatschen
- Department of Diagnostic and Interventional Radiology, Medizinische Hochschule Hannover, Hannover, Germany.
| | - Bisharah Soudah
- Department of Pathology, Medizinische Hochschule Hannover, Hannover, Germany.
| | - Ulrich Lehmann
- Department of Pathology, Medizinische Hochschule Hannover, Hannover, Germany.
| | - Andrea Schneider
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule, OE 6810 Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
| | - Michael J Gebel
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule, OE 6810 Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule, OE 6810 Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule, OE 6810 Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
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Hatting M, Spannbauer M, Peng J, Al Masaoudi M, Sellge G, Nevzorova YA, Gassler N, Liedtke C, Cubero FJ, Trautwein C. Lack of gp130 expression in hepatocytes attenuates tumor progression in the DEN model. Cell Death Dis 2015; 6:e1667. [PMID: 25741592 PMCID: PMC4385909 DOI: 10.1038/cddis.2014.590] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Revised: 11/30/2014] [Accepted: 12/15/2014] [Indexed: 12/21/2022]
Abstract
Chronic liver inflammation is a crucial event in the development and growth of hepatocellular carcinoma (HCC). Compelling evidence has shown that interleukin-6 (IL-6)/gp130-dependent signaling has a fundamental role in liver carcinogenesis. Thus, in the present study we aimed to investigate the role of gp130 in hepatocytes for the initiation and progression of HCC. Hepatocyte-specific gp130 knockout mice (gp130(Δhepa)) and control animals (gp130(f/f)) were treated with diethylnitrosamine (DEN). The role of gp130 for acute injury (0-144 h post treatment), tumor initiation (24 weeks) and progression (40 weeks) was analyzed. After acute DEN-induced liver injury we observed a reduction in the inflammatory response in gp130(Δhepa) animals as reflected by decreased levels of IL-6 and oncostatin M. The loss of gp130 slightly attenuated the initiation of HCC 24 weeks after DEN treatment. In contrast, 40 weeks after DEN treatment, male and female gp130(Δhepa) mice showed smaller tumors and reduced tumor burden, indicating a role for hepatocyte-specific gp130 expression during HCC progression. Oxidative stress and DNA damage were substantially and similarly increased by DEN in both gp130(f/f) and gp130(Δhepa) animals. However, gp130(Δhepa) livers revealed aberrant STAT5 activation and decreased levels of transforming growth factor-β (TGFβ), pSMAD2/3 and SMAD2, whereas phosphorylation of STAT3 at Tyr705 and Ser727 was absent. Our results indicate that gp130 deletion in hepatocytes reduces progression, but not HCC initiation in the DEN model. Gp130 deletion resulted in STAT3 inhibition but increased STAT5 activation and diminished TGF-dependent signaling. Hence, blocking gp130 in hepatocytes might be an interesting therapeutic target to inhibit the growth of HCC.
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Affiliation(s)
- M Hatting
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany
| | - M Spannbauer
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany
| | - J Peng
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany
| | - M Al Masaoudi
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany
| | - G Sellge
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany
| | - Y A Nevzorova
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany
| | - N Gassler
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany
| | - C Liedtke
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany
| | - F J Cubero
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany
| | - C Trautwein
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany
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20
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Shi L, Feng Y, Lin H, Ma R, Cai X. Role of estrogen in hepatocellular carcinoma: is inflammation the key? J Transl Med 2014; 12:93. [PMID: 24708807 PMCID: PMC3992128 DOI: 10.1186/1479-5876-12-93] [Citation(s) in RCA: 104] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Accepted: 03/28/2014] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and accounts for the third-leading cause of cancer-related deaths. Over the past decades, advances have been made in the field of surgery, but effective treatment of HCC is lacking. Due to a marked male predominance in morbidity and mortality in HCC patients, it has long been considered that sex hormones play a role in HCC development. Recently estrogen has been proven to exert protective effects against HCC through IL-6 restrictions, STAT3 inactivation and tumour-associated macrophage inhibition. While IL-6-dependent STAT3 activation is considered a key event in inflammation-induced liver cancer, the anti-inflammation effect of estrogen is well documented. The roles of the estrogen receptor and aromatase and interactions between microRNAs and estrogen in HCC have been investigated. In this review, we present a novel model to elucidate the mechanism of estrogen-mediated inhibition of HCC development through an anti-inflammation effect and provide new insights into the roles of estrogen in liver disease.
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Affiliation(s)
| | | | | | | | - Xiujun Cai
- Chawnshang Chang Live Cancer Center, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China.
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21
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Foxa1 and Foxa2 are essential for sexual dimorphism in liver cancer. Cell 2012; 148:72-83. [PMID: 22265403 DOI: 10.1016/j.cell.2011.11.026] [Citation(s) in RCA: 310] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2011] [Revised: 08/26/2011] [Accepted: 11/07/2011] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is sexually dimorphic in both rodents and humans, with significantly higher incidence in males, an effect that is dependent on sex hormones. The molecular mechanisms by which estrogens prevent and androgens promote liver cancer remain unclear. Here, we discover that sexually dimorphic HCC is completely reversed in Foxa1- and Foxa2-deficient mice after diethylnitrosamine-induced hepatocarcinogenesis. Coregulation of target genes by Foxa1/a2 and either the estrogen receptor (ERα) or the androgen receptor (AR) was increased during hepatocarcinogenesis in normal female or male mice, respectively, but was lost in Foxa1/2-deficient mice. Thus, both estrogen-dependent resistance to and androgen-mediated facilitation of HCC depend on Foxa1/2. Strikingly, single nucleotide polymorphisms at FOXA2 binding sites reduce binding of both FOXA2 and ERα to their targets in human liver and correlate with HCC development in women. Thus, Foxa factors and their targets are central for the sexual dimorphism of HCC.
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Cervello M, McCubrey JA, Cusimano A, Lampiasi N, Azzolina A, Montalto G. Targeted therapy for hepatocellular carcinoma: novel agents on the horizon. Oncotarget 2012; 3:236-60. [PMID: 22470194 PMCID: PMC3359882 DOI: 10.18632/oncotarget.466] [Citation(s) in RCA: 143] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2012] [Accepted: 03/31/2012] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common liver cancer, accounting for 90% of primary liver cancers. In the last decade it has become one of the most frequently occurring tumors worldwide and is also considered to be the most lethal of the cancer systems, accounting for approximately one third of all malignancies. Although the clinical diagnosis and management of early-stage HCC has improved significantly, HCC prognosis is still extremely poor. Furthermore, advanced HCC is a highly aggressive tumor with a poor or no response to common therapies. Therefore, new effective and well-tolerated therapy strategies are urgently needed. Targeted therapies have entered the field of anti-neoplastic treatment and are being used on their own or in combination with conventional chemotherapy drugs. Molecular-targeted therapy holds great promise in the treatment of HCC. A new therapeutic opportunity for advanced HCC is the use of sorafenib (Nexavar). On the basis of the recent large randomized phase III study, the Sorafenib HCC Assessment Randomized Protocol (SHARP), sorafenib has been approved by the FDA for the treatment of advanced HCC. Sorafenib showed to be able to significantly increase survival in patients with advanced HCC, establishing a new standard of care. Despite this promising breakthrough, patients with HCC still have a dismal prognosis, as it is currently the major cause of death in cirrhotic patients. Nevertheless, the successful results of the SHARP trial underscore the need for a comprehensive understanding of the molecular pathogenesis of this devastating disease. In this review we summarize the most important studies on the signaling pathways implicated in the pathogenesis of HCC, as well as the newest emerging drugs and their potential use in HCC management.
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Affiliation(s)
- Melchiorre Cervello
- Institute of Biomedicine and Molecular Immunology, "Alberto Monroy" National Research Council (C.N.R), Palermo, Italy.
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Mancinelli R, Onori P, DeMorrow S, Francis H, Glaser S, Franchitto A, Carpino G, Alpini G, Gaudio E. Role of sex hormones in the modulation of cholangiocyte function. World J Gastrointest Pathophysiol 2010; 1:50-62. [PMID: 21607142 PMCID: PMC3097944 DOI: 10.4291/wjgp.v1.i2.50] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2010] [Revised: 05/28/2010] [Accepted: 06/04/2010] [Indexed: 02/06/2023] Open
Abstract
Over the last years, cholangiocytes, the cells that line the biliary tree, have been considered an important object of study for their biological properties which involves bile formation, proliferation, injury repair, fibrosis and angiogenesis. Cholangiocyte proliferation occurs in all pathologic conditions of liver injury where it is associated with inflammation and regeneration. During these processes, biliary cells start to secrete different cytokines, growth factors, neuropeptides and hormones which represent potential mechanisms for cross talk with other liver cells. Several studies suggest that hormones, and in particular, sex hormones, play a fundamental role in the modulation of the growth of this compartment in the injured liver which functionally conditions the progression of liver disease. Understanding the mechanisms of action and the intracellular pathways of these compounds on cholangiocyte pathophysiology will provide new potential strategies for the management of chronic liver diseases. The purpose of this review is to summarize the recent findings on the role of sex hormones in cholangiocyte proliferation and biology.
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24
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Villa E. Androgen receptor alterations in hepatocarcinogenesis. Dig Liver Dis 2009; 41:632-3. [PMID: 19608466 DOI: 10.1016/j.dld.2009.06.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2009] [Accepted: 06/08/2009] [Indexed: 12/11/2022]
Affiliation(s)
- E Villa
- Gastroenterology Unit, University of Modena and Reggio Emilia, Via del Pozzo 71, 41100 Modena, Italy.
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Kupcsulik P. [Liver surgery]. Magy Seb 2008; 61:359-74. [PMID: 19073492 DOI: 10.1556/maseb.61.2008.6.8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Affiliation(s)
- Péter Kupcsulik
- Semmelweis Egyetem I. sz. Sebészeti Klinika Budapest, Hungary
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Kalra M, Mayes J, Assefa S, Kaul AK, Kaul R. Role of sex steroid receptors in pathobiology of hepatocellular carcinoma. World J Gastroenterol 2008; 14:5945-5961. [PMID: 18932272 PMCID: PMC2760195 DOI: 10.3748/wjg.14.5945] [Citation(s) in RCA: 109] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2008] [Revised: 09/16/2008] [Accepted: 09/23/2008] [Indexed: 02/06/2023] Open
Abstract
The striking gender disparity observed in the incidence of hepatocellular carcinoma (HCC) suggests an important role of sex hormones in HCC pathogenesis. Though the studies began as early as in 1980s, the precise role of sex hormones and the significance of their receptors in HCC still remain poorly understood and perhaps contribute to current controversies about the potential use of hormonal therapy in HCC. A comprehensive review of the existing literature revealed several shortcomings associated with the studies on estrogen receptor (ER) and androgen receptor (AR) in normal liver and HCC. These shortcomings include the use of less sensitive receptor ligand binding assays and immunohistochemistry studies for ERalpha alone until 1996 when ERbeta isoform was identified. The animal models of HCC utilized for studies were primarily based on chemical-induced hepatocarcinogenesis with less similarity to virus-induced HCC pathogenesis. However, recent in vitro studies in hepatoma cells provide newer insights for hormonal regulation of key cellular processes including interaction of ER and AR with viral proteins. In light of the above facts, there is an urgent need for a detailed investigation of sex hormones and their receptors in normal liver and HCC. In this review, we systematically present the information currently available on androgens, estrogens and their receptors in normal liver and HCC obtained from in vitro, in vivo experimental models and clinical studies. This information will direct future basic and clinical research to bridge the gap in knowledge to explore the therapeutic potential of hormonal therapy in HCC.
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