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Watling CZ, Kelly RK, Watts EL, Graubard BI, Petrick JL, Matthews CE, McGlynn KA. Total testosterone, sex hormone-binding globulin, and free testosterone concentrations and risk of primary liver cancer: A prospective analysis of 200,000 men and 180,000 postmenopausal women. Int J Cancer 2025; 156:1518-1528. [PMID: 39499225 PMCID: PMC11826138 DOI: 10.1002/ijc.35244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 10/07/2024] [Accepted: 10/17/2024] [Indexed: 11/07/2024]
Abstract
In most countries, males have ~2-3 times higher incidence of primary liver cancer than females. Sex hormones have been hypothesized to contribute to these differences, but the evidence remains unclear. Using data from the UK Biobank, which included ~200,000 males and ~180,000 postmenopausal females who provided blood samples at recruitment, we estimated hazard ratios (HR2) and 95% confidence intervals (CI) for a doubling in hormone concentration from multivariable adjusted Cox regression for circulating total testosterone, sex-hormone binding globulin (SHBG), and free testosterone concentrations and risk of primary liver cancer. After a median of 11.8 years of follow-up, 531 cases of primary liver cancer were observed, of which 366 occurred in males and 165 occurred in females. Total testosterone and SHBG were shown to be positively associated with liver cancer risk in both males and females (Total testosterone HR2: 3.42, 95% CI:2.42-4.84 and 1.29, 0.97-1.72, respectively; SHBG HR2: 5.44, 4.42-6.68 and 1.52, 1.09-2.12, respectively). However, free testosterone was inversely associated with primary liver cancer in males (HR2: 0.42, 0.32-0.55) and no association was observed in females. When analyses compared two main liver cancer subtypes, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), there was evidence of heterogeneity; associations for total testosterone and SHBG concentrations were only positively associated with HCC in both males (HR2: 3.56, 2.65-4.79 and 7.72, 6.12-9.73, respectively) and females (HR2: 1.65, 1.20-2.27 and 6.74, 3.93-11.5, respectively) but not with ICC. Further research understanding the mechanisms of how sex-steroids may influence liver cancer risk is needed.
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Affiliation(s)
- Cody Z. Watling
- Division of Cancer Epidemiology and GeneticsNational Cancer InstituteBethesdaMarylandUSA
| | - Rebecca K. Kelly
- The George Institute for Global HealthUniversity of New South WalesSydneyNew South WalesAustralia
- School of Medicine, College of Health and MedicineUniversity of TasmaniaHobartTasmaniaAustralia
| | - Eleanor L. Watts
- Division of Cancer Epidemiology and GeneticsNational Cancer InstituteBethesdaMarylandUSA
| | - Barry I. Graubard
- Division of Cancer Epidemiology and GeneticsNational Cancer InstituteBethesdaMarylandUSA
| | | | - Charles E. Matthews
- Division of Cancer Epidemiology and GeneticsNational Cancer InstituteBethesdaMarylandUSA
| | - Katherine A. McGlynn
- Division of Cancer Epidemiology and GeneticsNational Cancer InstituteBethesdaMarylandUSA
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Wang X, Liang X, Zhang N, Wang Y, Hu M, Shi Y, Yao M, Hou L, Jiang L. Gamma-tocotrienol Inhibits Proliferation and Growth of HSD17B4 Overexpressing HepG2 Liver Cancer Cells. Curr Cancer Drug Targets 2025; 25:170-182. [PMID: 38934283 DOI: 10.2174/0115680096319171240623091614] [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: 04/19/2024] [Revised: 05/24/2024] [Accepted: 06/10/2024] [Indexed: 06/28/2024]
Abstract
INTRODUCTION Hydroxysteroid 17-beta dehydrogenase 4 (HSD17B4) is involved in the progression of hepatocellular carcinoma (HCC). AIMS This study aimed to investigate the inhibitory effect of gamma-tocotrienol (γ-T3) on the proliferation and growth of HSD17B4-overexpressing HepG2 cells. METHODS HepG2 cells were transfected with empty or HSD17B4-overexpressing plasmids, followed by vitamin E (VE) or γ-T3 treatment. MTS assay, Western blotting, qRT-PCR, and flow cytometry were employed to assess cell proliferation, protein expression, mRNA levels, and apoptosis. HSD17B4 interaction with γ-T3 was assessed by quantifying γ-T3 in the collected precipitate of HSD17B4 using anti-flag magnetic beads. Tumor xenografts were established in NSG mice, and tumor growth was monitored. RESULTS HSD17B4 overexpression significantly promoted HepG2 cell proliferation, which was effectively counteracted by VE or γ-T3 treatment in a dose-dependent manner. VE and γ-T3 did not exert their effects through direct regulation of HSD17B4 expression. Instead, γ-T3 was found to interact with HSD17B4, inhibiting its activity in catalyzing the conversion of estradiol (E2) into estrone. Moreover, γ-T3 treatment led to a reduction in cyclin D1 expression and suppressed key proliferation signaling pathways, such as ERK, MEK, AKT, and STAT3. Additionally, γ-T3 promoted apoptosis in HSD17B4-overexpressing HepG2 cells. In an in vivo model, γ-T3 effectively reduced the growth of HepG2 xenograft tumors. CONCLUSION In conclusion, our study demonstrates that γ-T3 exhibits potent anti-proliferative and anti-tumor effects against HepG2 cells overexpressing HSD17B4. These findings highlight the therapeutic potential of γ-T3 in HCC treatment and suggest its role in targeting HSD17B4-associated pathways to inhibit tumor growth and enhance apoptosis.
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Affiliation(s)
- Xiaoming Wang
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, Shijiazhuang, 050000, Hebei, China
- Department of Clinical Laboratory, First Hospital of Tsinghua University (Beijing Huaxin Hospital), Beijing, 100016, China
| | - Xijia Liang
- Department of Clinical Laboratory, The 980th Hospital of PLA Joint Logistical Support Force (Bethune International Peace Hospital), Shijiazhuang, 050000, Hebei, China
| | - Nan Zhang
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, Shijiazhuang, 050000, Hebei, China
- College of Integrative Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, 050000, Hebei, China
| | - Yaqi Wang
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, Shijiazhuang, 050000, Hebei, China
- Department of Clinical Laboratory, Hebei Province Hospital of Chinese Medicine, Shijiazhuang, 050000, Hebei, China
| | - Meng Hu
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, Shijiazhuang, 050000, Hebei, China
- Department of Complex Preparation, Shijiazhuang No.4 Pharmaceutical, Shijiazhuang, 050000, Hebei, China
| | - Yun Shi
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, Shijiazhuang, 050000, Hebei, China
| | - Min Yao
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, Shijiazhuang, 050000, Hebei, China
| | - Lianguo Hou
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, Shijiazhuang, 050000, Hebei, China
| | - Lingling Jiang
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, Shijiazhuang, 050000, Hebei, China
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Boye A, Osei SA, Brah AS. Therapeutic prospects of sex hormone receptor signaling in hormone-responsive cancers. Biomed Pharmacother 2024; 180:117473. [PMID: 39326105 DOI: 10.1016/j.biopha.2024.117473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 09/11/2024] [Accepted: 09/19/2024] [Indexed: 09/28/2024] Open
Abstract
Globally, hormone-responsive cancers afflict millions of people contributing to cancer-related morbidity and mortality. While hormone-responsive cancers overburden patients, their close families, and even health budgets at the local levels, knowledge of these cancers particularly their biology and possible avenues for therapy remains poorly exploited. Herewith, this review highlights the role of sex hormones (estrogens and androgens) in the pathophysiology of hormone-responsive cancers and the exploration of therapeutic targets. Major scientific databases including but not limited to Scopus, PubMed, Science Direct, Web of Science core collections, and Google Scholar were perused using a string of search terms: Hormone-responsive cancers, androgens and cancers, estrogens and cancer, androgen receptor signalling, estrogen receptor signalling, etc.
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Affiliation(s)
- Alex Boye
- Department of Medical Laboratory Science, School of Allied Health Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana.
| | - Silas Acheampong Osei
- Department of Pharmacology, School of Pharmacy and Pharmaceutical Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Augustine Suurinobah Brah
- Department of Biomedical Sciences, School of Allied Health Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
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Pang C, Li JM, Wang Z, Luo YC, Cheng ZG, Han ZY, Liu FY, Yu XL, Liang F, Xi HQ, Zheng RQ, Cheng W, Wei Q, Yu SY, Li QY, He GZ, Yu J, Liang P. Age-Dependent Female Survival Advantage in Hepatocellular Carcinoma: A Multicenter Cohort Study. Clin Gastroenterol Hepatol 2024; 22:305-314. [PMID: 37659766 DOI: 10.1016/j.cgh.2023.07.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 07/17/2023] [Accepted: 07/25/2023] [Indexed: 09/04/2023]
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) has a higher incidence in males, but the association of sex with survival remains controversial. This study aimed to examine the effect of sex on HCC survival and its association with age. METHODS Among 33,238 patients with HCC from 12 Chinese tertiary hospitals, 4175 patients who underwent curative-intent hepatectomy or ablation were analyzed. Cancer-specific survival (CSS) was analyzed using Cox regression and Kaplan-Meier methods. Two propensity score methods and multiple mediation analysis were applied to mitigate confounding. To explore the effect of estrogen, a candidate sex-specific factor that changes with age, female participants' history of estrogen use, and survival were analyzed. RESULTS There were 3321 males and 854 females included. A sex-related disparity of CSS was present and showed a typical age-dependent pattern: a female survival advantage over males appeared at the perimenopausal age of 45 to 54 years (hazard risk [HR], 0.77; 5-year CSS, 85.7% vs 70.6%; P = .018), peaked at the early postmenopausal age of 55 to 59 years (HR, 0.57; 5-year CSS, 89.8% vs 73.5%; P = .015), and was not present in the premenopausal (<45 y) and late postmenopausal groups (≥60 y). Consistent patterns were observed in patients after either ablation or hepatectomy. These results were sustained with propensity score analyses. Confounding or mediation effects accounted for only 19.5% of sex survival disparity. Female estrogen users had significantly longer CSS than nonusers (HR, 0.74; 5-year CSS, 79.6% vs 72.5%; P = .038). CONCLUSIONS A female survival advantage in HCC depends on age, and this may be associated with age-dependent, sex-specific factors.
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Affiliation(s)
- Chuan Pang
- Department of Interventional Ultrasound, Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China; Department of General Surgery, First Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China
| | - Jian-Ming Li
- Department of Interventional Ultrasound, Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China
| | - Zhen Wang
- Department of Interventional Ultrasound, Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China
| | - Yan-Chun Luo
- Department of Interventional Ultrasound, Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China
| | - Zhi-Gang Cheng
- Department of Interventional Ultrasound, Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China
| | - Zhi-Yu Han
- Department of Interventional Ultrasound, Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China
| | - Fang-Yi Liu
- Department of Interventional Ultrasound, Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China
| | - Xiao-Ling Yu
- Department of Interventional Ultrasound, Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China
| | - Feng Liang
- Department of General Surgery, First Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China
| | - Hong-Qing Xi
- Department of General Surgery, First Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China
| | - Rong-Qin Zheng
- Department of Medical Ultrasound, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Wen Cheng
- Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin City, China
| | - Qiang Wei
- Department of Ultrasound, The Second Hospital of Nanjing, Nanjing, China
| | - Song-Yuan Yu
- Department of Wuhan University of Science and Technology, Tianyou Hospital, Wuhan, China
| | - Qin-Ying Li
- Department of Ultrasound, Puyang Hospital of Traditional Chinese Medicine of Henan Province, Puyang, China
| | - Guang-Zhi He
- Department of Ultrasound, University of Chinese Academy of Sciences Shenzhen Hospital, Shenzhen, China
| | - Jie Yu
- Department of Interventional Ultrasound, Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China.
| | - Ping Liang
- Department of Interventional Ultrasound, Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China.
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Huang Y, Su X, Chen K, Zhang L, Xu W, Pu Y, Xu F, Gong R, Zhang J, Nie Y, Shi Q. Epidemiological characteristics of suspected adenomyosis in the Chinese physical examination population: a nested case-control study. BMJ Open 2024; 14:e074488. [PMID: 38216177 PMCID: PMC10806687 DOI: 10.1136/bmjopen-2023-074488] [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: 04/07/2023] [Accepted: 11/27/2023] [Indexed: 01/14/2024] Open
Abstract
OBJECTIVES We aimed to explore the epidemiological characteristics of suspected adenomyosis within a physical examination population in China. DESIGN A retrospective, nested case-control study; we matched healthy people and those with potential adenomyosis on a 1:2 ratio by age. SETTING A tertiary hospital health management centre. PARTICIPANTS We included 15-60 years old women who underwent at least one uterine examination from October 2017 to December 2020, excluding those who had undergone hysterectomy and menopause. PRIMARY AND SECONDARY OUTCOME MEASURES We estimated the incidence and prevalence rate of suspected adenomyosis. Conditional logistic regression was used to estimate associations between serum biomarkers and potential adenomyosis. Areas under the receiver-operating characteristic curves (AUC) were used to determine the cut-off point of the cancer antigen 125 (CA125) level for suspected adenomyosis. RESULTS A total of 30 629 women had uterus-related imaging examinations; 877 had suspected adenomyosis. The standardised incidence and prevalence of suspected adenomyosis was 1.32% and 2.35%, respectively, for all age groups. The conditional logistic regression analysis results showed that total bilirubin≥18.81 µmol/L (HR: 2.129; 95% CI 1.067 to 4.249; p<0.0321) and CA125 levels (HR: 1.014; 95% CI 1.002 to 4.731; p<0.0273) were positively correlated with onset of suspected adenomyosis; body mass index>24 kg/m2 (HR: 1.262; 95% CI 1.055 to 1.511; p<0.0109), CA125 levels (HR: 1.007; 95% CI 1.006 to 1.009; p<0.0001), and blood platelet levels (HR: 1.002; 95% CI 1 to 1.003; p<0.0141) were positively correlated with potential adenomyosis. The optimal cut-off of CA125 for new suspected adenomyosis was 10.714 U/mL, with a sensitivity of 77.42%, specificity of 53.76%, and AUC of 0.7841 (95% CI 0.7276 to 0.8407). CONCLUSIONS The disease burden of suspected adenomyosis remains huge and can be informed by biomarkers. The disease-specific threshold of CA125 will support further preventive strategy development in population. TRIAL REGISTRATION NUMBER ChiCTR2100049520, 2021/8/2.
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Affiliation(s)
| | - Xueyao Su
- Chongqing Medical University, Chongqing, China
| | - Ke Chen
- Nanchong Central Hospital, North Sichuan Medical University, Nanchong, China
| | - Lijun Zhang
- Chongqing Medical University, Chongqing, China
| | - Wei Xu
- Chongqing Medical University, Chongqing, China
| | - Yang Pu
- Chongqing Medical University, Chongqing, China
| | - Fan Xu
- Nanchong Central Hospital, North Sichuan Medical University, Nanchong, China
| | - Ruoyan Gong
- Chongqing Medical University, Chongqing, China
| | | | - Yuxian Nie
- State Key Laboratory of Ultrasound in Medicine and Engineering, Chongqing Medical University, Chongqing, China
| | - Qiuling Shi
- State Key Laboratory of Ultrasound in Medicine and Engineering, Chongqing Medical University, Chongqing, China
- School of Public Health and Management, Chongqing Medical University, Chongqing, China
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Smiriglia A, Lorito N, Serra M, Perra A, Morandi A, Kowalik MA. Sex difference in liver diseases: How preclinical models help to dissect the sex-related mechanisms sustaining NAFLD and hepatocellular carcinoma. iScience 2023; 26:108363. [PMID: 38034347 PMCID: PMC10682354 DOI: 10.1016/j.isci.2023.108363] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2023] Open
Abstract
Only a few preclinical findings are confirmed in the clinic, posing a critical issue for clinical development. Therefore, identifying the best preclinical models can help to dissect molecular and mechanistic insights into liver disease pathogenesis while being clinically relevant. In this context, the sex relevance of most preclinical models has been only partially considered. This is particularly significant in NAFLD and HCC, which have a higher prevalence in men when compared to pre-menopause women but not to those in post-menopausal status, suggesting a role for sex hormones in the pathogenesis of the diseases. This review gathers the sex-relevant findings and the available preclinical models focusing on both in vitro and in vivo studies and discusses the potential implications and perspectives of introducing the sex effect in the selection of the best preclinical model. This is a critical aspect that would help to tailor personalized therapies based on sex.
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Affiliation(s)
- Alfredo Smiriglia
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy
| | - Nicla Lorito
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy
| | - Marina Serra
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy
| | - Andrea Perra
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy
| | - Andrea Morandi
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy
| | - Marta Anna Kowalik
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy
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7
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Nuermaimaiti A, Chang L, Yan Y, Sun H, Xiao Y, Song S, Feng K, Lu Z, Ji H, Wang L. The role of sex hormones and receptors in HBV infection and development of HBV-related HCC. J Med Virol 2023; 95:e29298. [PMID: 38087447 DOI: 10.1002/jmv.29298] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 10/02/2023] [Accepted: 11/18/2023] [Indexed: 12/18/2023]
Abstract
Gender disparity in hepatitis B virus (HBV)-related diseases has been extensively documented. Epidemiological studies consistently reported that males have a higher prevalence of HBV infection and incidence of hepatocellular carcinoma (HCC). Further investigations have revealed that sex hormone-related signal transductions play a significant role in gender disparity. Sex hormone axes showed significantly different responses to virus entry and replication. The sex hormones axes change the HBV-specific immune responses and antitumor immunity. Additionally, Sex hormone axes showed different effects on the development of HBV-related disease. But the role of sex hormones remains controversial, and researchers have not reached a consensus on the role of sex hormones and the use of hormone therapies in HCC treatment. In this review, we aim to summarize the experimental findings on sex hormones and provide a comprehensive understanding of their roles in the development of HCC and their implications for hormone-related HCC treatment.
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Affiliation(s)
- Abudulimutailipu Nuermaimaiti
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Le Chang
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | - Ying Yan
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | - Huizhen Sun
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yingzi Xiao
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Shi Song
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Kaihao Feng
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Zhuoqun Lu
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | - Huimin Ji
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | - Lunan Wang
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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Xu Y, Zhu Y, Wu Z, Li S, Shao M, Tao Q, Xu Q, Chen Y, Shu Y, Chen M, Zhou Y, Shi Y. Hepatocyte-specific HDAC3 ablation promotes hepatocellular carcinoma in females by suppressing Foxa1/2. BMC Cancer 2023; 23:906. [PMID: 37752418 PMCID: PMC10521566 DOI: 10.1186/s12885-023-11393-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 09/10/2023] [Indexed: 09/28/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC), the most common primary liver cancer, prevails mainly in males and has long been attributed to androgens and higher circumstantial levels of interleukin-6 (IL-6) produced by resident hepatic macrophages. METHODS Constitutively hepatocyte-specific histone deacetylase 3 (HDAC3)-deficient (HDAC3LCKO) mice and constitutively hepatocyte-specific HDAC3 knockout and systemic IL-6 simultaneously ablated (HDAC3LCKO& IL-6-/-) mice were used in our study to explore the causes of sex differences in HCC. Additionally, we performed human HCC tissues with an IHC score. Correlation analysis and linear regression plots were constructed to reveal the association between HDAC3 and its candidate genes. To further elucidate that HDAC3 controls the expression of Foxa1/2, we knocked down HDAC3 in HUH7 liver cancer cells. RESULTS We observed a contrary sex disparity, with an earlier onset and higher incidence of HCC in female mice when HDAC3 was selectively ablated in the liver. Loss of HDAC3 led to constant liver injury and the spontaneous development of HCC. Unlike the significant elevation of IL-6 in male mice at a very early age, female mice exhibit stable IL-6 levels, and IL-6 ablation did not eliminate the sex disparity in hepatocarcinogenesis in HDAC3-deficient mice. Oestrogen often protects the liver when combined with oestrogen receptor alpha (ERα); however, ovariectomy in HDAC3-ablated female mice significantly delayed tumourigenesis. The oestrogen-ERα axis can also play a role in tumour promotion in the absence of Foxa1 and Foxa2 in the receptor complex. Loss of HDAC3 profoundly reduced the expression of both Foxa1 and Foxa2 and impaired the binding between Foxa1/2 and ERα. Furthermore, a more frequent HDAC3 decrease accompanied by the simultaneous Foxa1/2 decline was found in female HCC compared to that in male HCC. CONCLUSION In summary, we reported that loss of HDAC3 reduces Foxa1/2 and thus promotes HCC development in females in an oestrogen-dependent manner.
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Affiliation(s)
- Yahong Xu
- Department of Pathology & Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Transplant Engineering and Immunology, West China Hospital, NHC, Sichuan University, Chengdu, 610041, China
| | - Yongjie Zhu
- Department of Targeting Therapy & Immunology and Laboratory of Animal Tumor Models, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhenru Wu
- Department of Pathology & Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Transplant Engineering and Immunology, West China Hospital, NHC, Sichuan University, Chengdu, 610041, China
| | - Shengfu Li
- Department of Pathology & Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Transplant Engineering and Immunology, West China Hospital, NHC, Sichuan University, Chengdu, 610041, China
| | - Mingyang Shao
- Department of Pathology & Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Transplant Engineering and Immunology, West China Hospital, NHC, Sichuan University, Chengdu, 610041, China
| | - Qing Tao
- Department of Pathology & Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Transplant Engineering and Immunology, West China Hospital, NHC, Sichuan University, Chengdu, 610041, China
| | - Qing Xu
- Department of Pathology & Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Transplant Engineering and Immunology, West China Hospital, NHC, Sichuan University, Chengdu, 610041, China
| | - Yuwei Chen
- Department of Pathology & Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Transplant Engineering and Immunology, West China Hospital, NHC, Sichuan University, Chengdu, 610041, China
| | - Yuke Shu
- Department of Pathology & Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Transplant Engineering and Immunology, West China Hospital, NHC, Sichuan University, Chengdu, 610041, China
| | - Menglin Chen
- Department of Pathology & Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Transplant Engineering and Immunology, West China Hospital, NHC, Sichuan University, Chengdu, 610041, China
| | - Yongjie Zhou
- Laboratory of Liver Transplantation, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yujun Shi
- Department of Pathology & Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Key Laboratory of Transplant Engineering and Immunology, West China Hospital, NHC, Sichuan University, Chengdu, 610041, China.
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9
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Abdel-Hamid MS, Mansour AM, Hassan MH, Abdelhady R, Elsadek BEM, El-Sayed ESM, Salama SA. Estrogen Attenuates Diethylnitrosamine-Induced Hepatocellular Carcinoma in Female Rats via Modulation of Estrogen Receptor/FASN/CD36/IL-6 Axis. Biol Pharm Bull 2023; 46:1558-1568. [PMID: 37914358 DOI: 10.1248/bpb.b23-00342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2023]
Abstract
This study was designed to evaluate the potential protective impact of estrogen and estrogen receptor against diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) in rats. The levels of liver injury serum biomarkers, liver content of interleukin-6 (IL-6), relative liver weight and distortion of liver histological pictures were significantly increased in ovariectomized (OVX) rats and SHAM rats that received DEN alone and were further exaggerated when DEN was combined with fulvestrant (F) compared to non-DEN treated rats. The OVX rats showed higher insults than SHAM rats. The tapering impact on these parameters was clear in OVX rats that received estradiol benzoate (EB), silymarin (S) or orlistat (ORS). The immunohistochemistry and/or Western blot analysis of liver tissues showed a prominent increase in fatty acid synthase (FASN) and cluster of differentiation 36 (CD36) expressions in OVX and SHAM rats who received DEN and/ or F compared to SHAM rats. In contrast to S, treatment of OVX rats with EB mitigated DEN-induced expression of FASN and CD36 in liver tissue, while ORS improved DEN-induced expression of FASN. In conclusion, the protective effect against HCC was mediated via estrogen receptor alpha (ER-α) which abrogates its downstream genes involved in lipid metabolism namely FASN and CD36 depriving the tumor from survival vital energy source. In addition, ORS induced similar mitigating effect against DEN-induced HCC which could be attributed to FASN inhibition and anti-inflammatory effect. Furthermore, S alleviated DEN-induced HCC, independent of its estrogenic effect.
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Affiliation(s)
| | - Ahmed M Mansour
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University
| | - Memy H Hassan
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University
| | - Rasha Abdelhady
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Fayoum University
| | - Bakheet E M Elsadek
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Al-Azhar University
| | - El-Sayed M El-Sayed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University
| | - Salama A Salama
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University
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10
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Wang CH, Lin RC, Hsu HY, Tseng YT. Hormone replacement therapy is associated with reduced hepatocellular carcinoma risk and improved survival in postmenopausal women with hepatitis B: A nationwide long-term population-based cohort study. PLoS One 2022; 17:e0271790. [PMID: 35862398 PMCID: PMC9302748 DOI: 10.1371/journal.pone.0271790] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 07/07/2022] [Indexed: 11/19/2022] Open
Abstract
Postmenopausal women with hepatitis B virus (HBV) infection are more likely to have accelerated liver fibrosis, eventually advancing to liver cirrhosis or hepatocellular carcinoma (HCC). The association between sex hormones and HBV-related HCC risk is unclear. We investigated whether hormone replacement therapy (HRT) is beneficial to postmenopausal women with HBV infection. This retrospective study selected the data of 44,465patients with HBV infection between January 2000 and December 2018 from Taiwan’s National Health Insurance Research Database. After excluding patients with preexisting liver diseases, liver cirrhosis, or liver malignancies, we grouped the remaining 10,474 patients by whether they had undergone HRT for at least 3 months (n = 5,638) and whether they had not received HRT (n = 4,836). After propensity score matching, we assigned 3080 patients to an HRT cohort and matched them (1:1) with those in a non-HRT cohort. The incidence of HCC (P < 0.022) and all-cause mortality rate (P < 0.001) were lower in the HRT cohort than in the non-HRT cohort. The liver cirrhosis risk was not significantly higher in the HRT cohort (P = 0.355). HRT is associated with reduced HCC risk and improved survival outcomes but is unrelated to liver cirrhosis development in postmenopausal women.
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Affiliation(s)
- Chun-Hsiang Wang
- Department of Hepatogastroenterology, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan, Taiwan
- Department of Optometry, Chung Hwa Medical University, Tainan, Taiwan
| | - Ruey-Chang Lin
- Department of Hepatogastroenterology, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan, Taiwan
| | - Hua-Yin Hsu
- Departments of Nursing, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan City, Taiwan
| | - Yuan-Tsung Tseng
- Committee of Medical Research, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan, Taiwan
- * E-mail:
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11
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Huang S, Wang W, Cheng Y, Lin J, Wang M. Clinicopathological and Prognostic Significance of Klotho and Estrogen Receptors Expression in Human Hepatocellular Carcinoma. THE TURKISH JOURNAL OF GASTROENTEROLOGY : THE OFFICIAL JOURNAL OF TURKISH SOCIETY OF GASTROENTEROLOGY 2021; 32:828-836. [PMID: 34787087 PMCID: PMC8975321 DOI: 10.5152/tjg.2021.19986] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 09/21/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is male-predominant cancer, but the underlying mechanism remains unclear. This study aimed to investigate the expression of the age-suppressing gene klotho and estrogen receptors (ERs) in HCC patients and analyze their association with clinicopathological variables and their effects on prognosis. METHODS The expression patterns of klotho, ERα, and ERβ were determined by tissue microarray and immunohistochemical technique, and their correlations with clinicopathological characteristics were investigated using univariate and multivariate analysis. RESULTS Klotho expression was significantly lower in HCC than in the adjacent noncancerous tissues (52.7% (49/93) vs. 90.8% (79/87), P = .000), and its protein level in HCC tissue was negatively correlated with clinical staging, histological grade, and stage of the primary tumor (T) (P < .05). Whereas the expression of nuclear ERα and ERβ was higher in HCC than their corresponding non-neoplastic tissues (55.9% (52/93) vs. 35.6% (31/87), P = .006; 59.1% (55/93) vs. 43.7% (38/87), P = .038), and the level of nuclear ERα and ERβ in HCC tissue was inversely correlated with T stage, tumor size, and clinical staging (P < .05). Correlation analysis showed the expression level of klotho, which is positively correlated with that of nuclear ERα (r = 0.243, P = .019). Patients with klotho-positive tumors had longer survival than those with klotho-negative tumors (P = .002). Cox proportional hazards model analysis demonstrated that positive expression of klotho was an important factor indicating good prognosis (P = .003). CONCLUSION Klotho, partially regulated by ERα-mediated estrogen pathway, acts as a tumor suppressor and might be a novel biomarker candidate for predicting progression and prognosis in HCC patients.
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Affiliation(s)
- Shu Huang
- Department of Gastroenterology, The People’s Hospital of Lianshui, Huaian, China
| | - Wei Wang
- Department of Gastroenterology, The People’s Hospital of Lianshui, Huaian, China
| | - Yajun Cheng
- Department of Gastroenterology, The People’s Hospital of Lianshui, Huaian, China
| | - Jie Lin
- Medical Center for Digestive Diseases, The Second Affiliated Hospital, Nanjing Medical University, China
- Department of Gastroenterology, The Fourth Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Min Wang
- Digestive Endoscopy Department, The First Affiliated Hospital, Nanjing Medical University, Nanjing, China
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12
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Shen M, Xu M, Zhong F, Crist MC, Prior AB, Yang K, Allaire DM, Choueiry F, Zhu J, Shi H. A Multi-Omics Study Revealing the Metabolic Effects of Estrogen in Liver Cancer Cells HepG2. Cells 2021; 10:cells10020455. [PMID: 33672651 PMCID: PMC7924215 DOI: 10.3390/cells10020455] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 02/14/2021] [Accepted: 02/16/2021] [Indexed: 12/19/2022] Open
Abstract
Hepatocellular carcinoma (HCC) that is triggered by metabolic defects is one of the most malignant liver cancers. A much higher incidence of HCC among men than women suggests the protective roles of estrogen in HCC development and progression. To begin to understand the mechanisms involving estrogenic metabolic effects, we compared cell number, viability, cytotoxicity, and apoptosis among HCC-derived HepG2 cells that were treated with different concentrations of 2-deoxy-d-glucose (2-DG) that blocks glucose metabolism, oxamate that inhibits lactate dehydrogenase and glycolysis, or oligomycin that blocks ATP synthesis and mitochondrial oxidative phosphorylation. We confirmed that HepG2 cells primarily utilized glycolysis followed by lactate fermentation, instead of mitochondrial oxidative phosphorylation, for cell growth. We hypothesized that estrogen altered energy metabolism via its receptors to carry out its anticancer effects in HepG2 cells. We treated cells with 17β-estradiol (E2), 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT) an estrogen receptor (ER) α (ERα) agonist, or 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), an ERβ agonist. We then used transcriptomic and metabolomic analyses and identified differentially expressed genes and unique metabolite fingerprints that are produced by each treatment. We further performed integrated multi-omics analysis, and identified key genes and metabolites in the gene–metabolite interaction contributed by E2 and ER agonists. This integrated transcriptomic and metabolomic study suggested that estrogen acts on estrogen receptors to suppress liver cancer cell growth via altering metabolism. This is the first exploratory study that comprehensively investigated estrogen and its receptors, and their roles in regulating gene expression, metabolites, metabolic pathways, and gene–metabolite interaction in HCC cells using bioinformatic tools. Overall, this study provides potential therapeutic targets for future HCC treatment.
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Affiliation(s)
- Minqian Shen
- Department of Biology, Miami University, Oxford, OH 45056, USA; (M.S.); (M.X.); (M.C.C.); (A.B.P.); (D.M.A.)
| | - Mengyang Xu
- Department of Biology, Miami University, Oxford, OH 45056, USA; (M.S.); (M.X.); (M.C.C.); (A.B.P.); (D.M.A.)
- Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USA; (F.Z.); (K.Y.)
| | - Fanyi Zhong
- Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USA; (F.Z.); (K.Y.)
| | - McKenzie C. Crist
- Department of Biology, Miami University, Oxford, OH 45056, USA; (M.S.); (M.X.); (M.C.C.); (A.B.P.); (D.M.A.)
| | - Anjali B. Prior
- Department of Biology, Miami University, Oxford, OH 45056, USA; (M.S.); (M.X.); (M.C.C.); (A.B.P.); (D.M.A.)
| | - Kundi Yang
- Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USA; (F.Z.); (K.Y.)
| | - Danielle M. Allaire
- Department of Biology, Miami University, Oxford, OH 45056, USA; (M.S.); (M.X.); (M.C.C.); (A.B.P.); (D.M.A.)
| | - Fouad Choueiry
- Department of Human Sciences, College of Education and Human Ecology, Columbus, OH 43210, USA;
- James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Jiangjiang Zhu
- Department of Human Sciences, College of Education and Human Ecology, Columbus, OH 43210, USA;
- James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
- Correspondence: (J.Z.); (H.S.); Tel.: +1-614-685-2226 (J.Z.); +1-513-529-3162 (H.S.)
| | - Haifei Shi
- Department of Biology, Miami University, Oxford, OH 45056, USA; (M.S.); (M.X.); (M.C.C.); (A.B.P.); (D.M.A.)
- Correspondence: (J.Z.); (H.S.); Tel.: +1-614-685-2226 (J.Z.); +1-513-529-3162 (H.S.)
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13
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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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14
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Beneficial and Deleterious Effects of Female Sex Hormones, Oral Contraceptives, and Phytoestrogens by Immunomodulation on the Liver. Int J Mol Sci 2019; 20:ijms20194694. [PMID: 31546715 PMCID: PMC6801544 DOI: 10.3390/ijms20194694] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 09/13/2019] [Accepted: 09/20/2019] [Indexed: 12/11/2022] Open
Abstract
The liver is considered the laboratory of the human body because of its many metabolic processes. It accomplishes diverse activities as a mixed gland and is in continuous cross-talk with the endocrine system. Not only do hormones from the gastrointestinal tract that participate in digestion regulate the liver functions, but the sex hormones also exert a strong influence on this sexually dimorphic organ, via their receptors expressed in liver, in both health and disease. Besides, the liver modifies the actions of sex hormones through their metabolism and transport proteins. Given the anatomical position and physiological importance of liver, this organ is evidenced as an immune vigilante that mediates the systemic immune response, and, in turn, the immune system regulates the hepatic functions. Such feedback is performed by cytokines. Pro-inflammatory and anti-inflammatory cytokines are strongly involved in hepatic homeostasis and in pathological states; indeed, female sex hormones, oral contraceptives, and phytoestrogens have immunomodulatory effects in the liver and the whole organism. To analyze the complex and interesting beneficial or deleterious effects of these drugs by their immunomodulatory actions in the liver can provide the basis for either their pharmacological use in therapeutic treatments or to avoid their intake in some diseases.
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15
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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: 9] [Impact Index Per Article: 1.3] [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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16
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Shen M, Cao J, Shi H. Effects of Estrogen and Estrogen Receptors on Transcriptomes of HepG2 Cells: A Preliminary Study Using RNA Sequencing. Int J Endocrinol 2018; 2018:5789127. [PMID: 30510575 PMCID: PMC6230429 DOI: 10.1155/2018/5789127] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 08/12/2018] [Indexed: 12/23/2022] Open
Abstract
Men have a much higher incidence of hepatocellular carcinoma (HCC), the predominant form of liver cancer, than women, suggesting that estrogens play a protective role in liver cancer development and progression. To begin to understand the potential mechanisms of estrogens' inhibitory effects on HCC development, RNA sequencing was used to generate comprehensive global transcriptome profiles of the human HCC-derived HepG2 cell line following treatment of vehicle (control), estradiol (E2), estrogen receptor alpha- (ERα-) specific agonist 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT), or ERβ-specific agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) using a small set of cells. Gene ontology (GO) analysis identified increased expression of genes involved in the biological process (BP) of response to different stimuli and metabolic processes by E2 and ER agonists, which enhanced molecular function (MF) in various enzyme activities and chemical bindings. Kyoto Encyclopedia of Genes and Genomes (KEGG) functional pathway analysis indicated enhanced pathways associated with carbohydrate metabolism, complement and coagulation cascades, and HIF-1 signaling pathway by E2 and ER agonists. GO analysis also identified decreased expression of genes by E2, PPT, and DPN involved in BP related to the cell cycle and cell division, which reduced MF in activity of multiple enzymes and microtubule activity. KEGG analysis indicated that E2, PPT, and DPN suppressed pathways associated with the cell cycle; E2 and PPT suppressed pathways associated with chemical carcinogenesis and drug metabolism, and DPN suppressed DNA replication, recombination, and repair. Collectively, these differentially expressed genes across HepG2 cell transcriptome involving cellular and metabolic processes by E2 and ER agonists provided mechanistic insight into protective effects of estrogens in HCC development.
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Affiliation(s)
- Minqian Shen
- Department of Biology, Miami University, 700 E. High St., Oxford, OH, USA
| | - Jingyi Cao
- Department of Biology, Miami University, 700 E. High St., Oxford, OH, USA
| | - Haifei Shi
- Department of Biology, Miami University, 700 E. High St., Oxford, OH, USA
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17
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Kong XQ, Dong YP, Wu JX, He JY, Le YY, Du KX, Peng QQ, Li JL. High-biologically effective dose palliative radiotherapy for a tumor thrombus might improve the long-term prognosis of hepatocellular carcinoma: a retrospective study. Radiat Oncol 2017; 12:92. [PMID: 28569169 PMCID: PMC5452386 DOI: 10.1186/s13014-017-0831-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 05/25/2017] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND This study aimed to highlight the type of tumor thrombus and identify the prognostic factors influencing the long-term survival outcomes in patients with hepatocellular carcinoma (HCC) having a tumor thrombus. A tumor thrombus in HCC is associated with poor prognosis. METHODS Eighty patients diagnosed with HCC having a tumor thrombus between May 2006 and April 2014 were enrolled in this study. Age, gender, clinical characteristics, laboratory findings, Child-Pugh classification, performance status (ECOG), types of tumor thrombi, radiotherapy method, biologically effective dose (BED), and primary treatment method were analyzed to identify the prognostic factors associated with the overall survival (OS) rates. Statistical analyses were performed using SPSS version 19.0. RESULTS The median follow-up duration was 24 months (range 6-90). The 1-, 3-, and 5-year OS rates of the patients were 77.6%, 37.6%, and 18.8%, respectively. On univariate analysis, gender, radiotherapy method, BED, types of tumor thrombi, Child-Pugh classification, ECOG, and total bilirubin were associated with OS (P < 0.001, P = 0.001, P = 0.016, P = 0.003, P < 0.001, P < 0.001, P = 0.039, respectively). The prognostic factors for OS in multi-variate analyses were gender (P < 0.001), BED (P = 0.044), Child Pugh classification (P = 0.020), performance status (ECOG) (P = 0.004), and types of tumor thrombi (P = 0.001). The median OS for the high-BED group was better than that for the low-BED groups (42 months vs. 19 months, P = 0.016). CONCLUSIONS Gender, BED, performance status (ECOG), Child-Pugh classification, and types of tumor thrombi seemed to affect OS, and a stepwise decrease in survival was observed with the types of tumor thrombi ranging from I to IV. High-BED palliative radiotherapy might improve the long-term outcomes for patients with HCC having a tumor thrombus.
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Affiliation(s)
- Xiang-quan Kong
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, 420 Fuma Rd, Jinan District, Fuzhou, 350014 China
| | - Ya-ping Dong
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, 420 Fuma Rd, Jinan District, Fuzhou, 350014 China
| | - Jun-xin Wu
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, 420 Fuma Rd, Jinan District, Fuzhou, 350014 China
| | - Jun-yan He
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, 420 Fuma Rd, Jinan District, Fuzhou, 350014 China
| | - Yu-yin Le
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, 420 Fuma Rd, Jinan District, Fuzhou, 350014 China
| | - Kai-xin Du
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, 420 Fuma Rd, Jinan District, Fuzhou, 350014 China
| | - Qing-qin Peng
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, 420 Fuma Rd, Jinan District, Fuzhou, 350014 China
| | - Jin-luan Li
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, 420 Fuma Rd, Jinan District, Fuzhou, 350014 China
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18
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Li J, Wang Y, Zhu Y, Gong Y, Yang Y, Tian J, Zhang Y, Zou D, Peng X, Ke J, Gong J, Zhong R, Chang J. Breast cancer risk-associated variants at 6q25.1 influence risk of hepatocellular carcinoma in a Chinese population. Carcinogenesis 2017; 38:447-454. [PMID: 28334234 DOI: 10.1093/carcin/bgx024] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 03/02/2017] [Indexed: 12/16/2022] Open
Abstract
The gender disparity observed in the incidence of hepatocellular carcinoma (HCC) suggests an important role of estrogens in HCC pathogenesis. In this study, we conducted a case-control study to investigate whether breast cancer risk-associated single nucleotide polymorphisms (SNPs) located at estrogens loci identified by genome-wide association studies (GWASs) also predispose to HCC in a Chinese population. Three candidate SNPs at 6q25.1 were genotyped in 2025 HCC cases and 2032 healthy controls. Differential expression analyses and expression quantitative trait loci (eQTL) analyses were conducted to further explore the potential function of significant SNPs and genes they reside in. Two of the three candidate SNPs (rs9383951 and rs9485372) were observed to be significantly associated with HCC risk. Under a dominant model, the odds ratios (OR) for rs9383951 and rs9485372 were 1.28 (95% CI: 1.10-1.49, P = 0.002) and 1.34 (95% CI: 1.17-1.53, P = 2.75 × 10-5), respectively. We also found a significant accumulative effect of these two SNPs and there was a gradual increase in OR with a greater number of hazard genotypes. Moreover, the association between rs9383951 and HCC risk was specific in males. Lower ESR1 and TAB2 expressions were investigated in hepatic tumor tissues than adjacent normal tissues. We found a significant association between rs9383951 and ESR1 expression (P = 0.047). Besides, ESR1 expression was significantly correlated with the expression of TAB2. Taken together, our study identified two genetic variants at 6q25.1 newly associated with HCC risk, suggesting ESR1 and estrogen signaling may play a role in mediating susceptibility to HCC in Chinese population.
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Affiliation(s)
- Jiaoyuan Li
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China and
| | - Ying Wang
- Department of Virology, Wuhan Centers for Disease Prevention and Control, Wuhan, Hubei, China
| | - Ying Zhu
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China and
| | - Yajie Gong
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China and
| | - Yang Yang
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China and
| | - Jianbo Tian
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China and
| | - Yi Zhang
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China and
| | - Danyi Zou
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China and
| | - Xiating Peng
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China and
| | - Juntao Ke
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China and
| | - Jing Gong
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China and
| | - Rong Zhong
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China and
| | - Jiang Chang
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Nguyen KH, Ande SR, Mishra S. Prohibitin: an unexpected role in sex dimorphic functions. Biol Sex Differ 2016; 7:30. [PMID: 27347368 PMCID: PMC4921003 DOI: 10.1186/s13293-016-0083-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 06/17/2016] [Indexed: 12/20/2022] Open
Abstract
Sex differences are known to exist in adipose and immune functions in the body, and sex steroid hormones are known to be involved in sexually dimorphic biological and pathological processes related to adipose-immune interaction. However, our knowledge of proteins that mediate such differences is poor. Two novel obese mice models, Mito-Ob and m-Mito-Ob, that have been reported recently have revealed an unexpected role of a pleiotropic protein, prohibitin (PHB), in sex differences in adipose and immune functions. This discovery points towards a role of pleiotropic proteins and their potential interplay with sex steroid hormones in mediating sexually dimorphic adipose-immune interaction.
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Affiliation(s)
- K Hoa Nguyen
- Department of Internal Medicine, John Buhler Research Centre, University of Manitoba, Rm 843, 715 McDermot Avenue, Winnipeg, Manitoba R3E 3P4 Canada
| | - Sudharsana R Ande
- Department of Internal Medicine, John Buhler Research Centre, University of Manitoba, Rm 843, 715 McDermot Avenue, Winnipeg, Manitoba R3E 3P4 Canada
| | - Suresh Mishra
- Department of Internal Medicine, John Buhler Research Centre, University of Manitoba, Rm 843, 715 McDermot Avenue, Winnipeg, Manitoba R3E 3P4 Canada.,Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Canada
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20
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Shen M, Shi H. Estradiol and Estrogen Receptor Agonists Oppose Oncogenic Actions of Leptin in HepG2 Cells. PLoS One 2016; 11:e0151455. [PMID: 26982332 PMCID: PMC4794158 DOI: 10.1371/journal.pone.0151455] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Accepted: 02/28/2016] [Indexed: 11/19/2022] Open
Abstract
Obesity is a significant risk factor for certain cancers, including hepatocellular carcinoma (HCC). Leptin, a hormone secreted by white adipose tissue, precipitates HCC development. Epidemiology data show that men have a much higher incidence of HCC than women, suggesting that estrogens and its receptors may inhibit HCC development and progression. Whether estrogens antagonize oncogenic action of leptin is uncertain. To investigate potential inhibitory effects of estrogens on leptin-induced HCC development, HCC cell line HepG2 cells were treated with leptin in combination with 17 β-estradiol (E2), estrogen receptor-α (ER-α) selective agonist PPT, ER-β selective agonist DPN, or G protein-coupled ER (GPER) selective agonist G-1. Cell number, proliferation, and apoptosis were determined, and leptin- and estrogen-related intracellular signaling pathways were analyzed. HepG2 cells expressed a low level of ER-β mRNA, and leptin treatment increased ER-β expression. E2 suppressed leptin-induced HepG2 cell proliferation and promoted cell apoptosis in a dose-dependent manner. Additionally E2 reversed leptin-induced STAT3 and leptin-suppressed SOCS3, which was mainly achieved by activation of ER-β. E2 also enhanced ERK via activating ER-α and GPER and activated p38/MAPK via activating ER-β. To conclude, E2 and its receptors antagonize the oncogenic actions of leptin in HepG2 cells by inhibiting cell proliferation and stimulating cell apoptosis, which was associated with reversing leptin-induced changes in SOCS3/STAT3 and increasing p38/MAPK by activating ER-β, and increasing ERK by activating ER-α and GPER. Identifying roles of different estrogen receptors would provide comprehensive understanding of estrogenic mechanisms in HCC development and shed light on potential treatment for HCC patients.
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Affiliation(s)
- Minqian Shen
- Department of Biology, Cell, Molecular, and Structural Biology, Miami University, Oxford, Ohio, United States of America
| | - Haifei Shi
- Department of Biology, Cell, Molecular, and Structural Biology, Miami University, Oxford, Ohio, United States of America
- * E-mail:
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21
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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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22
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Lu X, Ma P, Shi Y, Yao M, Hou L, Zhang P, Jiang L. NF-κB increased expression of 17β-hydroxysteroid dehydrogenase 4 promotes HepG2 proliferation via inactivating estradiol. Mol Cell Endocrinol 2015; 401:1-11. [PMID: 25448063 DOI: 10.1016/j.mce.2014.11.016] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Revised: 11/15/2014] [Accepted: 11/20/2014] [Indexed: 01/27/2023]
Abstract
Hepatocellular carcinoma (HCC) arises in a setting of chronic inflammation induced by inflammatory cytokines, such as nuclear factor-kappaB (NF-κB). HCC is a male-predominant cancer that can be attenuated by estradiol (E2) in vitro and in vivo. Although 17β-hydroxysteroid dehydrogenase 4 (HSD17B4) has been implicated as an estradiol-inactivating enzyme, and its promoter sequence contains two putative NF-κB elements: it is currently unknown whether HSD17B4 is the link between inflammation, estradiol and proliferation in hepatoma cells. In this study, HepG2 cells were used to investigate the role of HSD17B4 in the proliferation of liver cancer cells treated with the NF-κB activator, tumor necrosis factor-alpha (TNF-α), with the inhibitor of NF-κB activation, pyrrolidinedithiocarbamate (PDTC), or with a related specific siRNA. We demonstrated that the human HSD17B4 gene is a target for NF-κB activation in inflammation-stimulated HepG2 cells. HSD17B4 is up-regulated via the binding of activated NF-κB to the distal NF-κB-responsive element via TNF-α stimulation, which then promotes cell proliferation by decreasing the levels of E2 and enhancing the expression of interleukin 6 (IL-6), cyclin D1 and proliferating cell nuclear antigen (PCAN). These results from HepG2 cells are consistent with the observation that HSD17B4 is highly expressed and activated NF-κB is highly co-localized with the NF-κB-responsive element of HSD17B4 in liver tumor tissues from HCC patients. Our findings indicate for the first time that HSD17B4 plays an important role in aggravated HCC progression and provides a novel therapeutic target for HCC.
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Affiliation(s)
- Xin Lu
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neurobiology and Vascular Biology, China Administration of Education, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang 050017, China
| | - Panpan Ma
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neurobiology and Vascular Biology, China Administration of Education, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang 050017, China
| | - Yun Shi
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neurobiology and Vascular Biology, China Administration of Education, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang 050017, China
| | - Min Yao
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neurobiology and Vascular Biology, China Administration of Education, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang 050017, China
| | - Lianguo Hou
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neurobiology and Vascular Biology, China Administration of Education, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang 050017, China
| | - Pingping Zhang
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neurobiology and Vascular Biology, China Administration of Education, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang 050017, China
| | - Lingling Jiang
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neurobiology and Vascular Biology, China Administration of Education, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang 050017, China.
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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: 103] [Impact Index Per Article: 9.4] [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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Luisier R, Unterberger EB, Goodman JI, Schwarz M, Moggs J, Terranova R, van Nimwegen E. Computational modeling identifies key gene regulatory interactions underlying phenobarbital-mediated tumor promotion. Nucleic Acids Res 2014; 42:4180-95. [PMID: 24464994 PMCID: PMC3985636 DOI: 10.1093/nar/gkt1415] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Gene regulatory interactions underlying the early stages of non-genotoxic carcinogenesis are poorly understood. Here, we have identified key candidate regulators of phenobarbital (PB)-mediated mouse liver tumorigenesis, a well-characterized model of non-genotoxic carcinogenesis, by applying a new computational modeling approach to a comprehensive collection of in vivo gene expression studies. We have combined our previously developed motif activity response analysis (MARA), which models gene expression patterns in terms of computationally predicted transcription factor binding sites with singular value decomposition (SVD) of the inferred motif activities, to disentangle the roles that different transcriptional regulators play in specific biological pathways of tumor promotion. Furthermore, transgenic mouse models enabled us to identify which of these regulatory activities was downstream of constitutive androstane receptor and β-catenin signaling, both crucial components of PB-mediated liver tumorigenesis. We propose novel roles for E2F and ZFP161 in PB-mediated hepatocyte proliferation and suggest that PB-mediated suppression of ESR1 activity contributes to the development of a tumor-prone environment. Our study shows that combining MARA with SVD allows for automated identification of independent transcription regulatory programs within a complex in vivo tissue environment and provides novel mechanistic insights into PB-mediated hepatocarcinogenesis.
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Affiliation(s)
- Raphaëlle Luisier
- Discovery and Investigative Safety, Novartis Institutes for Biomedical Research, 4057 Basel, Switzerland, Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Tübingen, 72074 Tübingen, Germany, Department of Pharmacology and Toxicology, Michigan State University, MI 48824, USA and Biozentrum, University of Basel and Swiss Institute of Bioinformatics, 4056 Basel, Switzerland
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Progesterone and related compounds in hepatocellular carcinoma: basic and clinical aspects. BIOMED RESEARCH INTERNATIONAL 2013; 2013:290575. [PMID: 23484104 PMCID: PMC3581253 DOI: 10.1155/2013/290575] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/20/2012] [Revised: 12/20/2012] [Accepted: 12/26/2012] [Indexed: 12/28/2022]
Abstract
Primary liver cancer is the fifth most common cancer worldwide and the third most common cause of cancer mortality. Hepatocellular carcinoma (HCC) accounts for 85% to 90% of primary liver cancers. Major risk factors for HCC include infection with HBV or HCV, alcoholic liver disease, and most probably nonalcoholic fatty liver disease. In general, men are two to four times more often associated with HCC than women. It can be suggested that sex hormones including progesterone may play some roles in HCC. Rather, very limited information discusses its potential involvement in HCC. This paper thus collects some recent studies of the potential involvement of progesterone and related compounds in HCC from basic and clinical aspects. In addition, two synthetic progestins, megestrol acetate (MA) and medroxyprogesterone acetate (MPA), will be discussed thoroughly. It is noted that progesterone can also serve as the precursor for androgens and estrogens produced by the gonadal and adrenal cortical tissues, while men have a higher incidence of HCC than women might be due to the stimulatory effects of androgen and the protective effects of estrogen. Eventually, this paper suggests a new insight on the associations of progesterone and related compounds with HCC development and treatment.
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26
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Tu CC, Kumar VB, Day CH, Kuo WW, Yeh SP, Chen RJ, Liao CR, Chen HY, Tsai FJ, Wu WJ, Huang CY. Estrogen receptor α (ESR1) over-expression mediated apoptosis in Hep3B cells by binding with SP1 proteins. J Mol Endocrinol 2013; 51:203-12. [PMID: 23733894 DOI: 10.1530/jme-13-0085] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Previous studies have reported that estrogen receptors (ERs) are expressed in normal human liver, chronic hepatitis, and benign hepatic tumor tissues. However, decreased expression of ERs can be observed in hepatocellular carcinoma (HCC) and the role of ERs in HCC is not fully understood. Thus, the present study aimed to investigate the molecular mechanism induced by the overexpression of ERα (ERα (ESR1)) in Hep3B cells. We first detected the induction of apoptosis in ER-negative Hep3B cells using DNA fragmentation assay and flow cytometry. We found that ERα and ERα plus 17β-estradiol treatment increased apoptosis in Hep3B cells. Additionally, western blotting showed increased expression of active caspase 3 and tumor necrosis factor α (TNFα (TNF)) in ERα-transfected cells. To further understand the importance of SP1-binding sites in the TNFα promoter, ERα-negative Hep3B cells were co-transfected with ERα and a wild-type TNFα plasmid or TNFα with deleted SP1 regions. Deletion of both distant and primal SP1 sites abolished the activity of ERα, and similar results were observed by blocking the expression of SP1 protein using mithramycin (MA). This result indicates that SP1 protein is essential for ERα-activated TNFα promoter activity. Co-immunoprecipitation assay further confirmed the binding interaction between ERα and SP1 in a ligand-dependent manner. In general, we demonstrate that the overexpression of ERα mediates apoptosis in ERα-negative Hep3B cells by the binding of ERα to SP1 protein. Additionally, this ERα-SP1 complex binds to the proximal and distal sites of the TNFα gene promoter and further induces the expression of active caspase 3 in a ligand-dependent manner.
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Affiliation(s)
- Chuan-Chou Tu
- Institute of Medical and Molecular Toxicology and Institute of Medicine, Chung Shan University, Taichung, Taiwan Division of Chest Medicine, Department of Internal Medicine, Armed Force Taichung General Hospital, Taichung, Taiwan
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Wang YC, Xu GL, Jia WD, Han SJ, Ren WH, Wang W, Liu WB, Zhang CH, Chen H. Estrogen suppresses metastasis in rat hepatocellular carcinoma through decreasing interleukin-6 and hepatocyte growth factor expression. Inflammation 2012; 35:143-9. [PMID: 21302136 DOI: 10.1007/s10753-011-9299-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Metastasis remains one of the major challenges before hepatocellular carcinoma (HCC) is finally conquered. Estrogen has recently emerged as a protective factor in the development and progression of HCC, but whether and how it reduces metastasis of HCC remain to be elucidated. We conducted an in vivo highly metastatic rat HCC model in female Sprague-Dawley rats induced by diethylnitrosamine and N-nitrosomorpholine to examine the effects of estrogen on HCC metastasis. Moreover, female rats were randomly distributed into four groups: ovariectomy (OVX), sham operation, ovariectomy followed by 30 μg/kg body weight/day 17α-ethynylestradiol supplementation, and sexually intact control groups. Here, we show that, 60% lung metastasis was observed in the rats of OVX group, whereas 17-25% lung metastasis was found in rats of the other three groups. Furthermore, physiological doses of estrogen, no matter endogenous or exogenous, can suppress metastasis of HCC through decreasing interleukin-6 (IL-6) and hepatocyte growth factor (HGF) expression in the tumor microenvironment. In conclusion, the present study demonstrated that estrogen has the potential to inhibit lung metastasis from rat HCCs in vivo. Its mechanism of action may involve modulation of inflammatory tumor microenvironment by suppression of HGF and IL-6 production.
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Affiliation(s)
- Yong-Cang Wang
- Centre for Study of Liver Cancer, Affiliated Provincial Hospital, Anhui Medical University, No. 17, Lujiang Road, Hefei, 230001, China
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28
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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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29
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Wu CH, Chan TF, Changchien CC, Yang CY. Parity, age at first birth, and risk of death from liver cancer: Evidence from a cohort in Taiwan. J Gastroenterol Hepatol 2011; 26:334-9. [PMID: 21261724 DOI: 10.1111/j.1440-1746.2010.06365.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM The present study was undertaken to examine whether there is an association between parity and age at first birth and risk of liver cancer. METHODS The study cohort consisted of 1,292,462 women who had a first and singleton childbirth between 1 January 1978 and 31 December 1987. We tracked each woman from the time of their first childbirth to 31 December 2007, and their vital status was ascertained by linking records with the computerized mortality database. Cox proportional hazard regression models were used to estimate the relative risks (RR) of death from liver cancer associated with parity and age at first birth. RESULTS There were 826 liver cancer deaths during 32,464,186.58 person-years of follow-up. The mortality rate of liver cancer was 2.54 cases per 100,000 person-years. The adjusted RR was 1.59 (95% confidence interval [CI] = 1.36-1.86) for women who gave birth between 26 and 30, 2.41 (95% CI = 1.81-3.20) for women who gave birth between 31 and 35, and 6.26 (95% CI = 4.27-9.19) for women who gave birth after 35 years of age, respectively, when compared with women who gave birth at less than 25 years of age. The adjusted RR was 0.72 (95% CI = 0.59-0.87) for women who had two to three children, and 0.63 (95% CI = 0.47-0.84) for women with four or more births, respectively, when compared with women who had given birth to only one child. CONCLUSIONS The present study suggests that reproductive factors (parity and early age at first birth) may confer a protective effect on the risk of liver cancer.
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Affiliation(s)
- Chen-Hsuan Wu
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital- Kaohsiung Medical Center, College of Medicine, Chang Gung University, Kaohsiung, Taiwan
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30
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Alcohol and Cancer Epidemiology. ALCOHOL AND CANCER 2011. [PMCID: PMC7122198 DOI: 10.1007/978-1-4614-0040-0_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
In a comprehensive worldwide assessment of cancer risk related to food and nutrition, the American Institute for Cancer Research (AICR 2007) identified alcohol consumption as a “convincing” or “probable” risk factor for esophageal, mouth, and laryngeal cancers, for liver cancer, for breast cancer in women, and for colorectal cancer especially in men. The World Health Organization’s Global Burden of Disease Project concluded that “A total of 390,000 cases of cancer are attributable to alcohol drinking worldwide, representing 3.6% of all cancers (5.2% in men, 1.7% in women)” each year, with a corresponding annual mortality rate of 233,000, representing 3.5% of all cancer deaths (Boffetta et al. 2006). For the USA, the Alcohol-Related Disease Impact (ARDI) report indicates an annual rate of 2,464 deaths in six different alcohol-related cancer categories for the period 2001–2006 (CDC 2010).
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Hayashida K, Shoji I, Deng L, Jiang DP, Ide YH, Hotta H. 17β-estradiol inhibits the production of infectious particles of hepatitis C virus. Microbiol Immunol 2010; 54:684-90. [DOI: 10.1111/j.1348-0421.2010.00268.x] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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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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Involvement of Egr-1 in HGF-induced elevation of the human 5alpha-R1 gene in human hepatocellular carcinoma cells. Biochem J 2008; 411:379-86. [PMID: 18215136 DOI: 10.1042/bj20071343] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Steroid 5alpha-reductase 1 (5alpha-R1), a key enzyme in the conversion of steroids into their respective 5alpha-reduced derivatives, plays a key role in some hormone-dependent tumours and is abundant in the liver, although it is also widely distributed throughout the body. HGF (hepatocyte growth factor) is a pleiotropic cytokine/growth factor involved in the progression of hepatocellular carcinoma. In the present paper, we report the stimulatory effect of HGF on human 5alpha-R1 transcription in hepatocellular carcinoma cells. Pre-treatment with actinomycin D or cycloheximide blocked the up-regulation of 5alpha-R1 mRNA expression by HGF, indicating that the increased level of 5alpha-R1 mRNA expression is regulated by transcriptional activation and was dependent on de novo protein synthesis. Functional analysis of the 5'-flanking region of the 5alpha-R1 gene by transfection analysis showed that the -79 to -50 region functioned as the HGF-responsive region. Mutagenesis and electrophoretic mobility-shift assays demonstrated that induction of 5a-R1 by HGF is mediated by an Egr-1 (early growth-response gene 1)-binding site at -60/-54. In addition, overexpression of Egr-1 was sufficient to transactivate 5alpha-R1 promoter activity, and knockdown of Egr-1 with gene-specific small interfering RNA resulted in inhibition of HGF-induced up-regulation of endogenous 5alpha-R1 expression. These data provide the first evidence that HGF stimulates 5alpha-R1 expression through up-regulation of the transcription factor Egr-1, thus suggesting the possibility that regulation of steroid metabolism by HGF represents a mechanism for high risk of hepatocellular carcinogenesis in males.
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Bagnyukova TV, Tryndyak VP, Montgomery B, Churchwell MI, Karpf AR, James SR, Muskhelishvili L, Beland FA, Pogribny IP. Genetic and epigenetic changes in rat preneoplastic liver tissue induced by 2-acetylaminofluorene. Carcinogenesis 2008; 29:638-46. [PMID: 18204080 DOI: 10.1093/carcin/bgm303] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Genotoxic carcinogens, including 2-acetylaminofluorene (2-AAF), in addition to exerting their genotoxic effects, often cause a variety of non-genotoxic alterations in cells. It is believed that these non-genotoxic effects may be indispensable events in tumorigenesis; however, there is insufficient knowledge to clarify the role of carcinogens in both the genetic and epigenetic changes in premalignant tissues and a lack of conclusive information on the link between epigenetic alterations and carcinogenic exposure. In the current study, we investigated whether or not the mechanism of 2-AAF-induced hepatocarcinogenesis consists of both genotoxic (genetic) and non-genotoxic (epigenetic) alterations. Male and female Sprague-Dawley rats were fed NIH-31 diet containing 0.02% of 2-AAF for 6, 12, 18 or 24 weeks. The levels of DNA adducts obtained from 2-AAF in liver and kidney tissues were assessed by high-performance liquid chromatography combined with electrospray tandem mass spectrometry (HPLC-ES-MS/MS). N-(Deoxyguanosine-8-yl)-2-aminofluorene was the major adduct detected at all time points in both tissues. Global DNA methylation in the livers and kidneys, as determined by an HpaII-based cytosine extension assay and by HPLC-ES-MS/MS, did not change over the 24-week period. In the livers of male rats, there was a progressive decrease of global and long interspersed nucleotide element-1-associated histone H4 lysine 20 trimethylation, as well as hypermethylation of the p16(INK4A) gene. These epigenetic changes were not observed in the livers of female rats or the kidneys of both sexes. Importantly, morphological evidence of formation and progression of neoplastic process was observed in the liver of male rats only. In conclusion, we have demonstrated that exposure of rats to genotoxic hepatocarcinogen 2-AAF, in addition to formation of 2-AAF-specific DNA lesions, resulted in substantial alterations in cellular epigenetic status.
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Affiliation(s)
- Tetyana V Bagnyukova
- Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA
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Baig S, Siddiqui AA, Ahmed W, Qureshi H, Arif A. The association of complex liver disorders with HBV genotypes prevalent in Pakistan. Virol J 2007; 4:128. [PMID: 18042293 PMCID: PMC2212638 DOI: 10.1186/1743-422x-4-128] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2007] [Accepted: 11/27/2007] [Indexed: 02/06/2023] Open
Abstract
Background Genotyping of HBV is generally used for determining the epidemiological relationship between various virus strains and origin of infection mostly in research studies. The utility of genotyping for clinical applications is only beginning to gain importance. Whether HBV genotyping will constitute part of the clinical evaluation of Hepatitis B patients depends largely on the availability of the relevance of the evidence based information. Since Pakistan has a HBV genotype distribution which has been considered less virulent as investigated by earlier studies from south East Asian countries, a study on correlation between HBV genotypes and risk of progression to further complex hepatic infection was much needed Methods A total of 295 patients with HBsAg positive were selected from the Pakistan Medical Research Council's (PMRC) out patient clinics. Two hundred and twenty six (77%) were males, sixty nine (23%) were females (M to F ratio 3.3:1). Results Out of 295 patients, 156 (53.2%) had Acute(CAH), 71 (24.2%) were HBV Carriers, 54 (18.4%) had Chronic liver disease (CLD) Hepatitis. 14 (4.7%) were Cirrhosis and HCC patients. Genotype D was the most prevalent genotype in all categories of HBV patients, Acute (108), Chronic (39), and Carrier (53). Cirrhosis/HCC (7) were HBV/D positive. Genotype A was the second most prevalent with 28 (13%) in acute cases, 12 (22.2%) in chronics, 14 (19.7%) in carriers and 5 (41.7) in Cirrhosis/HCC patients. Mixed genotype (A/D) was found in 20 (12.8%) of Acute patients, 3 (5.6%) of Chronic and 4 (5.6%) of carriers, none in case of severe liver conditions. Conclusion Mixed HBV genotypes A, D and A/D combination were present in all categories of patients except that no A/D combination was detected in severe conditions. Genotype D was the dominant genotype. However, genotype A was found to be more strongly associated with severe liver disease. Mixed genotype (A/D) did not significantly appear to influence the clinical outcome.
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Affiliation(s)
- Saeeda Baig
- Department of Biochemistry, Ziauddin Medical College, Ziauddin University, Karachi, Pakistan.
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Shimizu I, Kohno N, Tamaki K, Shono M, Huang HW, He JH, Yao DF. Female hepatology: Favorable role of estrogen in chronic liver disease with hepatitis B virus infection. World J Gastroenterol 2007; 13:4295-305. [PMID: 17708600 PMCID: PMC4250853 DOI: 10.3748/wjg.v13.i32.4295] [Citation(s) in RCA: 100] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection is the most common cause of hepatic fibrosis and hepatocellular carcinoma (HCC), mainly as a result of chronic necroinflammatory liver disease. A characteristic feature of chronic hepatitis B infection, alcoholic liver disease and nonalcoholic fatty liver disease (NAFLD) is hepatic steatosis. Hepatic steatosis leads to an increase in lipid peroxidation in hepatocytes, which, in turn, activates hepatic stellate cells (HSCs). HSCs are the primary target cells for inflammatory and oxidative stimuli, and these cells produce extracellular matrix components. Chronic hepatitis B appears to progress more rapidly in males than in females, and NAFLD, cirrhosis and HCC are predominately diseases that tend to occur in men and postmenopausal women. Premenopausal women have lower hepatic iron stores and a decreased production of proinflammatory cytokines. Hepatic steatosis has been observed in aromatase-deficient mice, and has been shown to decrease in animals after estradiol treatment. Estradiol is a potent endogenous antioxidant which suppresses hepatic fibrosis in animal models, and attenuates induction of redox sensitive transcription factors, hepatocyte apoptosis and HSC activation by inhibiting a generation of reactive oxygen species in primary cultures. Variant estrogen receptors are expressed to a greater extent in male patients with chronic liver disease than in females. These lines of evidence suggest that the greater progression of hepatic fibrosis and HCC in men and postmenopausal women may be due, at least in part, to lower production of estradiol and a reduced response to the action of estradiol. A better understanding of the basic mechanisms underlying the sex-associated differences in hepatic fibrogenesis and carciogenesis may open up new avenues for the prevention and treatment of chronic liver disease.
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Affiliation(s)
- Ichiro Shimizu
- Department of Digestive and Cardiovascular Medicine, Institute of Health Biosciences, University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
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Tilton SC, Hendricks JD, Orner GA, Pereira CB, Bailey GS, Williams DE. Gene expression analysis during tumor enhancement by the dietary phytochemical, 3,3'-diindolylmethane, in rainbow trout. Carcinogenesis 2007; 28:1589-98. [PMID: 17272308 DOI: 10.1093/carcin/bgm017] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM), a primary I3C derivative, are known dietary chemopreventive agents also available as supplements. However, I3C has been found to act as a tumor promoter in rat (multi-organ) and trout (liver) models. I3C and DIM were previously found to be estrogenic in trout liver based on toxicogenomic profiles. In this study, we compare the post-initiation effects of DIM and 17beta-estradiol (E2) on aflatoxin B(1) (AFB(1))-induced hepatocarcinogenesis in trout. Trout were initiated as embryos with AFB(1) and juvenile fish were fed diets containing 0, 120 or 400 p.p.m. DIM or 5 p.p.m. E2 for 18 weeks. Tumor incidence was determined at 13 months and found to be significantly elevated in AFB(1)-initiated trout fed either 400 p.p.m. DIM or 5 p.p.m. E2 compared with control animals. To evaluate the mechanism of tumor enhancement, hepatic gene expression profiles were examined in animals fed promotional diets during the course of tumorigenesis and in hepatocellular carcinomas (HCCs) of initiated animals. We demonstrate that DIM alters gene expression profiles similar to E2 in liver samples during tumorigenesis and in HCC tumors. Further, HCCs from animals on DIM and E2 promotional diets had a transcriptional signature indicating decreased invasive or metastatic potential compared with HCCs from control animals. Overall, these findings are the first to demonstrate tumor promotion by DIM. They confirm the importance of estrogenic signaling in the mechanism of promotion by dietary indoles in trout liver and indicate a possible dual effect that enhances tumor incidence and decreases potential for metastasis.
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Affiliation(s)
- Susan C Tilton
- Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA
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De Miglio MR, Virdis P, Calvisi DF, Frau M, Muroni MR, Simile MM, Daino L, Careddu GM, Sanna-Passino E, Pascale RM, Feo F. Mapping a Sex Hormone–Sensitive Gene Determining Female Resistance to Liver Carcinogenesis in a Congenic F344.BN-Hcs4Rat. Cancer Res 2006; 66:10384-90. [PMID: 17079458 DOI: 10.1158/0008-5472.can-06-2881] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Hepatocellular carcinoma (HCC) is prevalent in human and rodent males. Hepatocarcinogenesis is controlled by various genes in susceptible F344 and resistant Brown Norway (BN) rats. B alleles at Hcs4 locus, on RNO16, control neoplastic nodule volume. We constructed the F344.BN-Hcs4 recombinant congenic strain (RCS) by introgressing a 4.41-cM portion of Hcs4 from BN strain in an isogenic F344 background. Preneoplastic and neoplastic lesions were induced by the "resistant hepatocyte" protocol. Eight weeks after initiation, lesion volume and positivity for proliferating cell nuclear antigen (PCNA) were much higher in lesions of F344 than BN rats of both sexes. These variables were lower in females than in males. Lesion volume and PCNA values of male RCS were similar to those of F344 rats, but in females corresponded to those of BN females. Carcinomatous nodules and HCC developed at 32 and 60 weeks, respectively, in male F344 and congenics and, rarely, in F344 females. BN and congenic females developed only eosinophilic/clear cells nodules. Gonadectomy of congenic males, followed by beta-estradiol administration, caused a decrease in Ar expression, an increase in Er-alpha expression, and development of preneoplastic lesions comparable to those from BN females. Administration of testosterone to gonadectomized females led to Ar increase and development of preneoplastic lesions as in F344 males. This indicates a role of homozygous B alleles at Hcs4 in the determination of phenotypic patterns of female RCS and presence at Hcs4 locus of a high penetrance gene(s), activated by estrogens and inhibited/unaffected by testosterone, conferring resistance to females in which the B alleles provide higher resistance.
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Affiliation(s)
- Maria R De Miglio
- Department of Biomedical Sciences, Division of Experimental Pathology and Oncology, University of Sassari, Sassari, Italy
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Huang EJ, Wu CC, Huang HP, Liu JY, Lin CS, Chang YZ, Lin JA, Lin JG, Chen LM, Lee SD, Kuo WW, Huang CY. Apoptotic and anti-proliferative effects of 17beta-estradiol and 17beta-estradiol-like compounds in the Hep3B cell line. Mol Cell Biochem 2006; 290:1-7. [PMID: 16924424 DOI: 10.1007/s11010-005-9000-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2005] [Accepted: 09/09/2005] [Indexed: 12/01/2022]
Abstract
Since there is evidence for estrogen and estrogen-like compounds to have beneficial effect on the pathogenesis of hepatocellular carcinoma (HCC), this study was designed to investigative the apoptotic and anti-proliferative effects of these compounds on the human hepatoma Hep3B cell line. The Hep3B cells were treated with 17beta-estradiol (E2), diethylstilbestrol (DES), tamoxifen, and genistein. After treatments of these compounds at the concentration of 10(-6) or 10(-8) M, the Hep3B cells were demonstrated to have significant DNA fragmentation, nucleus condensation, cytochrome-c leaking from the mitochondria and caspase-3 activation by DAPI and Western blotting. The cells were also observed to have declined proliferative potential by MTT assay, arrested cell cycle by flow-cytometry measurements. However, the cytochrome-c leaking from the mitochondria induced by E2 and E2-like compounds was blocked totally by ICI 182,780 treatment. These finding suggest that estrogen and the estrogen-like compounds may induce anti-proliferative and apoptotic effects in Hep3B cells, and the E2 and the E2-like compounds mediated apoptotic effect was estrogen receptor dependent. Among the drugs tested, E2, E2 agonists (DES and genistein) and partial antagonist (tamoxifen), all showed the stronger anti-tumor potential.
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Affiliation(s)
- Erh-Jung Huang
- Center of General Education, Central Taiwan, University of Science and Technology, 406 Taichung, Taiwan
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Cheng X, Shimizu I, Yuan Y, Wei M, Shen M, Huang H, Urata M, Sannomiya K, Fukuno H, Hashimoto-Tamaoki T, Ito S. Effects of estradiol and progesterone on tumor necrosis factor alpha-induced apoptosis in human hepatoma HuH-7 cells. Life Sci 2006; 79:1988-94. [PMID: 16860828 DOI: 10.1016/j.lfs.2006.06.044] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2006] [Revised: 06/13/2006] [Accepted: 06/23/2006] [Indexed: 12/23/2022]
Abstract
Oxidative stress, including the generation of reactive oxygen species (ROS), is known to be involved in apoptosis. Preventing apoptosis may thereby induce a malignant transformation of liver tumor cells. Estradiol (E2) is a potent endogenous antioxidant. We examined the proapoptotic role of progesterone as well as the antiapoptotic role of E2 in human hepatoma HuH-7 cells in a state of early apoptosis induced by tumor necrosis factor (TNF) alpha. The TNF alpha-induced ROS generation, lipid peroxidation, antioxidant enzyme consumption, a proapoptotic predominant expression of Bcl-2 family proteins, and a disruption of mitochondrial membrane potential were all inhibited by E2, and then they were further stimulated by progesterone in HuH-7 cells. The inhibitory effects of E2 were blocked by coincubation with progesterone. Treatment with the progesterone receptor antagonist RU486 led to the blockage of the progesterone-mediated responses to E2 pretreatment in TNF alpha-induced apoptosis. These findings demonstrate that E2 inhibits the TNF alpha-induced early apoptosis in hepatoma cells, by suppressing the oxidative stress processes, whereas progesterone acts in a manner opposite from the effects of E2, and the inhibitory effects of E2 were blocked by progesterone, thus leading to the apoptosis of hepatoma cells.
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Affiliation(s)
- Xinliang Cheng
- Department of Digestive and Cardiovascular Medicine, Tokushima University Graduate School of Medicine, Kuramoto-cho, Tokushima 770-8503, Japan
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Dombrowski F, Flaschka C, Klotz L, von Netzer B, Schulz C, Lehnert H, Evert M. Hepatocellular neoplasms after intrahepatic transplantation of ovarian fragments into ovariectomized rats. Hepatology 2006; 43:857-67. [PMID: 16557532 DOI: 10.1002/hep.21124] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Abstract
Intrahepatic transplantation of ovarian fragments in ovariectomized rats results in morphological abnormalities. The liver acini draining blood from ovarian grafts show alterations resembling chemically induced amphophilic hepatocellular preneoplasias. We investigated the long-term development of these estrogen-induced foci of altered hepatocytes (FAH). We divided 451 Lewis rats into one main group (MG) and 11 (7 female, 4 male) control groups and observed them for up to 30 months. MG animals were ovariectomized and received ovarian transplants into the right liver part. Different combinations of castration, transplantation of ovarian or testicular fragments, and administration of antiestrogenic toremifene were used in controls. In the MG, transplants showed signs of gonadotropic stimulation, and estrogen levels were strongly increased in the downstream liver acini. After 6 and 12 months, FAH developed in hepatocytes downstream of the transplants. After 18 months, 27% of the MG animals showed transformation of FAH into hepatocellular adenomas; this figure increased to 42% after 24 months (8/19), significantly outnumbering four spontaneous adenomas that developed between 18 and 30 months in 258 control animals. Hepatocellular carcinoma (HCC) appeared only in the MG. At 24 and 30 months, 18 HCCs developed; thus, 78% of MG animals showed at least one carcinoma. Administration of toremifene in ovariectomized and transplanted animals completely prevented hepatocarcinogenesis. Testicular grafts showed no influence on liver tissue. In conclusion, initially adaptive but preneoplastic alterations in hepatocytes downstream of intrahepatically transplanted ovarian fragments may transform into HCC, indicating a strong hepatocarcinogenic potential of high local levels of endogenous estrogens in the rat liver.
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Affiliation(s)
- Frank Dombrowski
- Institut für Pathologie, Zentrum für Innere Medizin, Otto-von-Guericke-Universität Magdeburg, Magdeburg, Germany.
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Yokohira M, Takeuchi H, Yamakawa K, Saoo K, Matsuda Y, Zeng Y, Hosokawa K, Maeta H, Imaida K. A COX-2 Inhibitor, SC58125, Promotes Liver Carcinogenesis in a Rat Medium-Term Liver Bioassay, Possibly due to Induction of CYP 2B1 and 3A1. J Toxicol Pathol 2006. [DOI: 10.1293/tox.19.37] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Affiliation(s)
- Masanao Yokohira
- Onco-Pathology, Department of Pathology and Host-Defence, Faculty of Medicine, Kagawa University
- 1st Department of Surgery, Faculty of Medicine, Kagawa University
| | - Hijiri Takeuchi
- Onco-Pathology, Department of Pathology and Host-Defence, Faculty of Medicine, Kagawa University
- 1st Department of Surgery, Faculty of Medicine, Kagawa University
| | - Keiko Yamakawa
- Onco-Pathology, Department of Pathology and Host-Defence, Faculty of Medicine, Kagawa University
| | - Kousuke Saoo
- Onco-Pathology, Department of Pathology and Host-Defence, Faculty of Medicine, Kagawa University
| | - Yoko Matsuda
- Onco-Pathology, Department of Pathology and Host-Defence, Faculty of Medicine, Kagawa University
| | - Yu Zeng
- Onco-Pathology, Department of Pathology and Host-Defence, Faculty of Medicine, Kagawa University
| | - Kyoko Hosokawa
- Onco-Pathology, Department of Pathology and Host-Defence, Faculty of Medicine, Kagawa University
| | - Hajime Maeta
- 1st Department of Surgery, Faculty of Medicine, Kagawa University
| | - Katsumi Imaida
- Onco-Pathology, Department of Pathology and Host-Defence, Faculty of Medicine, Kagawa University
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Chen T, Hutts RC, Mei N, Liu X, Bishop ME, Shelton S, Manjanatha MG, Aidoo A. Endogenous estrogen status, but not genistein supplementation, modulates 7,12-dimethylbenz[a]anthracene-induced mutation in the liver cII gene of transgenic big blue rats. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2005; 45:409-418. [PMID: 15662719 DOI: 10.1002/em.20102] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
A growing number of studies suggest that isoflavones found in soybeans have estrogenic activity and may safely alleviate the symptoms of menopause. One of these isoflavones, genistein, is commonly used by postmenopausal women as an alternative to hormone replacement therapy. Although sex hormones have been implicated as an important risk factor for the development of hepatocellular carcinoma, there are limited data on the potential effects of the estrogens, including phytoestrogens, on chemical mutagenesis in liver. Because of the association between mutation induction and the carcinogenesis process, we investigated whether endogenous estrogen and supplemental genistein affect 7,12-dimethylbenz[a]anthracene (DMBA)-induced mutagenesis in rat liver. Intact and ovariectomized female Big Blue rats were treated with 80 mg DMBA/kg body weight. Some of the rats also received a supplement of 1,000 ppm genistein. Sixteen weeks after the carcinogen treatment, the rats were sacrificed, their livers were removed, and mutant frequencies (MFs) and types of mutations were determined in the liver cII gene. DMBA significantly increased the MFs in liver for both the intact and ovariectomized rats. While there was no significant difference in MF between the ovariectomized and intact control animals, the mutation induction by DMBA in the ovariectomized groups was significantly higher than that in the intact groups. Dietary genistein did not alter these responses. Molecular analysis of the mutants showed that DMBA induced chemical-specific types of mutations in the liver cII gene. These results suggest that endogenous ovarian hormones have an inhibitory effect on liver mutagenesis by DMBA, whereas dietary genistein does not modulate spontaneous or DMBA-induced mutagenesis in either intact or ovariectomized rats.
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Affiliation(s)
- Tao Chen
- Division of Genetic and Reproductive Toxicology, Food and Drug Administration/National Center for Toxicological Research, Jefferson, Arkansas 72079, USA.
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Mei N, Heflich RH, Moore MM, Chen T. Age-dependent sensitivity of Big Blue transgenic mice to the mutagenicity of N-ethyl-N-nitrosourea (ENU) in liver. Mutat Res 2005; 572:14-26. [PMID: 15790487 PMCID: PMC6441962 DOI: 10.1016/j.mrfmmm.2004.11.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2004] [Revised: 11/03/2004] [Accepted: 11/14/2004] [Indexed: 10/25/2022]
Abstract
The incidence of childhood cancer is increasing and recent evidence suggests an association between childhood cancer and environmental exposure to genotoxins. In the present study, the Big Blue transgenic mouse model was used to determine whether specific periods in early life represent windows of vulnerability to mutation induction by genotoxins in mouse liver. Groups of mice were treated with single doses of 120 mg N-ethyl-N-nitrosourea (ENU)/kg body weight or the vehicle either transplacentally to the 18-day-old fetus or at postnatal days (PNDs) 1, 8, 15, 42 or 126; the animals were sacrificed 6 weeks after their treatment. The cII mutation assay was performed to determine the mutant frequencies (MFs) in the livers of the mice. Liver cII MFs for both sexes were dependent on the age at which the animals were treated. Perinatal treatment with ENU (either transplacental treatment to the 18-day-old fetus or i.p. injection at PND 1) induced relatively high MFs. However, ENU treatment at PNDs 8 and 15 resulted in the highest mutation induction. The lowest mutation induction occurred in those animals treated as adults (PND 126). For instance, the cII MF for the PND 8 female group was 646 x 10(-6) while the MF for female adults was only 145 x 10(-6), a more than 4-fold difference. Molecular analysis of the mutants found that A:T-->T:A transversions and A:T-->G:C transitions characterized the pattern of mutations induced by ENU in both the neonate and adult mice, while the predominate type of mutation in the controls was G:C-->A:T. The results indicate that mouse liver is most sensitive to ENU-induced mutation during infancy. This period correlates well with the age-dependent sensitivity to carcinogenicity in mouse liver, suggesting that mutation is an important rate-limiting factor for age-related carcinogenesis.
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Affiliation(s)
| | | | | | - Tao Chen
- Corresponding author. Tel.: +1 870 543 7954; fax: +1 870 543 7682. (T. Chen)
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Manjanatha MG, Shelton SD, Rhodes BS, Bishop ME, Lyn-Cook LE, Aidoo A. 17 Beta-estradiol and not genistein modulates lacI mutant frequency and types of mutation induced in the heart of ovariectomized big blue rats treated with 7, 12-dimethylbenz[a]anthracene. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2005; 45:70-79. [PMID: 15611980 DOI: 10.1002/em.20080] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
In industrialized countries, heart disease rates are higher among women after menopause. Recent studies indicate that consumption of phytoestorogens, e.g., isoflavones such as genistein (GE), may have potential cardiovascular health benefits; however, no studies have evaluated the effect of these agents on toxicant-induced damage in the heart. Since estrogen receptors are found in the heart, and GE mimics estrogenic effects, we have examined whether or not dietary GE or 17 beta-estradiol (E2) modulates the lacI mutant frequency (MF) in the heart of ovariectomized (OVX) Big Blue rats exposed to the model carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). Groups of female rats were administered 80 mg/kg DMBA or vehicle by gavage and were chronically fed with diets containing 0, 250, or 1,000 microg/g GE or 5 microg/g E2. Sixteen weeks after carcinogen treatment, the animals were sacrificed and the hearts were removed and processed for determining the frequency and types of mutations in the heart tissue. GE and E2 supplementation alone resulted in nonsignificant increases in MF. The DMBA-induced lacI MF in the heart was sevenfold higher than the control (119.8 +/- 18.7 x 10(-6) vs. 17.4 +/- 3.2 x 10(-6); P < 0.001). GE in the diet had no significant effect on DMBA mutagenicity, while feeding E2 to DMBA-treated rats caused a significant reduction in the MF (119.8+/- 18.7 x 10(-6) vs. 61.4 +/- 13.5 x 10(-6); P < 0.017). DNA sequence analysis revealed that the majority of DMBA-induced mutations in rats fed control diet were A:T-->T:A (42%) and G:C-->T:A (19%) transversions, followed by G:C-->A:T (13%) and A:T-->G:C (8%) transitions. Feeding E2 altered the DMBA-induced mutational spectra by decreasing A:T-->T:A (23%) and G:C-->T:A (13%) transversions and increasing G:C-->A:T (24%) and A:T-->G:C (21%) transitions. Taken together, the results suggest that DMBA can induce gene mutations in heart tissue of OVX rats, and while dietary GE had little or no effect on DMBA-induced mutation, dietary E2 reduced the mutagenicity of DMBA.
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Affiliation(s)
- Mugimane G Manjanatha
- Division of Genetic and Reproductive Toxicology, Food and Drug Administration/National Center for Toxicological Research, Jefferson, Arkansas 72079, USA.
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Lu G, Shimizu I, Cui X, Itonaga M, Tamaki K, Fukuno H, Inoue H, Honda H, Ito S. Antioxidant and antiapoptotic activities of idoxifene and estradiol in hepatic fibrosis in rats. Life Sci 2004; 74:897-907. [PMID: 14659978 DOI: 10.1016/j.lfs.2003.08.004] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Oxidative stress plays a causative role in the development of hepatic fibrosis and apoptosis. Estradiol (E2) is an antioxidant, and idoxifene is a tissue-specific selective estrogen receptor modulator. We have previously demonstrated that E2 inhibits hepatic fibrosis in a rat model of hepatic fibrosis induced with dimethylnitrosamine (DMN), and suppresses activation of the nuclear factor (NF)-kappaB proinflammatory transcription factor in cultured rat hepatocytes undergoing oxidative stress. This study reports on the antioxidant and antiapoptotic role of idoxifene and E2 in the DMN model of hepatic fibrosis. The DMN model rats were administered with idoxifene or E2, and were examined activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx) and expression of Bcl-2 family proteins in the liver. During the course of hepatofibrogenesis after DMN treatment, serum levels of lactate dehydrogenase (LDH), a biomarker for necrosis, and hepatic levels of malondialdehyde (MDA), an end product of lipid peroxidation, increased rapidly for 3 days. On day 14, serum LDH levels normalized, and hepatic fibrosis developed with increased levels of MDA and collagen and decreased production of SOD and GPx in the liver. Fibrotic liver also showed downregulation of Bcl-2 and Bcl-X(L) expression and upregulation of Bad expression. Idoxifene and E2 suppressed DMN-mediated necrosis, lipid peroxidation, the loss of antioxidant enzyme activity, and proapoptotic status in Bcl-2 family protein expression as well as hepatic fibrosis. These findings indicate that, in addition to their antiinflammatory and antifibrotic action, idoxifene and E2 could enhance antioxidant and antiapoptotic activity in hepatic fibrosis in rats.
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Affiliation(s)
- Guangming Lu
- Department of Digestive and Cardiovascular Medicine, Tokushima University School of Medicine, Kuramoto-cho, Tokushima 770-8503, Japan
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Yu MW, Chang HC, Chang SC, Liaw YF, Lin SM, Liu CJ, Lee SD, Lin CL, Chen PJ, Lin SC, Chen CJ. Role of reproductive factors in hepatocellular carcinoma: Impact on hepatitis B- and C-related risk. Hepatology 2003; 38:1393-400. [PMID: 14647050 DOI: 10.1016/j.hep.2003.09.041] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Hepatocellular carcinoma (HCC) is more prevalent in men than in women. Estrogen may play some role in the development of HCC. We conducted a multicenter case-control study to evaluate the effects of reproductive factors on HCC risk, and to assess whether the association between each factor and HCC differs between hepatitis B surface antigen (HBsAg)-positive and -negative women, in which hepatitis C virus (HCV) is the major cause of HCC. The study included 218 women with HCC and 729 control women selected from nonbiological and first-degree female relatives of patients with HCC. The risk of HCC was inversely related to the number of full-term pregnancies (FTP) (P(trend) =.0216) and age at natural menopause (P(trend) =.0251 among women aged 45-55 without prior surgical menopause). Oophorectomy at age <or=50 during premenopausal years was also a risk factor (multivariate-adjusted OR, 2.57; 95% CI, 1.42-4.63). Use of hormone replacement therapy (HRT) (multivariate-adjusted OR, 0.46; 95% CI, 0.27-0.79) was associated with a lower risk of HCC, and there was a trend in the risk with increasing duration of HRT (P(trend) = 0.0013). All reproductive factors had a similar impact on HBsAg-positive and -negative women except for an early menarche (<or=12 vs. >or=16 years), which increased HCC risk in HBsAg carriers (multivariate-adjusted OR, 6.96; 95% CI, 2.52-19.18) but posed no increased risk in noncarriers (P(interaction) =.0053). In conclusion, increased exposure to estrogen during adulthood may provide a protective effect against HCC. Nevertheless, an early menarche, which results in early estrogen exposure, does not confer protection for HBsAg carriers.
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Affiliation(s)
- Ming-Whei Yu
- Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan.
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Iavarone M, Lampertico P, Seletti C, Francesca Donato M, Ronchi G, del Ninno E, Colombo M. The clinical and pathogenetic significance of estrogen receptor-beta expression in chronic liver diseases and liver carcinoma. Cancer 2003; 98:529-34. [PMID: 12879470 DOI: 10.1002/cncr.11528] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND Estrogen receptor-alpha (ERalpha) is variably expressed in hepatocellular carcinoma (HCC) and is believed to be correlated with prognosis and survival. Recently, another estrogen receptor (ERbeta) has been identified, but its relevance in liver diseases is unknown. METHODS The expression of ERbeta in the liver of 42 patients with HCC (10 with paired extratumoral tissues) and 26 with chronic liver disease without HCC was studied by a reverse transcriptase-polymerase chain reaction method, and correlated with the expression of ERalpha and severity of the liver disease. RESULTS Both ERbeta and wild-type ERalpha were found to be expressed more often in patients with chronic liver disease compared with those with HCC (69% vs. 45% [P = 0.046] and 46% vs. 10% [P = 0.0008], respectively). ERs were similarly expressed in HCC and in the paired extratumoral tissue. Wild-type receptors, either alone or together with the deleted mutants ERdelta5, were more often coexpressed in chronic liver disease (58%) than in HCC (29%); in 13 tumors (31%), either ERdelta5 or no receptors at all were detected (P = 0.006). Hepatitis B virus (HBV)-related tumors either did not appear to express ERs or expressed ERdelta5 more often than hepatitis C virus (HCV)-related tumors (67% vs. 15%; P = 0.007). The same was true for multinodular compared with single nodular tumors (50% vs. 19%; P = 0.04). CONCLUSIONS Both receptors were expressed in chronic liver disease and neoplastic livers demonstrating different patterns in relation to the etiology and clinical presentation of the tumor. These differences might underscore different pathogenetic mechanisms in HBV-related and HCV-related HCC and a different evolutionary course for the tumor.
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MESH Headings
- Aged
- Base Sequence
- Carcinoma, Hepatocellular/etiology
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/virology
- Chronic Disease
- DNA Primers/chemistry
- Estrogen Receptor alpha
- Estrogen Receptor beta
- Female
- Hepacivirus/genetics
- Hepacivirus/isolation & purification
- Hepatitis B/virology
- Hepatitis B Surface Antigens/metabolism
- Hepatitis B virus/genetics
- Hepatitis B virus/isolation & purification
- Humans
- Liver Diseases/etiology
- Liver Diseases/metabolism
- Liver Diseases/pathology
- Liver Diseases/virology
- Liver Neoplasms/etiology
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Liver Neoplasms/virology
- Male
- Middle Aged
- Molecular Sequence Data
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- RNA, Neoplasm/metabolism
- Receptors, Estrogen/genetics
- Receptors, Estrogen/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Sequence Deletion
- Sequence Homology, Nucleic Acid
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Affiliation(s)
- Massimo Iavarone
- A.M. and A. Migliavacca Center, Division of Hepatology and FIRC Liver Cancer Unit, IRCCS Maggiore Policlinico Hospital, University of Milan, Milan, Italy.
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Fernandez E, Gallus S, Bosetti C, Franceschi S, Negri E, La Vecchia C. Hormone replacement therapy and cancer risk: a systematic analysis from a network of case-control studies. Int J Cancer 2003; 105:408-12. [PMID: 12704678 DOI: 10.1002/ijc.11083] [Citation(s) in RCA: 127] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
To provide comprehensive and quantitative information on the benefits and risks of hormone replacement therapy (HRT) on several cancer sites, we systematically examined the relation between HRT use and the risk of various cancers in women aged 45-79 by using data from a framework of case-control studies conducted in Italy between 1983 and 1999. The overall data set included the following incident, histologically confirmed neoplasms: oral cavity, pharynx, larynx and esophagus (n = 253), stomach (n = 258), colon (n = 886), rectum (n = 488), liver (n = 105), gallbladder (n = 31), pancreas (n = 122), breast (n = 4,713), endometrium (n = 704), ovary (n = 1,614), urinary bladder (n = 106), kidney (n = 102), thyroid (n = 65), Hodgkin's disease (n = 26), non-Hodgkin's lymphomas (n = 145), multiple myeloma (n = 65) and sarcomas (n = 78). The control group comprised 6,976 women aged 45-79 years, admitted for a wide spectrum of acute, nonneoplastic conditions. Odds ratios (OR) and the corresponding 95% confidence intervals (CI) for use of HRT were derived from multiple logistic regression equations. There was an inverse association between ever use of HRT and colon (OR = 0.7), rectum (OR = 0.5) and liver cancer (OR = 0.2), with a consistent pattern of protection for duration of use. An excess risk was found for gallbladder (OR = 3.2), breast (OR = 1.1), endometrial (OR = 3.0) and urinary bladder cancer (OR = 2.0). These data from a southern European population add some useful information on the risk-benefit assessment of HRT among postmenopausal women.
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Affiliation(s)
- Esteve Fernandez
- Cancer Prevention and Control Unit, Institut Català d'Oncologia, L'Hospitalet (Barcelona), Catalonia, Spain.
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Abstract
As of this writing, the most common cause of hepatic fibrosis is chronic hepatitis C virus infection (HCV), the characteristic feature of which is hepatic steatosis. Hepatic steatosis leads to an increase in lipid peroxidation in hepatocytes, which in turn activates hepatic stellate cells (HSCs). HSCs are also thought to be the primary target cells for inflammatory stimuli, and produce extracellular matrix components. Based on available clinical information, chronic hepatitis C appears to progress more rapidly in men than in women, and cirrhosis is predominately a disease of men and postmenopausal women. It should be noted that estradiol (E2) is a potent endogenous antioxidant. A recent study has shown that hepatic steatosis became evident in an aromatase-deficient mouse and was diminished in animals, after treatment with E2. Our studies showed that E2 suppressed hepatic fibrosis in hepatic fibrosis models, inhibited the activation of activator protein 1 and nuclear factor-kappa B in cultured hepatocytes undergoing oxidative stress, and attenuated HSC activation in primary culture. Recently, variant oestrogen receptors (ERs) were found to be expressed to a greater extent in male patients with chronic liver disease than in female subjects. We also demonstrated decreased levels of ERs in postmenopausal women and cirrhotic patients of both genders. The actions of E2 are mediated through ER alpha and beta. HSCs have also been found to possess functional ER beta but not ER alpha. A better understanding the basic mechanisms underlying the gender-associated differences observed in the development of hepatic fibrosis would provide valuable information relative to the search for effective antifibrogenic therapies.
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Affiliation(s)
- Ichiro Shimizu
- Department of Digestive and Cardiovascular Medicine, Tokushima University School of Medicine, Tokushima, Japan.
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