Testosterone regulation of cyclin E kinase: A key factor in determining gender differences in hepatocarcinogenesis

Pok, Sharon; Barn, Vanessa; Wong, Heng Jian; Blackburn, Anneke C.; Board, Philip G.; Farrell, Geoffrey C.; Teoh, Narci C.

doi:10.1111/jgh.13232

Cited by 26 publications

(31 citation statements)

References 32 publications

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“…This hypothesis has been examined in several animal studies [30, 31]. Estrogen exposure has been associated with decreased risk of HCC, while the administration of testosterone accelerated HCC development in an animal study [31]. Pok et al observed that testosterone enhanced the expression of liver cell cycle regulators, while estradiol suppressed the expression of liver cell cycle markers.…”

Section: Discussionmentioning

confidence: 99%

“…Pok et al observed that testosterone enhanced the expression of liver cell cycle regulators, while estradiol suppressed the expression of liver cell cycle markers. Both estrogen and testosterone hormones might jointly determine the gender discrepancy of HCC in mice [31]. On the other hand, work by Kemp et al indicated that testicular feminized mutant mice, which lack functional androgen receptors, have a similar risk of drug induced HCC compared to female mice but much less than other male mice [32].…”

Section: Discussionmentioning

confidence: 99%

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No contribution of lifestyle and environmental exposures to gender discrepancy of liver disease severity in chronic hepatitis b infection: Observations from the Haimen City cohort

et al. 2017

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BackgroundPrevious studies have noted significant gender difference in the risk of liver cancer among hepatitis B chronic infection patients. Some indicated that it might be due to lifestyle-related differences. This paper tests whether or not such a gender discrepancy among the chronic hepatitis B population is confounded by lifestyle and environment related exposures.MethodsWe retrieved a sample of 1863 participants from a prospective cohort in Haimen City, China in 2003. Liver disease severity was categorized as “normal”, “mild”, “moderate”, and “severe” based on a clinical diagnosis. Lifestyle and environmental exposures were measured by questionnaires. We used factor analysis and individual variables to represent lifestyle and environmental exposures. We applied the cumulative logit models to estimate the effect of gender on liver disease severity and how it was impacted by lifestyle and environmental exposures.ResultsGender and HBeAg positivity were independent risk factors for more severe liver disease. Compared to females, males were 2.08 times as likely to develop more severe liver disease (95% CI: 1.66–2.61). Participants who were HBeAg positivite were 2.19 times (95% CI: 1.61–2.96) as likely to develop more severe liver disease compared to those who were negative. Controlling for lifestyle and environmental exposures did not change these estimations.ConclusionsMales in the HBV infected population have an increased risk of severe liver disease. This gender effect is independent of the lifestyle and environmental exposures addressed in this study. Our findings support the hypothesis that gender discrepancies in HCC risk are attributable to intrinsic differences between males and females.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

No contribution of lifestyle and environmental exposures to gender discrepancy of liver disease severity in chronic hepatitis b infection: Observations from the Haimen City cohort

et al. 2017

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“…DEN-injected female mice exhibited scarcer dysplastic foci and less acute early stage of HCC than males, with more differentiated tumors and fewer metastases [120]. Castration of these mice down-regulated cyclin E kinase and amplified hepatocyte apoptosis, and estradiol/progesterone enhanced those effects.…”

Section: Hcc Malignancy and Sex Hormonesmentioning

confidence: 94%

Sex Hormone-Dependent Physiology and Diseases of Liver

Kur

Kolasa

Misiakiewicz-Has

et al. 2020

IJERPH

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Sexual dimorphism is associated not only with somatic and behavioral differences between men and women, but also with physiological differences reflected in organ metabolism. Genes regulated by sex hormones differ in expression in various tissues, which is especially important in the case of liver metabolism, with the liver being a target organ for sex hormones as its cells express estrogen receptors (ERs: ERα, also known as ESR1 or NR3A; ERβ; GPER (G protein-coupled ER, also known as GPR 30)) and the androgen receptor (AR) in both men and women. Differences in sex hormone levels and sex hormone-specific gene expression are mentioned as some of the main variations in causes of the incidence of hepatic diseases; for example, hepatocellular carcinoma (HCC) is more common in men, while women have an increased risk of autoimmune liver disease and show more acute liver failure symptoms in alcoholic liver disease. In non-alcoholic fatty liver disease (NAFLD), the distinction is less pronounced, but increased incidences are suggested among men and postmenopausal women, probably due to an increased tendency towards visceral fat accumulation.

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“…Sex differences in sex hormones appear to be important as a risk factor for HCC. Testosterone is a positive regulator of hepatocyte cell‐cycle regulators, which, in turn, accelerates hepatocarcinogenesis, in contrast estradiol, suppresses cell‐cycle regulators thereby suppressing the development of liver cancer …”

Section: Epidemiologymentioning

confidence: 99%

Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases

et al. 2018

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Testosterone regulation of cyclin E kinase: A key factor in determining gender differences in hepatocarcinogenesis

Abstract: Testosterone is the positive regulator of hepatocyte cell cycle via cyclin E, while estradiol plays a negative role by effects of p53 and p21. Together, both sex hormones determine the male predominance of gender differences in hepatocarcinogenesis.

Cited by 26 publications

References 32 publications

No contribution of lifestyle and environmental exposures to gender discrepancy of liver disease severity in chronic hepatitis b infection: Observations from the Haimen City cohort

No contribution of lifestyle and environmental exposures to gender discrepancy of liver disease severity in chronic hepatitis b infection: Observations from the Haimen City cohort

Sex Hormone-Dependent Physiology and Diseases of Liver

Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases

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