Sex steroid axes in determining male predominance in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death. The mechanisms for male propensity in HCC incidence, prognosis and treatment responses are complicated and remain inconclusive. Sex-biased molecular signatures in carcinogenesis, viral infections and immune responses have been studied predominantly within the context of sex hormones effects. This review integrates current knowledge on the mechanisms through which the hormones regulate HCC development in sexually dimorphic fashion. Firstly, the androgen/androgen receptor (AR) accelerate cell proliferation and virus infection, especially during the initial stage of HCC, while estrogen/estrogen receptor (ER) function in an opposite way to induce cell apoptosis and immune responses. Interestingly, the controversial effects of AR in late stage of HCC metastasis are summarized and the reasons are attributed to inconsistent cancer grading or experimental models between the studies. In addition, the new insights into these intricate cellular and molecular mechanisms underlying sexual dimorphism are fully discussed. A detailed understanding of sex hormones-associated regulation to male predominance in HCC may help to develop personalized therapeutic strategies in high-risk populations.