Gender-based investigation of 17 β hydroxysteroid dehydrogenase 13 in HCV-induced cirrhosis and hepatocellular carcinoma

Introduction/Objectives: Hepatitis C virus (HCV) infection- related inflammation, liver fibrosis and cirrhosis often lead to development of hepatocellular carcinoma (HCC). In the United States, 4.6 million people are infected with HCV. Studies show that chronic HCV infections are more prevalent in males and progress more rapidly to cirrhosis and cancer development as compared to females. In contrast, premenopausal females and women on hormone replacement therapy have been associated with lesssevere disease through all stages of HCV infection. Estrogen Receptor signaling is known to regulate inflammation and immunity. We have previously identified sex-based differences in the expression of estrogen receptors (ERs) in normal livers and dysregulated mRNA and protein expression of ER subtypes in both HCV-related cirrhosis and HCC suggesting a possible role in its pathogenesis. Given the United States opioid epidemic and high rates of intravenous drug use, Hepatitis C is an emerging disease among women of child-bearing age (and subsequently, pregnant women). Therefore, HCV-positive pregnant women with high levels estrogen may also be affected by modified behavior of HSDs. As such, our studies can apply to a broad group of people and demand further investigation. Our current study investigates the hydroxysteroid dehydrogenase enzyme family (HSD). HSDs contribute largely to the synthesis and degradation of steroid hormones such as testosterone and estrogen sex-hormones, as well as cholesterol and fatty acid metabolism. They have also been shown to confer involvement in carcinogenesis of extra-hepatic cancers affecting structures such as prostate, breast, and pancreas. Estrogen Receptor signaling is known to regulate inflammation and immunity. Chronic inflammation due to HCV infection in the liver may alter HSD enzyme regulation and alter hormone metabolism. Further, this pro-inflammatory state may contribute to the development of HCC which may be modulated by altered HSDs.

Methods/Results: Our current study utilized proteomic analysis to determine sex-based differences in HSD protein expression in male and female HCV cirrhosis and Hepatocellular Carcinoma (HCC), with specific interest in 17 β Hydroxysteroid Dehydrogenase 13 (HSD17B13). We studied a total 65 liver tissues that included both sexes from HCV-related cirrhosis, HCC, and normal controls. Using proteomics analysis, clinical correlates, western blotting, and immunohistochemistry techniques, our studies showed that HSD17B13 is present in both males and females and that females with HCC and females with HCVinduced cirrhosis have statistically significantly higher levels of the enzyme as compared to healthy control females and male with HCV-induced cirrhosis, respectively. Clinical marker aspartate aminotransferase (AST) shows a significant and inverse relationship to HSD17B13 expression among the HCC cohort as well. HSD17B13 protein may serve as a sex-based biomarker in liver cirrhosis and cancer development.

Conclusion: To the best of our knowledge this is the first report showing sex-based differences in HSD proteins in premalignant HCV-related cirrhosis. Further investigations with a larger group of patients may impress upon us new sex-based tailored clinical therapies in halting cirrhosis and HCC progression in males.