Oklahoma State University Center for Health Sciences
Abstract
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, pre-menopausal females and women on hormone replacement therapy have been associated with less-severe disease through all stages of HCV infection. 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. Sex based differential biomarkers could serve as an early prognostic tool for HCV cirrhosis and HCC development. The enzyme families including hydroxysteroid dehydrogenases (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. Chronic inflammation due to HCV infection in the liver may alter HSD enzyme regulation and affect hormone metabolism. We hypothesized that chronic HCV infection leads to dysregulated HSDs in male HCV cirrhosis patients leading to development of HCC. Our current study utilized proteomic analysis to determine sex-based differences in HSD protein expression in male and female HCV cirrhosis. We studied a total 40 liver tissues that included both sexes from HCV-related cirrhosis and normal controls. The liver tissues extracts were prepared and sent to NIH IDeA National Resource of Quantitative Proteomics core lab for DIA proteomic analysis. We were able to profile 4,443 genes belonging to different protein families that were differentially expressed in HCV cirrhosis and controls. Within the HSD protein cohort 7 exhibited differential expression in the liver cirrhosis groups compared to healthy controlss. Of these 7 proteins, only HSD17B13 demonstrated a significant sex-based differential expression between male and female HCV cirrhosis groups. More specifically, HCV cirrhosis females demonstrated a positive logFC value of 2.241 (p < 0.01) when compared to HCV cirrhosis males, suggesting HSD17B13 may serve as sex-based pre-cancerous biomarker. Further, HSD17B13 showed downregulation in HCV cirrhosis males compared to normal control males, but not significantly. No differences were observed in the remaining experimental groups (HCV F vs. normal control F and normal control M vs. normal control F). HSD17B13 protein may serve as a sex-based biomarker in liver cirrhosis and cancer development. To the best of our knowledge this is the first report showing sex-based differences in HSD proteins in premalignant HCV-related cirrhosis. Further, detailed studies may lead us to new sex-based tailored clinical therapies in halting cirrhosis and HCC progression in males
