Omics-Based Identification of Shared and Gender Disparity Routes in Hras12V-Induced Hepatocarcinogenesis: An Important Role for Dlk1-Dio3 Genomic Imprinting Region

The phenomenon of gender disparity is very profound in hepatocellular carcinoma (HCC). Although previous research has revealed important roles of microRNA (miRNA) in HCC, there are no studies investigating the role of miRNAs in gender disparity observed hepatocarcinogenesis. In the present study, we investigated the global miRNAomics changes related to Ras-induced male-prevalent hepatocarcinogenesis in a Hras12V-transgenic mouse model (Ras-Tg) by next-generation sequencing (NGS). We identified shared by also unique changes in miRNA expression profiles in gender-dependent hepatocarcinogenesis. Two hundred sixty-four differentially expressed miRNAs (DEMIRs) with q value ≤0.05 and fold change ≥2 were identified. A vertical comparison revealed that the lower numbers of DEMIRs in the hepatic tumor (T) compared with the peri-tumor precancerous tissue (P) of Ras-Tg and normal liver tissue of wild-type C57BL/6J mice (W) in males indicated that males are more susceptible to develop HCC. The expression pattern analysis revealed 43 common HCC-related miRNAs and 4 Ras-positive-related miRNAs between males and females. By integrating the mRNA transcriptomic data and using 3-node FFL analysis, a group of significant components commonly contributing to HCC between sexes were filtered out. A horizontal comparison showed that the majority of DEMIRs are located in the Dlk1-Dio3 genomic imprinting region (GIR) and that they are closely related to not only hepatic tumorigenesis but also to gender disparity in hepatocarcinogenesis. This is achieved by regulating multiple metabolic pathways, including retinol, bile acid, and steroid hormones. In conclusion, the identification of shared and gender-dependent DEMIRs in hepatocarcinogenesis provides valuable insights into the mechanisms that contribute to male-biased Ras-induced hepatic carcinogenesis.