Potential dual functional roles of the Y‐linked RBMY in hepatocarcinogenesis

Hepatocellular carcinoma (HCC) is a highly heterogeneous liver cancer with significant male biases in incidence, disease progression, and outcomes. Previous studies have suggested that genes on the Y chromosome could be expressed and exert various male‐specific functions in the oncogenic processes. In particular, the RNA‐binding motif on the Y chromosome (RBMY) gene is frequently activated in HCC and postulated to promote hepatic oncogenesis in patients and animal models. In the present study, immunohistochemical analyses of HCC specimens and data mining of The Cancer Genome Atlas (TCGA) database revealed that high‐level RBMY expression is associated with poor prognosis and survival of the patients, suggesting that RBMY could possess oncogenic properties in HCC. To examine the immediate effect(s) of the RBMY overexpression in liver cancer cells, cell proliferation was analyzed on HuH‐7 and HepG2 cells. The results unexpectedly showed that RBMY overexpression inhibited cell proliferation in both cell lines as its immediate effect, which led to vast cell death in HuH‐7 cells. Transcriptome analysis showed that genes involved in various cell proliferative pathways, such as the RAS/RAF/MAP and PIP3/AKT signaling pathways, were downregulated by RBMY overexpression in HuH‐7 cells. Furthermore, in vivo analyses in a mouse liver cancer model using hydrodynamic tail vein injection of constitutively active AKT and RAS oncogenes showed that RBMY abolished HCC development. These findings support the notion that Y‐linked RBMY could serve dual tumor‐suppressing and tumor‐promoting functions, depending on the spatiotemporal and magnitude of its expression during oncogenic processes, thereby contributing to sexual dimorphisms in liver cancer.