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

Abstract

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.

The RNA-Binding Motif Protein Family in Cancer: Friend or Foe?

“…It was not clarified that why RBM proteins family members play a dual role in tumors. Kido et al found that the dual role of RBM proteins family genes may be related to time and space (77). They discovered that RBMY acts as a suppressor in the early stages of the tumor and shows a cancer-promoting effect in RBMX competitively inhibited the combination of the RGG motif in hnRNP A1 and the sequences flanking PKM exon 9, leading to the formation of lower PKM2 and higher PKM1 levels, which attenuated the tumorigenicity and progression of BCa.…”

“…Kido et al. found that the dual role of RBM proteins family genes may be related to time and space ( 77 ). They discovered that RBMY acts as a suppressor in the early stages of the tumor and shows a cancer-promoting effect in the long-term progression of tumors.…”

Y chromosome is moving out of sex determination shadow

“…Dual functional roles of the Y-linked RBMY have been reported in hepatocarcinogenesis in different studies [ 101 , 103 , 105 – 107 ]. Tsuei et al showed the expression of one to four different transcripts of RBMY including wild type and variants with N-terminal RRM deletion, C-terminal SRGY (serine–arginine–glycine–tyrosine) boxes deletion, or deletion of both domains in males with HCC and hepatoblastoma.…”

“…It seems that RBMY functions as a male-specific tumor suppressor at early stages of HCC development and can suppress cell proliferation and pro-oncogenic pathways. However, after surviving and adapting tumor cells in proliferative mode, RBMY acts as a proto-oncogene and induces its chronic effects to promote HCC progression [ 107 ].…”

Y Chromosome Genes May Play Roles in Directed Differentiation of Human Embryonic Stem Cells.

“…RBMY1A1 contains a conserved domain called the SRGY motif (serine, arginine, glycine, and tyrosine) that modulated its function. RBMY1 plays a signi cant role in cardiac development, spermatogenesis, infertility, prostate cancer, and hepatocellular carcinoma (HCC) (Meyfour et al, 2017b, Chua et al, 2015, Kido et al, 2020, Jangravi et al, 2013, Dasari et al, 2001.…”