The splicing factor HNRNPM promotes hepatocellular carcinoma by decreasing TRIM7 expression through the alternative splicing of lncRNA-TRIM7-AS

Understanding the roles of splicing factors and splicing events during tumorigenesis would open new avenues for targeted therapies. Here we identify an oncofetal splicing factor, heterogeneous nuclear ribonucleoprotein M (HNRNPM), which promotes tumorigenesis and predicts poor prognosis of hepatocellular carcinoma (HCC) patients. HNRNPM knockdown almost completely abolishes HCC tumorigenesis. Transcriptomic analysis combined with RNA-immunoprecipatation sequencing revealed that HNRNPM induces lncRNA-TRIM7-AS exon 2 inclusion. The transcript containing exon 2 binds to coding sequences of TRIM7 mRNA, causes dissociation of translation elongation factors from TRIM7 mRNA, and thereby inhibits TRIM7 mRNA translation. In contrast, the transcript including exon 3 preferentially binds to the 3' untranslated region of TRIM7 mRNA, protects TRIM7 mRNA from microRNA-145-5p induced degradation, and thereby increases TRIM7 expression. Through inducing exon 2 inclusion, HNRNPM downregulates TRIM7 protein expression, which mediates the pro-tumorigenic roles of HNRNPM. Collectively, these data demonstrate detailed mechanistic links between an oncofetal splicing factor, a splicing event and tumorigenesis, and establish splicing factors and splicing events as potential therapeutic targets. Overall design: Examination of alternative splicing genes regulated by splicing factor HNRNPM