Journal Article

The MBNL3 splicing factor promotes hepatocellular carcinoma by increasing PXN expression through the alternative splicing of lncRNA-PXN-AS1

Tao, Qi-fei, Pan, Wei, Sun, Shu-han, Yuan, Ji-hang, Zhou, Wei-ping, Wang, Tian-tian, Wang, Fang, Liu, Xiao-ning

2017

Overview

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, MBNL3, which promotes tumorigenesis and indicates poor prognosis of hepatocellular carcinoma patients. MBNL3 knockdown almost completely abolishes hepatocellular carcinoma tumorigenesis. Transcriptomic analysis revealed that MBNL3 induces lncRNA-PXN-AS1 exon 4 inclusion. The transcript lacking exon 4 binds to coding sequences of PXN mRNA, causes dissociation of translation elongation factors from PXN mRNA, and thereby inhibits PXN mRNA translation. In contrast, the transcript containing exon 4 preferentially binds to the 3′ untranslated region of PXN mRNA, protects PXN mRNA from microRNA-24–AGO2 complex-induced degradation, and thereby increases PXN expression. Through inducing exon 4 inclusion, MBNL3 upregulates PXN, which mediates the pro-tumorigenic roles of MBNL3. 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. Yuan et al.  show that the MBNL3 splicing factor promotes alternative splicing of the lncRNA-PXN-AS1 antisense transcript of PXN, leading to the stabilization of PXN mRNA and increasing its protein levels to promote liver cancer growth.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/105 / 13/109 / 13/2 / 13/51 / 13/89 / 13/95 / 3' Untranslated Regions / 38/1 / 38/39 / 59 / 59/5 / 631/337/384/2568 / 631/67 / 631/67/395 / 64 / 64/60 / 82 / 82/29 / 82/80 / 96 / Alternative Splicing / Animals / Argonaute 2 protein / Argonaute Proteins - genetics / Argonaute Proteins - metabolism / Binding Sites / Cancer Research / Carcinoma, Hepatocellular - genetics / Carcinoma, Hepatocellular - metabolism / Carrier Proteins - metabolism / Cell Biology / Cell Proliferation / Development and progression / Developmental Biology / Diagnosis / Elongation / Exons / Gene expression / Gene Expression Profiling - methods / Gene Expression Regulation, Neoplastic / Gene sequencing / Genetic aspects / Health aspects / Hep G2 Cells / Hepatocellular carcinoma / High-Throughput Nucleotide Sequencing / Humans / Life Sciences / Liver cancer / Liver Neoplasms - genetics / Liver Neoplasms - metabolism / Male / Mice / Mice, Inbred C57BL / Mice, Nude / MicroRNAs - genetics / MicroRNAs - metabolism / miRNA / Nanog Homeobox Protein - genetics / Nanog Homeobox Protein - metabolism / Octamer Transcription Factor-3 - genetics / Octamer Transcription Factor-3 - metabolism / Paxillin - genetics / Paxillin - metabolism / Protein Binding / Ribonucleic acid / RNA / RNA Interference / RNA splicing / RNA, Long Noncoding - genetics / RNA, Long Noncoding - metabolism / RNA-Binding Proteins - genetics / RNA-Binding Proteins - metabolism / SOXB1 Transcription Factors - genetics / SOXB1 Transcription Factors - metabolism / Splicing / Splicing factors / Stem Cells / Time Factors / Transcription / Transfection / Translation / Translation elongation / Tumor Burden / Tumorigenesis / Up-Regulation