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Nature cell biology, 2017-07, Vol.19 (7), p.820

2017

Autor(en) / Beteiligte

Titel

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

Ist Teil von

Ort / Verlag

England

Erscheinungsjahr

2017

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

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.

Sprache: Englisch
Identifikatoren: eISSN: 1476-4679
DOI: 10.1038/ncb3538
Titel-ID: cdi_pubmed_primary_28553938

Format: –
Schlagworte: 3' Untranslated Regions, Alternative Splicing, Animals, Argonaute Proteins - genetics, Argonaute Proteins - metabolism, Binding Sites, Carcinoma, Hepatocellular - genetics, Carcinoma, Hepatocellular - metabolism, Carrier Proteins - metabolism, Cell Proliferation, Exons, Gene Expression Profiling - methods, Gene Expression Regulation, Neoplastic, Hep G2 Cells, High-Throughput Nucleotide Sequencing, Humans, Liver Neoplasms - genetics, Liver Neoplasms - metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Nude, MicroRNAs - genetics, MicroRNAs - metabolism, Nanog Homeobox Protein - genetics, Nanog Homeobox Protein - metabolism, Octamer Transcription Factor-3 - genetics, Octamer Transcription Factor-3 - metabolism, Paxillin - genetics, Paxillin - metabolism, Protein Binding, RNA Interference, RNA, Long Noncoding - genetics, RNA, Long Noncoding - metabolism, RNA-Binding Proteins - genetics, RNA-Binding Proteins - metabolism, SOXB1 Transcription Factors - genetics, SOXB1 Transcription Factors - metabolism, Time Factors, Transfection, Tumor Burden, Up-Regulation

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