Splicing factor hnRNP A2 activates the Ras-MAPK-ERK pathway by controlling A-Raf splicing in hepatocellular carcinoma development

Title: Splicing factor hnRNP A2 activates the Ras-MAPK-ERK pathway by controlling A-Raf splicing in hepatocellular carcinoma development
Authors: Shilo, Asaf
Ben Hur, Vered
Denichenko, Polina
Stein, Ilan
Pikarsky, Eli
Rauch, Jens
Kolch, Walter
Zender, Lars
Karni, Rotem
Permanent link: http://hdl.handle.net/10197/9160
Date: 26-Feb-2014
Abstract: In recent years, it has become clear that splicing factors play a direct role in cancer development. We showed previously that splicing factors SRSF1, SRSF6, and hnRNP A2/B1 are up-regulated in several cancers and can act as oncogenes when up-regulated. Here we examined the role of splicing factors hnRNP A1/A1b and hnRNP A2/B1 in hepatocellular carcinoma (HCC). We show that the splicing factors hnRNP A1 and hnRNP A2 are up-regulated in HCC tumors derived from inflammation-induced liver cancer mouse model. Overexpression of hnRNP A1 or hnRNP A2, but not the splicing isoform hnRNP B1, induced tumor formation of immortalized liver progenitor cells, while knockdown of these proteins inhibited anchorage-independent growth and tumor growth of human liver cancer cell lines. In addition, we found that cells overexpressing hnRNP A2 showed constitutive activation of the Ras-MAPK-ERK pathway. In contrast, knockdown of hnRNP A2 inhibited the Ras-MAPK-ERK pathway and prevented ERK1/2 activation by EGF. Moreover, we found that hnRNP A2 regulates the splicing of A-Raf, reducing the production of a short dominant-negative isoform of A-Raf and elevating the full-length A-Raf transcript. Taken together, our data suggest that hnRNP A2 up-regulation in HCC induces an alternative splicing switch that down-regulates a dominant-negative isoform of A-Raf, leading to activation of the Raf-MEK-ERK pathway and cellular transformation.
Funding Details: Science Foundation Ireland
Type of material: Journal Article
Publisher: Cold Spring Harbor Laboratory Press
Copyright (published version): 2014 the Authors
Keywords: A-Raf;MAPK;RNA processing;hnRNP A2/B1;Alternative splicing;Liver cancer
DOI: 10.1261/rna.042259.113
Language: en
Status of Item: Peer reviewed
Appears in Collections:SBI Research Collection

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