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

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.

• Authors: Asaf Shilo, Vered Ben Hur, Polina Denichenko, Ilan Stein, Eli Pikarsky, Jens Rauch, Walter Kolch, Lars Zender, Rotem Karni
• Journal: RNA (New York, N.Y.) (RNA) Vol. 20 Issue 4 Pg. 505-15 (Apr 2014) ISSN: 1469-9001 [Electronic] United States
• PMID: 24572810 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B
• Heterogeneous Nuclear Ribonucleoprotein A1
• Heterogeneous-Nuclear Ribonucleoprotein Group A-B
• P-glycoprotein 2
• RNA, Small Interfering
• Tumor Suppressor Protein p53
• hnRNP A2
• Proto-Oncogene Proteins A-raf
• MAPK1 protein, human
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases
• ras Proteins

Topics

• ATP Binding Cassette Transporter, Subfamily B (physiology)
• Alternative Splicing
• Animals
• Carcinoma, Hepatocellular (etiology, metabolism, pathology)
• Cell Transformation, Neoplastic (pathology)
• Cells, Cultured
• Hepatocytes (metabolism, pathology)
• Heterogeneous Nuclear Ribonucleoprotein A1
• Heterogeneous-Nuclear Ribonucleoprotein Group A-B (antagonists & inhibitors, genetics, metabolism)
• Humans
• Inflammation (complications, genetics, pathology)
• Liver Neoplasms (etiology, metabolism, pathology)
• Mice
• Mice, Knockout
• Mice, Nude
• Mice, SCID
• Mitogen-Activated Protein Kinase 1 (genetics, metabolism)
• Mitogen-Activated Protein Kinase 3 (genetics, metabolism)
• Mitogen-Activated Protein Kinases (genetics, metabolism)
• Proto-Oncogene Proteins A-raf (genetics)
• RNA, Small Interfering (genetics)
• Tumor Suppressor Protein p53 (physiology)
• Xenograft Model Antitumor Assays
• ras Proteins (genetics, metabolism)