Long Noncoding RNA MALAT1 Promotes Hepatocellular Carcinoma Development by SRSF1 Upregulation and mTOR Activation

Pushkar Malakar(Hadassah Medical Center), Asaf Shilo(Hadassah Medical Center), Adi Mogilevsky(Hadassah Medical Center), Ilan Stein(Hebrew University of Jerusalem), Eli Pikarsky(Hebrew University of Jerusalem), Yuval Nevo(Hadassah Medical Center), Hadar Benyamini(Hadassah Medical Center), Sharona Elgavish(Hadassah Medical Center), Xinying Zong(University of Illinois Urbana-Champaign), Kannanganattu V. Prasanth(University of Illinois Urbana-Champaign), Rotem Karni(Hadassah Medical Center)
Cancer Research
December 19, 2016
10.1158/0008-5472.can-16-1508
Cited by 328Open Access
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Abstract

Abstract Several long noncoding RNAs (lncRNA) are abrogated in cancer but their precise contributions to oncogenesis are still emerging. Here we report that the lncRNA MALAT1 is upregulated in hepatocellular carcinoma and acts as a proto-oncogene through Wnt pathway activation and induction of the oncogenic splicing factor SRSF1. Induction of SRSF1 by MALAT1 modulates SRSF1 splicing targets, enhancing the production of antiapoptotic splicing isoforms and activating the mTOR pathway by modulating the alternative splicing of S6K1. Inhibition of SRSF1 expression or mTOR activity abolishes the oncogenic properties of MALAT1, suggesting that SRSF1 induction and mTOR activation are essential for MALAT1-induced transformation. Our results reveal a mechanism by which lncRNA MALAT1 acts as a proto-oncogene in hepatocellular carcinoma, modulating oncogenic alternative splicing through SRSF1 upregulation. Cancer Res; 77(5); 1155–67. ©2016 AACR.

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