Long noncoding RNA MALAT1 promotes hepatocellular carcinoma development by SRSF1 upregulation and mTOR activation

Pushkar Malakar; Asaf Shilo; Adi Mogilevsky; Ilan Stein; Eli Pikarsky; Yuval Nevo; Hadar Benyamini; Sharona Elgavish; Xinying Zong; Kannanganattu V. Prasanth; Rotem Karni

doi:10.1158/0008-5472.CAN-16-1508

Long noncoding RNA MALAT1 promotes hepatocellular carcinoma development by SRSF1 upregulation and mTOR activation

Pushkar Malakar, Asaf Shilo, Adi Mogilevsky, Ilan Stein, Eli Pikarsky, Yuval Nevo, Hadar Benyamini, Sharona Elgavish, Xinying Zong, Kannanganattu V. Prasanth, Rotem Karni^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

248 Scopus citations

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.

Original language	English
Pages (from-to)	1155-1167
Number of pages	13
Journal	Cancer Research
Volume	77
Issue number	5
DOIs	https://doi.org/10.1158/0008-5472.CAN-16-1508
State	Published - 1 Mar 2017

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© 2017 American Association for Cancer Research.

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title = "Long noncoding RNA MALAT1 promotes hepatocellular carcinoma development by SRSF1 upregulation and mTOR activation",

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.",

author = "Pushkar Malakar and Asaf Shilo and Adi Mogilevsky and Ilan Stein and Eli Pikarsky and Yuval Nevo and Hadar Benyamini and Sharona Elgavish and Xinying Zong and Prasanth, {Kannanganattu V.} and Rotem Karni",

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AU - Malakar, Pushkar

AU - Shilo, Asaf

AU - Mogilevsky, Adi

AU - Stein, Ilan

AU - Pikarsky, Eli

AU - Nevo, Yuval

AU - Benyamini, Hadar

AU - Elgavish, Sharona

AU - Zong, Xinying

AU - Prasanth, Kannanganattu V.

AU - Karni, Rotem

PY - 2017/3/1

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AB - 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.

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Long noncoding RNA MALAT1 promotes hepatocellular carcinoma development by SRSF1 upregulation and mTOR activation

Abstract

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