Long Noncoding RNA MALAT1 Promotes Hepatocellular Carcinoma Development by SRSF1 Upregulation and mTOR Activation.
Long Noncoding RNA MALAT1 Promotes Hepatocellular Carcinoma Development by SRSF1 Upregulation and mTOR Activation.
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DOI：
10.1158/0008-5472.can-16-1508
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发表时间：
2017-03-01
期刊：
影响因子：
11.2
通讯作者：
Karni R
中科院分区：
文献类型：
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作者：
Malakar P;Shilo A;Mogilevsky A;Stein I;Pikarsky E;Nevo Y;Benyamini H;Elgavish S;Zong X;Prasanth KV;Karni R
一些长链非编码rna （lncRNA）在癌症中已被废除，但它们在肿瘤发生中的确切作用仍在研究中。在这里，我们报道了lncRNA MALAT1在肝细胞癌（HCC）中上调，并通过Wnt通路激活和诱导致癌剪接因子SRSF1作为原癌基因。MALAT1诱导SRSF1可调节SRSF1剪接靶点，增强抗凋亡剪接异构体的产生，并通过调节S6K1的选择性剪接激活mTOR通路。抑制SRSF1表达或mTOR活性可以消除MALAT1的致癌特性，这表明SRSF1的诱导和mTOR的激活对于MALAT1诱导的转化是必不可少的。我们的研究结果揭示了lncRNA MALAT1在HCC中作为原癌基因，通过上调SRSF1调节癌性选择性剪接的机制。
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 (HCC) 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 anti-apoptotic 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 HCC, modulating oncogenic alternative splicing through SRSF1 upregulation.