Splicing factor hnRNP A2 activates the Ras-MAPK-ERK pathway by controlling A-Raf splicing in hepatocellular carcinoma development.
Splicing factor hnRNP A2 activates the Ras-MAPK-ERK pathway by controlling A-Raf splicing in hepatocellular carcinoma development.
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剪接因子HNRNP A2通过控制肝细胞癌发育中的A-RAF剪接来激活RAS-MAPK-ERK途径。
DOI：
10.1261/rna.042259.113
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发表时间：
2014-04
期刊：
影响因子：
--
通讯作者：
Karni R
中科院分区：
文献类型：
--
作者：
Shilo A;Ben Hur V;Denichenko P;Stein I;Pikarsky E;Rauch J;Kolch W;Zender L;Karni R
越来越多的证据表明，RNA结合蛋白（RNA-BPs）和选择性剪接在癌症的发展中起作用。在这篇文章中，作者研究了两种hnRNP蛋白，hnRNP A1/A1 b和hnRNP A2/B1，在肝细胞癌中的参与。这些hnRNP蛋白在源自炎症诱导的肝癌小鼠模型的HCC肿瘤中上调。他们表明，hnRNP A2（但不是其剪接异构体hnRNP B1）和hnRNP A1的水平对肿瘤形成至关重要。这需要激活Ras-MAPK-ERK信号通路，其依赖于hnRNPA 2调节A-Raf剪接的能力，从而减少短显性负性同种型的表达。近年来，剪接因子在癌症发展中起直接作用已经变得很清楚。我们先前表明，剪接因子SRSF 1，SRSF 6和hnRNP A2/B1在几种癌症中上调，并且在上调时可以作为癌基因。在这里，我们研究剪接因子hnRNP A1/A1 b和hnRNP A2/B1在肝细胞癌（HCC）中的作用。我们发现剪接因子hnRNP A1和hnRNP A2在炎症诱导的肝癌小鼠模型的HCC肿瘤中上调。hnRNP A1或hnRNP A2的过表达，但不是剪接异构体hnRNP B1，诱导肿瘤形成的永生化肝祖细胞，而敲低这些蛋白质抑制锚定非依赖性生长和肿瘤生长的人肝癌细胞系。此外，我们发现过表达hnRNPA 2的细胞表现出Ras-MAPK-ERK通路的组成性激活。与此相反，敲低hnRNPA 2抑制Ras-MAPK-ERK通路，并阻止EGF激活ERK 1/2。此外，我们发现hnRNP A2调节A-Raf的剪接，减少A-Raf的短显性负性同种型的产生并提高全长A-Raf转录物。总之，我们的数据表明，hnRNP A2在HCC中的上调诱导了一个选择性剪接开关，该开关下调了A-Raf的显性负亚型，导致Raf-MEK-ERK通路的激活和细胞转化。
There has been increasing evidence implicating RNA-binding proteins (RNA-BPs) and alternative splicing in the development of cancer. In this article, the authors investigate the involvement of two hnRNP proteins, hnRNP A1/A1b and hnRNP A2/B1, in hepatocellular carcinoma. These hnRNP proteins are up-regulated in HCC tumors derived from an inflammation-induced liver cancer mouse model. They show that the levels of hnRNP A2 (but not of its splicing isoform hnRNP B1) and hnRNP A1 are critical for tumor formation. This requires the activation of the Ras-MAPK-ERK signaling pathway, which depends on the ability of hnRNP A2 to modulate splicing of A-Raf, reducing the expression of a short dominant-negative isoform. 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.
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影响因子：
64.5
作者：
Cooper TA;Wan L;Dreyfuss G
通讯作者：
Dreyfuss G
DOI：
10.1007/s00018-008-8532-1
发表时间：
2009-04
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
He Y;Smith R
通讯作者：
Smith R
影响因子：
7.3
作者：
Cohen-Eliav, Michal;Golan-Gerstl, Regina;Karni, Rotem
通讯作者：
Karni, Rotem
影响因子：
25.7
作者：
Calvisi DF;Ladu S;Conner EA;Seo D;Hsieh JT;Factor VM;Thorgeirsson SS
通讯作者：
Thorgeirsson SS
影响因子：
3.3
作者：
Chan, KL;Guan, XY;OI-Lin, I
通讯作者：
OI-Lin, I