Alternative splicing of the cell fate determinant Numb in hepatocellular carcinoma.
Alternative splicing of the cell fate determinant Numb in hepatocellular carcinoma.
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DOI：
10.1002/hep.27923
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发表时间：
2015-10
期刊：
影响因子：
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通讯作者：
Neckers L
中科院分区：
文献类型：
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作者：
Lu Y;Xu W;Ji J;Feng D;Sourbier C;Yang Y;Qu J;Zeng Z;Wang C;Chang X;Chen Y;Mishra A;Xu M;Lee MJ;Lee S;Trepel J;Linehan WM;Wang X;Yang Y;Neckers L
细胞命运决定因子Numb在癌症中异常表达。Numb与一种含有延伸的脯氨酸富集区（PRRL）的同种型（PRRS）相比，选择性剪接。PRRL最近被报道可以增强乳腺癌和肺癌细胞的增殖。然而，Numb选择性剪接在肝细胞癌（HCC）中的重要性尚未得到研究。我们在此报道Numb PRRL在HCC中表达增加，与术后早期复发和总生存率降低相关。在一组HCC细胞系中，PRRL通常促进而PRRS抑制增殖、迁移、侵袭和集落形成。PRRS敲低导致Akt磷酸化和c-Myc表达增加，Akt抑制或c-Myc沉默减弱Numb PRRS敲低的增殖影响。在本研究探索的细胞模型中，Numb PRR亚型的选择性剪接受剪接因子Rbfox 2和激酶SRPK 2的协调调节。Rbfox 2敲低导致PRRL的积累，而SRPK 2敲低导致PRRS的积累。SRPK 2的亚细胞定位受分子伴侣Hsp 90调节，Hsp 90抑制或敲低SRPK 2敲低表型促进Numb PRRS的积累。最后，主要表达PRRL的HCC细胞系对Hsp 90抑制的敏感性不同。我们的数据表明Numb的选择性剪接可能提供一个有用的HCC预后生物标志物，并且是可预测的。
The cell fate determinant Numb is aberrantly expressed in cancer. Numb is alternatively spliced with one isoform containing an extended proline rich region (PRRL) compared to the other (PRRS). PRRL was recently reported to enhance proliferation of breast and lung cancer cells. However, the importance of Numb alternative splicing in hepatocellular carcinoma (HCC) remain unexplored. We report here that Numb PRRL expression is increased in HCC and is associated with early recurrence and reduced overall survival after surgery. In a panel of HCC cell lines, PRRL generally promotes and PRRS suppresses proliferation, migration, invasion and colony formation. PRRS knockdown leads to increased Akt phosphorylation and c-Myc expression, and Akt inhibition or c-Myc silencing dampens the proliferative impact of Numb PRRS knockdown. In the cell models explored in this study, alternative splicing of Numb PRR isoforms is coordinately regulated by the splicing factor Rbfox2 and the kinase SRPK2. Rbfox2 knockdown causes accumulation of PRRL while SRPK2 knockdown causes accumulation of PRRS. SRPK2 subcellular location is regulated by the molecular chaperone Hsp90, and Hsp90 inhibition or knockdown phenocopies SRPK2 knockdown in promoting accumulation of Numb PRRS. Finally, HCC cell lines that predominately express PRRL are differentially sensitive to Hsp90 inhibition. Our data suggest that alternative splicing of Numb may provide a useful prognostic biomarker in HCC and is pharmacologically tractable.