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Alternative splicing of the cell fate determinant Numb in hepatocellular carcinoma
Author(s) -
Lu Yinying,
Xu Wanping,
Ji Junfang,
Feng Dechun,
Sourbier Carole,
Yang Youfeng,
Qu Jianhui,
Zeng Zhen,
Wang Chunping,
Chang Xiujuan,
Chen Yan,
Mishra Alok,
Xu Max,
Lee MinJung,
Lee Sunmin,
Trepel Jane,
Linehan W. Marston,
Wang Xinwei,
Yang Yongping,
Neckers Len
Publication year - 2015
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.27923
Subject(s) - numb , gene knockdown , protein kinase b , biology , alternative splicing , cancer research , microbiology and biotechnology , signal transducing adaptor protein , small interfering rna , cell growth , signal transduction , gene isoform , cell culture , apoptosis , transfection , biochemistry , gene , genetics
The cell fate determinant Numb is aberrantly expressed in cancer. Numb is alternatively spliced, with one isoform containing a long proline‐rich region (PRR L ) compared to the other with a short PRR (PRR S ). Recently, PRR L was reported to enhance proliferation of breast and lung cancer cells. However, the importance of Numb alternative splicing in hepatocellular carcinoma (HCC) remains unexplored. We report here that Numb PRR L expression is increased in HCC and associated with early recurrence and reduced overall survival after surgery. In a panel of HCC cell lines, PRR L generally promotes and PRR S suppresses proliferation, migration, invasion, and colony formation. Knockdown of PRR S leads to increased Akt phosphorylation and c‐Myc expression, and Akt inhibition or c‐Myc silencing dampens the proliferative impact of Numb PRR S knockdown. In the cell models explored in this study, alternative splicing of Numb PRR isoforms is coordinately regulated by the splicing factor RNA‐binding Fox domain containing 2 (RbFox2) and the kinase serine/arginine protein–specific kinase 2 (SRPK2). Knockdown of the former causes accumulation of PRR L , while SRPK2 knockdown causes accumulation of PRR S . The subcellular location of SRPK2 is regulated by the molecular chaperone heat shock protein 90, and heat shock protein 90 inhibition or knockdown phenocopies SRPK2 knockdown in promoting accumulation of Numb PRR S . Finally, HCC cell lines that predominantly express PRR L are differentially sensitive to heat shock protein 90 inhibition. Conclusion : Alternative splicing of Numb may provide a useful prognostic biomarker in HCC and is pharmacologically tractable. (H epatology 2015;62:1122‐1131)