Paradoxical overexpression of MBNL2 in hepatocellular carcinoma inhibits tumor growth and invasion
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Yu-Hsin Lee1, Yu-Lin Jhuang1, Yu-Ling Chen1, Yung-Ming Jeng1,2, Ray-Hwang Yuan3,4
1Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan
2Department of Pathology, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei 10051, Taiwan
3Department of Surgery, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei 10051, Taiwan
4Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, Taipei 10051, Taiwan
Yung-Ming Jeng, email: firstname.lastname@example.org
Ray-Huang Yuan, email: email@example.com
Keywords: hepatocellular carcinoma, alternative splicing, muscleblind proteins, hepatic progenitor cells, liver carcinogenesis
Received: June 03, 2016 Accepted: August 12, 2016 Published: August 24, 2016
Pre-mRNA alternative splicing is an essential step in the process of gene expression. It provides cells with the opportunity to create various protein isoforms. Disruptions of alternative splicing are associated with various diseases, including cancer. The muscleblind-like (MBNL) protein is a splicing regulatory protein. Overexpression of MBNL proteins in embryonic stem cells promotes differentiated cell-like alternative splicing patterns. We examined the expression level of MBNL2 in 143 resected HCCs using immunohistochemistry. MBNL2 was overexpressed in 51 (35.7%) HCCs. The overexpression of MBNL2 correlated with smaller tumor size (≤ 3 cm, P = 0.0108) and low tumor stage (Stage I, P = 0.0026), indicating that MBNL2 expression was lost in the late stage of HCC development. Furthermore, patients with MBNL2-positive HCCs had a borderline better 5-year overall survival (P = 0.0579). In non-cancerous liver parenchyma, MBNL2 was stained on the Canals of Hering and hepatocytes newly derived from hepatic progenitor cells. The overexpression of MBNL2 in Hep-J5 cells suppressed proliferation, tumorsphere formation, migration, and in vitro invasion, and also reduced in vivo tumor growth in NOD/SCID mice. In contrast, MBNL2 depletion with RNA interference in Huh7 cells increased in vitro migration and invasion, but did not enhance tumor growth. These results indicate that MBNL2 is a tumor suppressor in hepatocarcinogenesis.
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