title: Paradoxical overexpression of MBNL2 in hepatocellular carcinoma inhibits tumor growth and invasion.
abstract: 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.
authors: Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
authors: Yu-Hsin
authors: YH
authors: Lee
authors: Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
authors: Yu-Lin
authors: YL
authors: Jhuang
authors: Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
authors: Yu-Ling
authors: YL
authors: Chen
authors: Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.|Department of Pathology, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
authors: Yung-Ming
authors: YM
authors: Jeng
authors: Department of Surgery, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei 10051, Taiwan.|Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, Taipei 10051, Taiwan.
authors: Ray-Hwang
authors: RH
authors: Yuan
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006498:Hepatectomy; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011379:Prognosis; D016601:RNA-Binding Proteins / Q000378:metabolism*; D012189:Retrospective Studies; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; C499444:MBNL2 protein, human; D016601:RNA-Binding Proteins
keywords: alternative splicing; hepatic progenitor cells; hepatocellular carcinoma; liver carcinogenesis; muscleblind proteins