Paradoxical overexpression of MBNL2 in hepatocellular carcinoma inhibits tumor growth and invasion
Journal
Oncotarget
Journal Volume
7
Journal Issue
40
Pages
65589-65601
Date Issued
2016
Author(s)
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.
SDGs
Other Subjects
octamer transcription factor 4; transcription factor NANOG; transcription factor Sox2; MBNL2 protein, human; RNA binding protein; tumor marker; adult; alternative RNA splicing; animal experiment; animal model; Article; cancer staging; cancer survival; carcinogenicity; cell differentiation; cell proliferation; chemoembolization; controlled study; female; gene overexpression; human; human tissue; immunohistochemistry; liver carcinogenesis; liver cell; liver cell carcinoma; liver parenchyma; liver regeneration; major clinical study; male; MBNL2 gene; mouse; nonhuman; oncogene; open reading frame; overall survival; protein depletion; protein localization; protein secretion; real time polymerase chain reaction; RNA interference; transcriptomics; tumor growth; tumor volume; animal; apoptosis; C57BL mouse; cell proliferation; cytology; drug screening; embryonic stem cell; follow up; liver cell carcinoma; liver resection; liver tumor; metabolism; middle aged; nonobese diabetic mouse; pathology; prognosis; retrospective study; SCID mouse; survival rate; tumor cell culture; tumor invasion; Animals; Apoptosis; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Proliferation; Embryonic Stem Cells; Female; Follow-Up Studies; Hepatectomy; Humans; Liver Neoplasms; Liver Regeneration; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Middle Aged; Neoplasm Invasiveness; Prognosis; Retrospective Studies; RNA-Binding Proteins; Survival Rate; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
Publisher
Impact Journals LLC
Type
journal article