Journal Article

Upregulation of miR-27a contributes to the malignant transformation of human bronchial epithelial cells induced by SV40 small T antigen

Li, Z-F, Tang, S-F, Zeng, J-L, Chen, L-P, Xiao, Y-M, Xiao, Q, Liu, C-X, Zhao, J, Li, D-C, Zhuang, S-M, Lin, Z-N, Chen, W, Lin, Y-C, Xing, X-M, Yang, P, Lai, Y-D, Zhang, B, Zeng, X-W, Wang, Q, Li, X-D, Zhuang, Z-X

2011

Overview

The introduction of the Simian virus 40 (SV40) early region, the telomerase catalytic subunit ( hTERT ) and an oncogenic allele of H-Ras directly transforms primary human cells. SV40 small T antigen (ST), which forms a complex with protein phosphatase 2A (PP2A) and inhibits PP2A activity, is believed to have a critical role in the malignant transformation of human cells. Recent evidence has shown that aberrant microRNA (miRNA) expression patterns are correlated with cancer development. Here, we identified miR-27a as a differentially expressed miRNA in SV40 ST-expressing cells. miR-27a is upregulated in SV40 ST-transformed human bronchial epithelial cells (HBERST). Suppression of miR-27a expression in HBERST cells or lung cancer cell lines (NCI-H226 and SK-MES-1) that exhibited high levels of miR-27a expression lead to cell growth arrested in the G 0 –G 1 phase. In addition, suppression of miR-27a in HBERST cells attenuated the capacity of such cells to grow in an anchorage-independent manner. We also found that suppression of the PP2A B56γ expression resulted in upregulation of miR-27a similar to that achieved by the introduction of ST, indicating that dysregulation of miR-27a expression in ST-expressing cells was mediated by the ST–PP2A interaction. Moreover, we discovered that Fbxw7 gene encoding F-box/WD repeat-containing protein 7 was a potential miR-27a target validated by dual-luciferase reporter system analysis. The inverse correlation between miR-27a expression levels and Fbxw7 protein expression was further confirmed in both cell models and human tumor samples. Fbxw7 regulates cell-cycle progression through the ubiquitin-dependent proteolysis of a set of substrates, including c-Myc, c-Jun, cyclin E1 and Notch 1. Thus, promotion of cell growth arising from the suppression of Fbxw7 by miR-27a overexpression might be responsible for the viral oncoprotein ST-induced malignant transformation. These observations demonstrate that miR-27a functions as an oncogene in human tumorigenesis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/200 / 631/337/384/331 / 692/420/755 / Animals / Antigens / Antigens, Viral, Tumor - metabolism / Apoptosis / Biological and medical sciences / Bronchi - cytology / c-Jun protein / c-Myc protein / Cdc4 protein / Cell Biology / Cell culture / Cell growth / Cell Line, Tumor / Cell physiology / Cell Proliferation / Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes / Cell Transformation, Neoplastic / Cells / Cyclins / Early region / Epigenesis, Genetic / Epithelial cells / Epithelial Cells - cytology / Fundamental and applied biological sciences. Psychology / G1 phase / Gene Expression Regulation, Neoplastic / Genetic transformation / H-Ras protein / Human Genetics / Humans / Internal Medicine / Lung cancer / Medicine / Medicine & Public Health / Mice / Mice, SCID / MicroRNAs / MicroRNAs - metabolism / miRNA / Molecular and cellular biology / Monkeys & apes / Myc protein / Notch protein / Notch1 protein / Oncogenes / Oncology / original-article / Phosphoprotein phosphatase / Protein phosphatase / Proteins / Proteolysis / Signal Transduction / Simian virus 40 / Simian virus 40 - metabolism / Telomerase / Telomerase reverse transcriptase / Transcription factors / Transformation / Tumor cell lines / Tumorigenesis / Ubiquitin / Up-Regulation