title: Upregulation of miR-27a contributes to the malignant transformation of human bronchial epithelial cells induced by SV40 small T antigen.
abstract: 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.
authors: Department of Toxicology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, China.
authors: Q
authors: Q
authors: Wang
authors: D-C
authors: DC
authors: Li
authors: Z-F
authors: ZF
authors: Li
authors: C-X
authors: CX
authors: Liu
authors: Y-M
authors: YM
authors: Xiao
authors: B
authors: B
authors: Zhang
authors: X-D
authors: XD
authors: Li
authors: J
authors: J
authors: Zhao
authors: L-P
authors: LP
authors: Chen
authors: X-M
authors: XM
authors: Xing
authors: S-F
authors: SF
authors: Tang
authors: Y-C
authors: YC
authors: Lin
authors: Y-D
authors: YD
authors: Lai
authors: P
authors: P
authors: Yang
authors: J-L
authors: JL
authors: Zeng
authors: Q
authors: Q
authors: Xiao
authors: X-W
authors: XW
authors: Zeng
authors: Z-N
authors: ZN
authors: Lin
authors: Z-X
authors: ZX
authors: Zhuang
authors: S-M
authors: SM
authors: Zhuang
authors: W
authors: W
authors: Chen
mesh_terms: D000818:Animals; D000957:Antigens, Viral, Tumor / Q000378:metabolism; D001980:Bronchi / Q000166:cytology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000166:cytology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000378:metabolism*; D015398:Signal Transduction; D013539:Simian virus 40 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000957:Antigens, Viral, Tumor; C531388:MIRN27 microRNA, human; D035683:MicroRNAs