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: Q Wang, D-C Li, Z-F Li, C-X Liu, Y-M Xiao, B Zhang, X-D Li, J Zhao, L-P Chen, X-M Xing, S-F Tang, Y-C Lin, Y-D Lai, P Yang, J-L Zeng, Q Xiao, X-W Zeng, Z-N Lin, Z-X Zhuang, S-M Zhuang, W Chen
• Journal: Oncogene (Oncogene) Vol. 30 Issue 36 Pg. 3875-86 (Sep 08 2011) ISSN: 1476-5594 [Electronic] England
• PMID: 21460851 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Viral, Tumor
• MIRN27 microRNA, human
• MicroRNAs

Topics

• Animals
• Antigens, Viral, Tumor (metabolism)
• Bronchi (cytology)
• Cell Line, Tumor
• Cell Proliferation
• Cell Transformation, Neoplastic
• Epigenesis, Genetic
• Epithelial Cells (cytology)
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• Mice, SCID
• MicroRNAs (metabolism)
• Signal Transduction
• Simian virus 40 (metabolism)
• Up-Regulation