Exposure to airborne PM2.5 suppresses microRNA expression and deregulates target oncogenes that cause neoplastic transformation in NIH3T3 cells
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Chunling Liu1,*, Huan Guo2,*, Xinxin Cheng1, Mingming Shao1, Chen Wu1, Suhan Wang2, Hongmin Li1, Lixuan Wei1, Yanning Gao1, Wen Tan1, Shujun Cheng1, Tangchun Wu2, Dianke Yu1, Dongxin Lin1
1State Key Laboratory of Molecular Oncology and Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
2Department of Occupational and Environmental Health and Ministry of Education Key Lab for Environment and Health, School of Public Health, Huazhong University of Sciences and Technology, Wuhan, China
*These authors have contributed equally to this work
Dongxin Lin, e-mail: [email protected]
Dianke Yu, e-mail: [email protected]
Tangchun Wu, e-mail: [email protected]
Keywords: PM2.5, microRNA expression, gene expression, bronchial epithelial cell, neoplastic transformation
Received: May 25, 2015 Accepted: August 11, 2015 Published: August 21, 2015
Long-term exposure to airborne PM2.5 is associated with increased lung cancer risk but the underlying mechanism remains unclear. We characterized global microRNA and mRNA expression in human bronchial epithelial cells exposed to PM2.5 organic extract and integrally analyzed microRNA-mRNA interactions. Foci formation and xenograft tumorigenesis in mice with NIH3T3 cells expressing genes targeted by microRNAs were performed to explore the oncogenic potential of these genes. We also detected plasma levels of candidate microRNAs in subjects exposed to different levels of air PM2.5 and examined the aberrant expression of genes targeted by these microRNAs in human lung cancer. Under our experimental conditions, treatment of cells with PM2.5 extract resulted in downregulation of 138 microRNAs and aberrant expression of 13 mRNAs (11 upregulation and 2 downregulation). In silico and biochemical analyses suggested SLC30A1, SERPINB2 and AKR1C1, among the upregulated genes, as target for miR-182 and miR-185, respectively. Ectopic expression of each of these genes significantly enhanced foci formation in NIH3T3 cells. Following subcutaneous injection of these cells into nude mice, fibrosarcoma were formed from SLC30A1- or SERPINB2-expressing cells. Reduced plasma levels of miR-182 were detected in subjects exposed to high level of PM2.5 than in those exposed to low level of PM2.5 (P = 0.043). Similar results were seen for miR-185 although the difference was not statistically significant (P = 0.328). Increased expressions of SLC30A1, SERPINB2 and AKR1C1 were detected in human lung cancer. These results suggest that modulation of miR-182 and miR-185 and their target genes may contribute to lung carcinogenesis attributable to PM2.5 exposure.
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