Exposure to airborne PM 2.5 suppresses microRNA expression and deregulates target oncogenes that cause neoplastic transformation in NIH3T3 cells

// Chunling Liu 1, * , Huan Guo 2, * , Xinxin Cheng 1 , Mingming Shao 1 , Chen Wu 1 , Suhan Wang 2 , Hongmin Li 1 , Lixuan Wei 1 , Yanning Gao 1 , Wen Tan 1 , Shujun Cheng 1 , Tangchun Wu 2 , Dianke Yu 1 , Dongxin Lin 1 1 State 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 2 Department 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 Correspondence to: Dongxin Lin, e-mail: lindx@cicams.ac.cn Dianke Yu, e-mail: yudianking@gmail.com Tangchun Wu, e-mail: wut@mails.tjmu.edu.cn Keywords: PM 2.5 , microRNA expression, gene expression, bronchial epithelial cell, neoplastic transformation Received: May 25, 2015      Accepted: August 11, 2015      Published: August 21, 2015 ABSTRACT Long-term exposure to airborne PM 2.5 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 PM 2.5 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 PM 2.5 and examined the aberrant expression of genes targeted by these microRNAs in human lung cancer. Under our experimental conditions, treatment of cells with PM 2.5 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 PM 2.5 than in those exposed to low level of PM 2.5 ( 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 PM 2.5 exposure.