Hexavalent chromium induces malignant transformation of human lung bronchial epithelial cells via ROS-dependent activation of miR-21-PDCD4 signaling

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// Poyil Pratheeshkumar 1, 2, * , Young-Ok Son 1, 2, * , Sasidharan Padmaja Divya 1, 2 , Lilia Turcios 3 , Ram Vinod Roy 1, 2 , John Andrew Hitron 1, 2 , Lei Wang 1, 2 , Donghern Kim 2 , Jin Dai 2 , Padmaja Asha 4 , Zhuo Zhang 2 , Xianglin Shi 1, 2 1 Center for Research on Environmental Disease, University of Kentucky, Lexington, KY, USA 2 Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA 3 Department of Surgery, University of Kentucky, College of Medicine, Lexington, KY, USA 4 National Centre for Aquatic Animal Health, Cochin University of Science and Technology, Cochin, India * These authors equally contributed to this work Correspondence to: Xianglin Shi, email: xshi5@email.uky.edu Keywords: hexavalent chromium, ROS, miR-21-PDCD4 signaling, IL-6, STAT3 Received: April 05, 2016 Accepted: May 20, 2016 Published: June 13, 2016 ABSTRACT Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with an increased risk of lung cancer. However, the mechanisms underlying Cr(VI)-induced carcinogenesis remain unclear. MicroRNA-21 (miR-21) is a key regulator of oncogenic processes. Studies have shown that miR-21 exerts its oncogenic activity by targeting the tumor suppressor gene programmed cell death 4 (PDCD4). The present study examined the role of miR-21-PDCD4 signaling in Cr(VI)-induced cell transformation and tumorigenesis. Results showed that Cr(VI) induces ROS generation in human bronchial epithelial (BEAS-2B) cells. Chronic exposure to Cr(VI) is able to cause malignant transformation in BEAS-2B cells. Cr(VI) caused a significant increase of miR-21 expression associated with an inhibition of PDCD4 expression. Notably, STAT3 transcriptional activation by IL-6 is crucial for the Cr(VI)-induced miR-21 elevation. Stable knockdown of miR-21 or overexpression of PDCD4 in BEAS-2B cells significantly reduced the Cr(VI)-induced cell transformation. Furthermore, the Cr(VI) induced inhibition of PDCD4 suppressed downstream E-cadherin protein expression, but promoted β-catenin/TCF-dependent transcription of uPAR and c-Myc. We also found an increased miR-21 level and decreased PDCD4 expression in xenograft tumors generated with chronic Cr(VI)-exposed BEAS-2B cells. In addition, stable knockdown of miR-21 and overexpression of PDCD4 reduced the tumorogenicity of chronic Cr(VI)-exposed BEAS-2B cells in nude mice. Taken together, these results demonstrate that the miR-21-PDCD4 signaling axis plays an important role in Cr(VI)-induced carcinogenesis.