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 Pratheeshkumar1,2,*, Young-Ok Son1,2,*, Sasidharan Padmaja Divya1,2, Lilia Turcios3, Ram Vinod Roy1,2, John Andrew Hitron1,2, Lei Wang1,2, Donghern Kim2, Jin Dai2, Padmaja Asha4, Zhuo Zhang2, Xianglin Shi1,2
1Center for Research on Environmental Disease, University of Kentucky, Lexington, KY, USA
2Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA
3Department of Surgery, University of Kentucky, College of Medicine, Lexington, KY, USA
4National Centre for Aquatic Animal Health, Cochin University of Science and Technology, Cochin, India
*These authors equally contributed to this work
Xianglin Shi, email: [email protected]
Keywords: hexavalent chromium, ROS, miR-21-PDCD4 signaling, IL-6, STAT3
Received: April 05, 2016 Accepted: May 20, 2016 Published: June 13, 2016
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.
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