Hexavalent Chromium Induces Malignant Transformation of Human Lung Bronchial Epithelial Cells Via ROS-Dependent Activation of miR-21-PDCD4 Signaling

Authors

Poyil Pratheeshkumar, University of KentuckyFollow
Young-Ok Son, University of KentuckyFollow
Sasidharan Padmaja Divya, University of KentuckyFollow
Lilia Turcios, University of KentuckyFollow
Ram Vinod Roy, University of KentuckyFollow
John Andrew Hitron, University of KentuckyFollow
Lei Wang, University of KentuckyFollow
Donghern Kim, University of KentuckyFollow
Jin Dai, University of KentuckyFollow
Padmaja Asha, Cochin University of Science and Technology, India
Zhuo Zhang, University of KentuckyFollow
Xianglin Shi, University of KentuckyFollow

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.

Document Type

Article

Publication Date

6-13-2016

Notes/Citation Information

Published in Oncotarget, v. 7, no. 32, p. 51193-51210.

Licensed under a Creative Commons Attribution 3.0 License.

Digital Object Identifier (DOI)

https://doi.org/10.18632/oncotarget.9967

Funding Information

This research was supported by National Institutes of Health (R01ES017244, R01ES025515) and the Biospecimen and Tissue Procurement Shared Resource Facility and the Cytometry and Cell Sorting core facility of the University of Kentucky Markey Cancer Center (National Institutes of Health Grant P30CA177558).

Repository Citation

Pratheeshkumar, Poyil; Son, Young-Ok; Divya, Sasidharan Padmaja; Turcios, Lilia; Roy, Ram Vinod; Hitron, John Andrew; Wang, Lei; Kim, Donghern; Dai, Jin; Asha, Padmaja; Zhang, Zhuo; and Shi, Xianglin, "Hexavalent Chromium Induces Malignant Transformation of Human Lung Bronchial Epithelial Cells Via ROS-Dependent Activation of miR-21-PDCD4 Signaling" (2016). Center for Research on Environmental Disease Faculty Publications. 4.
https://uknowledge.uky.edu/environmental_disease_facpub/4