Hexavalent chromium induces malignant transformation of human lung bronchial epithelial cells via ROS-dependent activation of miR-21-PDCD4 signaling.
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.
Center for Research on Environmental Disease, University of Kentucky, Lexington, KY, USA.|Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA.
Poyil
P
Pratheeshkumar
Center for Research on Environmental Disease, University of Kentucky, Lexington, KY, USA.|Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA.
Young-Ok
YO
Son
Center for Research on Environmental Disease, University of Kentucky, Lexington, KY, USA.|Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA.
Sasidharan Padmaja
SP
Divya
Department of Surgery, University of Kentucky, College of Medicine, Lexington, KY, USA.
Lilia
L
Turcios
Center for Research on Environmental Disease, University of Kentucky, Lexington, KY, USA.|Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA.
Ram Vinod
RV
Roy
Center for Research on Environmental Disease, University of Kentucky, Lexington, KY, USA.|Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA.
John Andrew
JA
Hitron
Center for Research on Environmental Disease, University of Kentucky, Lexington, KY, USA.|Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA.
Lei
L
Wang
Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA.
Donghern
D
Kim
Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA.
Jin
J
Dai
National Centre for Aquatic Animal Health, Cochin University of Science and Technology, Cochin, India.
Padmaja
P
Asha
Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA.
Zhuo
Z
Zhang
Center for Research on Environmental Disease, University of Kentucky, Lexington, KY, USA.|Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA.
Xianglin
X
Shi
D000072283:A549 Cells; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002857:Chromium / Q000633:toxicity*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology*; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; C114487:PDCD4 protein, human; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D002857:Chromium; C074702:chromium hexavalent ion
IL-6; ROS; STAT3; hexavalent chromium; miR-21-PDCD4 signaling