Journal Article

Repression of miR-143 Mediates Cr (VI)–Induced Tumor Angiogenesis via IGF-IR/IRS1/ERK/IL-8 Pathway

Jun He, Xu Qian, Richard Carpenter, Qing Xu, Lin Wang, Yanting Qi, Zi-Xuan Wang, Ling-Zhi Liu and Bing-Hua Jiang

in Toxicological Sciences

Volume 134, issue 1, pages 26-38
Published in print July 2013 | ISSN: 1096-6080
Published online June 2013 | e-ISSN: 1096-0929 | DOI: https://dx.doi.org/10.1093/toxsci/kft101
Repression of miR-143 Mediates Cr (VI)–Induced Tumor Angiogenesis via IGF-IR/IRS1/ERK/IL-8 Pathway

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Hexavalent chromium [Cr (VI)] is a well-known human carcinogen associated with the increased risk of lung cancer. However, the mechanism underlying the Cr (VI)–induced carcinogenesis remains unclear due to the lack of suitable experimental models. In this study, we developed an in vitro model by transforming nontumorigenic human lung epithelial BEAS-2B cells through long-term exposure to Cr (VI). By utilizing this model, we found that miR-143 expression levels were dramatically repressed in Cr (VI)–transformed cells. The repression of miR-143 led to Cr (VI)–induced cell malignant transformation and angiogenesis via upregulation of insulin-like growth factor-1 receptor (IGF-IR) and insulin receptor substrate-1 (IRS1) expression. Moreover, we found that interleukin-8 is the major upregulated angiogenesis factor induced by Cr (VI) through activation of IGF-IR/IRS1 axis followed by activation of downstream ERK/hypoxia-induced factor-1α/NF-κB signaling pathway. These findings establish a causal role and mechanism of miR-143 in regulating Cr (VI)–induced malignant transformation and tumor angiogenesis.

Keywords: chromium (VI); miR-143; lung cancer; IGF-IR/IRS1; tumor angiogenesis.

Journal Article.  7114 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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