title: Repression of miR-143 mediates Cr (VI)-induced tumor angiogenesis via IGF-IR/IRS1/ERK/IL-8 pathway.
abstract: 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.
authors.affiliation: Department of Pathology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: He
authors.forename: Xu
authors.initials: X
authors.lastname: Qian
authors.forename: Richard
authors.initials: R
authors.lastname: Carpenter
authors.forename: Qing
authors.initials: Q
authors.lastname: Xu
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Yanting
authors.initials: Y
authors.lastname: Qi
authors.forename: Zi-Xuan
authors.initials: ZX
authors.lastname: Wang
authors.forename: Ling-Zhi
authors.initials: LZ
authors.lastname: Liu
authors.forename: Bing-Hua
authors.initials: BH
authors.lastname: Jiang
mesh_terms: D000818:Animals; D002274:Carcinogens, Environmental / Q000633:toxicity*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002857:Chromium / Q000633:toxicity*; D015536:Down-Regulation; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis; D015854:Up-Regulation
chemical_list: D002274:Carcinogens, Environmental; D055504:Insulin Receptor Substrate Proteins; D016209:Interleukin-8; C526295:Irs1 protein, mouse; C542359:MIRN143 microRNA, human; D035683:MicroRNAs; D002857:Chromium; C074702:chromium hexavalent ion; D017526:Receptor, IGF Type 1
keywords: IGF-IR/IRS1; chromium (VI); lung cancer; miR-143; tumor angiogenesis.