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 non-tumorigenic 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 up-regulation of IGF-IR and IRS1 expression. Moreover, we found that IL-8 is the major upregulated angiogenesis factor induced by Cr (VI) through activation of IGF-IR/IRS1 axis followed by activation of downstream ERK/HIF/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.