Repression of miR-143/145 Mediates Chromium (VI)-induced Cell Transformation, Tumor growth and Tumor angiogenesis via IGF-IR/IRS1/ERK/IL-8
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 non-tumorigenic human lung epithelial BEAS-2B cells through long-term exposure to Cr (VI). These Cr (VI)-transformed cells displayed features of transformed cells such as increased cell proliferation, increased anchorage-independent growth and tumor formation. The proposed mechanisms of Cr carcinogenesis include sustained oxidative stress, compromised DNA repair system and microsatellite instability. Besides these genotoxic effects, a number of studies show that aberrant gene expressions are critical events for cell malignant transformation induced by Cr (VI). Deregulation of miRNA profiles were observed in various cancers, suggesting possible roles in cancer progression. Although miRNAs are involved in lung cancer as indicated by tissue miRNA microarrays, there is little information on the involvement of miRNAs in environmental carcinogenesis. In particular, it remains to be determined whether the loss or gain of certain miRNA expression leads to cell malignant transformation and tumor angiogenesis in response to chemical carcinogens. By utilizing the in vitro model, we found that miR-143 and miR-145 expression levels were dramatically repressed in Cr (VI)-transformed cells. To determine whether it has broad impact on lung cancer, we also analyzed the miR-143/145 expression in 20 lung adenocarcinomas and 13 squamous lung carcinoma tissue sections and their corresponding normal tissue sections. More than 80% of patients displayed at least two fold lower levels of miR-143 or miR-145 expression in cancer tissues compared with their matched adjacent normal tissues. Functional studies revealed that overexpression of miR-143 or miR-145 was able to inhibit cell transformation, tumor growth and tumor-induced angiogenesis. We further identified that miR-143 and miR-145 target both IGF-IR and IRS1 which were downregulated both in Cr (VI)-transformed cells and human lung cancer tissues. Ectopic expression of IGF-IR or IRS1 was able to rescue the suppressive effect of miR-143/145, suggesting that the repression of miR-143 led to Cr (VI)-induced cell malignant transformation and angiogenesis via directly inducing IGF-IR and IRS1 expression. In addition, we found that IL-8 is the major 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-143/145 in Cr (VI)-induced malignant transformation and tumor angiogenesis and provide the first link of the same molecular changes and mechanism for regulating both heavy metal-induced lung carcinogenesis and human lung cancer development. Moreover, the current study provides another potential option for IGF-IR target therapy.
Subject Area
Molecular biology|Cellular biology
Recommended Citation
He, Jun, "Repression of miR-143/145 Mediates Chromium (VI)-induced Cell Transformation, Tumor growth and Tumor angiogenesis via IGF-IR/IRS1/ERK/IL-8" (2013). ProQuest ETD Collection - Thomas Jefferson University. AAI3549788.
https://jdc.jefferson.edu/dissertations/AAI3549788
