Chromium contributes to human bronchial epithelial cell carcinogenesis by activating Gli2 and inhibiting autophagy.

Occupational and environmental inhalation exposure to hexavalent chromium [Cr(vi)] compounds has been confirmed to cause respiratory system injury and cancer. The molecular mechanisms of chromium carcinogenesis still require further study. We established Cr(vi)-transformed cells (BEAS-2B-Cr) after chronic exposure of immortalized normal human bronchial epithelial BEAS-2B cells to low doses of Cr(vi), which obtained the ability of anchorage-independent growth. BEAS-2B-Cr cells not only exhibited stronger proliferation, migration, invasion and tumorigenesis capabilities but also acquired an altered and distinct Gli2 gene expression pattern compared with untreated parental BEAS-2B cells (P-NC) and the control BEAS-2B cells (NC). Interestingly, we found that activation of Gli2 by Cr(vi) treatment prevented the induction of autophagy. Using a gene silencing approach, we showed that Gli2 plays an important role in the malignant properties of BEAS-2B-Cr cells. Downregulation of Gli2 induced autophagy and inhibited cell proliferation and colony forming abilities, which are both upregulated in BEAS-2B-Cr cells compared to NC cells. In addition, inhibition of autophagy by 3-methyladenine (3-MA) partially suppressed the cytotoxicity induced by GANT61-induced inhibition of Gli2. These results demonstrate that hexavalent chromium Cr(vi) activates Gli2 to promote the proliferation of BEAS-2B-Cr cells by inhibition of autophagy, which contributes to human bronchial epithelial cell carcinogenesis. Gli2 may not only play an important role in lung cancer pathogenesis, but also be a promising early indicator in monitoring exposure to chromium.