Tiam1 up-regulation by long non-coding RNA ABHD11-AS1 sponging of miR-182-5p causes β-catenin pathway activation to promote hexavalent chromium lung carcinogenesis.

Lung cancer is the deadliest cancer worldwide; however, its pathogenesis remains incompletely understood. Cigarette smoking is the principal risk factor for lung cancer, however, approximately 20 % of lung cancer cases occur in non-smokers, suggesting that additional etiological factors play important roles. Hexavalent chromium [Cr(VI)] is identified as a lung carcinogen and constitutes a significant etiological factor. This study explored the mechanisms of Cr(VI)-induced lung cancer using cell culture systems and genetically modified mouse models. Chronic Cr(VI) exposure upregulated the long non-coding RNA (lncRNA) ABHD11-AS1, which functions as a sponge for miR-182-5p causing its downregulation. MiR-182-5p downregulation increased the expression of its target gene, Tiam1. By using gain-of-function approaches, it was determined that miR-182-5p downregulation and Tiam1 upregulation contribute significantly to Cr(VI)-induced cell transformation and tumorigenesis. Furthermore, Tiam1 knockout abolished Cr(VI)-induced lung carcinogenesis in mice. Mechanistic studies revealed that Cr(VI)-activated Tiam1/Rac signaling inhibits glycogen synthase kinase 3 (GSK3), resulting in β-catenin stabilization, nuclear translocation, and transcriptional activation. These findings underscore the pivotal contribution of Tiam1 upregulation to lung cancer development. Given the pivotal role of β-catenin in oncogenesis, we conclude that ABHD11-AS1-mediated sponging of miR-182-5p leads to Tiam1 upregulation and β-catenin pathway activation, thereby promoting Cr(VI)-induced pulmonary carcinogenesis.