摘要
Arsenic is a widespread carcinogen and an important etiological factor for lung cancer. Dysregulated miRNAs have been implicated in arsenic carcinogenesis and the mechanisms of arsenic-induced dysregulated miRNAs have not been fully elucidated. N 6 -methyladenosine (m 6 A) modification is known to modulate pri-miRNA processing. However, whether m 6 A-mediated pri-miRNA processing is involved in arsenic carcinogenesis is poorly understood. Here, we found that m 6 A modification was significantly increased in arsenite-transformed human bronchial epithelial BEAS-2B cells (0.5 µM arsenite, 16 weeks). Meanwhile, METTL3 was significantly upregulated at week 12 and 16 during cell transformation. The proliferation, migration, invasion, and anchorage-independent growth of arsenite-transformed cells were inhibited by the reduction of m 6 A levels through METTL3 knockdown. Further experiments suggest that the oncogene miR-106b-5p is a potentially essential m 6 A target mediating arsenic-induced lung cancer. miR-106b-5p was observed to be upregulated after exposure to arsenite for 12 and 16 weeks, and the reduction of m 6 A levels caused by METTL3 knockdown inhibited miR-106b-5p maturation in arsenite-transformed cells. What’s more, miR-106b-5p overexpression successfully rescued METTL3 knockdown-induced inhibition of the neoplastic phenotypes of transformed cells. Additionally, Basonuclin 2 (BNC2) was uncovered as a potential target of miR-106b-5p and downregulated by METTL3 via enhancing miR-106b-5p maturation. Additionally, the METTL3 inhibitor STM2457 suppressed neoplastic phenotypes of arsenite-transformed BEAS-2B cells by blocking pri-miR-106b methylation. These results demonstrate that m 6 A modification promotes the neoplastic phenotypes of arsenite-transformed BEAS-2B cells through METTL3/miR-106b-5p/BNC2 pathway, providing a new prospective for understanding arsenic carcinogenesis.
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