The key regulator circ_0003295 promotes arsenic-induced lung carcinogenesis and progression by enhancing mitochondrial function

Long-term exposure to arsenic increases the risk of multiple types of tumors, including lung tumors. Furthermore, circular RNAs (circRNAs), key participants in epigenetic regulation, play important roles in cancer initiation and progression. However, the molecular mechanisms by which circRNAs are involved in arsenic-induced lung carcinogenesis and progression remain incompletely understood. In this study, arsenic-induced malignantly transformed cells with stable silencing and overexpression of circ_0003295 were established. A series of functional experiments performed following prolonged low-dose arsenic exposure revealed that arsenic exposure upregulated the expression of circ_0003295. circ_0003295 promoted cell proliferation and inhibited apoptosis in arsenic-induced malignantly transformed cells. Through assays including RNA immunoprecipitation (RIP), co-immunoprecipitation (Co-IP), and immunofluorescence (IF) staining, the underlying molecular mechanism was elucidated, whereby circ_0003295 regulates the mTOR/PGC-1α signalling pathway by upregulating HSPA8 protein expression through inhibiting the ubiquitin-proteasome degradation pathway, to enhance mitochondrial function and promote arsenic-induced lung carcinogenesis and malignant progression. In conclusion, this study reveals the pivotal role of circ_0003295 in promoting arsenic-induced lung carcinogenesis and progression by enhancing mitochondrial function during arsenic exposure. This study highlights the importance of gene-environment interactions in disease progression and provides novel insights into the molecular mechanisms of circRNAs in chemical carcinogenesis.