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The pivotal regulatory factor circ_0006956 promotes arsenic-induced lung carcinogenesis by enhancing the Warburg
Deqing Li1, Xiaodong Zhou1, Dunyu Cai1
1School of Public Health, Guangxi Medical University, Nanning, 530021, China; Guangxi Key Laboratory of Environment and Health Research, Guangxi Medical University, Nanning, 530021, China; Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, 530021, China.
Abstract:
Arsenic (As) is a widespread environmental carcinogen. Long-term exposure to arsenic significantly increases the risk of lung cancer. In recent years, circRNAs have attracted widespread attention because of their crucial roles in tumorigenesis and development. However, the specific molecular mechanisms by which circRNAs promote lung carcinogenesis after arsenic exposure remain incompletely elucidated. This study revealed that the expression of circ_0006956 was significantly upregulated during the arsenic-induced malignant transformation of BEAS-2B cells and promoted the malignant transformation process. BEAS-2B cells stably overexpressing circ_0006956 were established and were then continuously exposed to 0.75 μM NaAsO2 for up to 40 passages. The results of functional assays indicated that circ_0006956 promoted cell proliferation and inhibited apoptosis, thereby accelerating the arsenic-induced malignant transformation of BEAS-2B cells. Mechanistically, arsenic exposure increased the cytoplasmic expression of circ_0006956, significantly promoting its direct binding to the PI3K mRNA. This interaction further increased PI3K mRNA stability, promoted PI3K expression, led to the excessive activation of the PI3K/AKT signalling pathway, significantly increased glycolysis, and ultimately promotes arsenic-induced lung carcinogenesis. This study revealed a pivotal role in circ_0006956 in increasing glycolysis via the PI3K/AKT signalling pathway, thereby promoting arsenic-induced lung carcinogenesis. These findings provide novel insights for early diagnosis and potential therapeutic strategies for lung cancer.
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