Chronic exposure to environmental carcinogens is a major cause of tumorigenesis. A potent tobacco-specific nitrosamine carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), exhibits high carcinogenicity to induce lung cancer. However, the function and mechanism of circular RNA (circRNA) in chemical carcinogenesis, especially the regulation of circRNA formation upon exposure to environmental chemicals, remain unclear. This study identified that circPRMT10 (hsa_circ_0009048) was downregulated in NNK-exposed human bronchial epithelial cells (16HBE and BEAS-2B). Additionally, the RNA-binding protein Quaking (QKI) was responsible for the biogenesis of circPRMT10 through its binding interaction with the flanking introns of circPRMT10. Moreover, NNK exposure resulted in hypermethylation of the QKI promoter, leading to QKI downregulation, which ultimately affected circPRMT10 formation. Using a cell model of chronic exposure to low-dose NNK, we found that overexpression of circPRMT10 significantly inhibited NNK-induced lung carcinogenesis by suppressing cell proliferation, cell cycle progression, and xenograft tumor growth. Finally, moesin (MSN) was identified as a downstream target of circPRMT10 via RNA pull-down and western blot assays and demonstrated a potential role in the regulation of lung cancer development. In conclusion, our findings reveal the underlying mechanisms of circRNA biogenesis following exposure to chemical carcinogens, providing novel insights into the role of circRNAs in chemical carcinogenesis.

中文翻译：

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QKI 高甲基化调控的 circPRMT10 减弱烟草致癌物 NNK 诱导的肺肿瘤发生


长期暴露于环境致癌物是肿瘤发生的主要原因。4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮 （NNK） 是一种强效烟草特异性亚硝胺致癌物，对诱发肺癌具有很高的致癌性。然而，环状 RNA （circRNA） 在化学致癌作用中的功能和机制，尤其是暴露于环境化学物质后对 circRNA 形成的调节仍不清楚。本研究发现 circPRMT10 （hsa_circ_0009048） 在 NNK 暴露的人支气管上皮细胞 （16HBE 和 BEAS-2B） 中下调。此外，RNA 结合蛋白 Quaking （QKI） 通过与 circPRMT10 侧翼内含子的结合相互作用负责 circPRMT10 的生物发生。此外，NNK 暴露导致 QKI 启动子高甲基化，导致 QKI 下调，最终影响 circPRMT10 的形成。使用长期暴露于低剂量 NNK 的细胞模型，我们发现 circPRMT10 的过表达通过抑制细胞增殖、细胞周期进程和异种移植肿瘤生长显着抑制 NNK 诱导的肺癌发生。最后，通过 RNA pull-down 和 western blot 测定将 moesin （MSN） 确定为 circPRMT10 的下游靶标，并显示出在肺癌发展调节中的潜在作用。总之，我们的研究结果揭示了暴露于化学致癌物后 circRNA 生物发生的潜在机制，为 circRNA 在化学致癌作用中的作用提供了新的见解。