Abstract

3-Methylcholanthracene (3-MC) is one of the most carcinogenic polycyclic aromatic hydrocarbons (PAHs). Long-term exposure to PAHs has been thought of as an important factor in urothelial tumorigenesis. N⁶-methyladenosine (m⁶A) exists widely in eukaryotic organisms and regulates the expression level of specific genes by regulating mRNA stability, translation efficiency, and nuclear export efficiency. Currently, the potential molecular mechanisms that regulate m⁶A modification for 3-MC carcinogenesis remain unclear. Here, we profiled mRNA, m⁶A, translation and protein level using “-omics” methodologies, including transcriptomes, m⁶A profile, translatomes, and proteomics in 3-MC-transformed urothelial cells and control cells. The key molecules SLC3A2/SLC7A5 were screened and identified in 3-MC-induced uroepithelial transformation. Moreover, SLC7A5/SLC3A2 promoted uroepithelial cells malignant phenotype in vitro and in vivo. Mechanically, METTL3 and ALKBH5 mediated m⁶A modification of SLC3A2/SLC7A5 mRNA in 3-MC-induced uroepithelial transformation by upregulating the translation of SLC3A2/SLC7A5. Furthermore, programmable m⁶A modification of SLC3A2/SLC7A5 mRNA affected the expression of its proteins. Taken together, our results revealed that the m⁶A modification-mediated SLC3A2/SLC7A5 translation promoted 3-MC-induced uroepithelial transformation, suggesting that targeting m⁶A modification of SLC3A2/SLC7A5 may be a potential therapeutic strategy for bladder cancer related to PAHs.

中文翻译：

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m6A 修饰介导 3-甲基胆蒽诱导的尿路上皮转化中的 SLC3A2/SLC7A5 翻译

摘要

3-甲基胆蒽（3-MC）是致癌性最强的多环芳烃（PAH）之一。长期接触多环芳烃被认为是尿路上皮肿瘤发生的一个重要因素。N ⁶ -甲基腺苷(m ⁶ A)广泛存在于真核生物中，通过调节mRNA稳定性、翻译效率和核输出效率来调节特定基因的表达水平。^{目前，调节 m 6} A 修饰促进 3-MC 致癌的潜在分子机制仍不清楚。在这里，我们使用“组学”方法对 3-MC 转化的尿路上皮细胞和对照细胞中的 mRNA、m 6 A、翻译和蛋白质水平进行了分析，包括转录组、m ^{6 A}谱、翻译组和蛋白质组。筛选并鉴定了3-MC诱导的尿路上皮转化中的关键分子SLC3A2/SLC7A5。此外，SLC7A5/SLC3A2在体外和体内促进尿上皮细胞恶性表型。从机械角度来说，METTL3 和 ALKBH5通过上调 SLC3A2/SLC7A5 的翻译，介导 3-MC 诱导的尿路上皮转化中 SLC3A2/SLC7A5 mRNA 的m ^{6 A 修饰。}此外，SLC3A2/SLC7A5 mRNA 的可编程 m ⁶ A 修饰影响其蛋白质的表达。综上所述，我们的结果表明，m ⁶ A 修饰介导的 SLC3A2/SLC7A5 翻译促进了 3-MC 诱导的尿上皮转化，表明针对 SLC3A2/SLC7A5 的 m ⁶ A 修饰可能是与 PAH 相关的膀胱癌的潜在治疗策略。