Reactivated telomerase is a crucial event in the development and progression of a variety of tumors. However, how telomerase is activated in gastric carcinogenesis has not been fully uncovered yet. Here, we identified a key role of the NF-κB/LIN28A/let-7a axis to promote human telomerase reverse transcriptase (hTERT) expression for gastric cancer initiation. Mechanistically, LIN28A expression was upregulated by H. pylori–induced NF-κB activation. And LIN28A, in turn, suppressed let-7a expression, forming the NF-κB/LIN28A/let-7a axis to regulate gene expression upon H. pylori infection. Of note, we first discovered hTERT as a direct target of let-7a, which inhibited hTERT expression by binding to its 3′UTR of mRNA. Therefore, H. pylori–triggered let-7a downregulation enhanced hTERT protein translation, resulting in telomerase reactivation. Furthermore, hTERT enhanced LIN28A expression, forming the positive feedback regulation between hTERT and NF-κB/LIN28A/let-7a axis to maintain the sustained overexpression of hTERT in gastric cancer. Implications: The NF-κB/LIN28A/Let-7a axis was crucial for the overexpression of hTERT upon H. pylori infection during gastric cancer development and may serve as a potential target to suppress hTERT expression for gastric cancer prevention and treatment.

中文翻译：

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H. pylori 诱导新的 NF-κB/Lin28A/let-7a/hTERT 轴促进胃癌发生

重新激活的端粒酶是多种肿瘤发生和进展的关键事件。然而，端粒酶在胃癌发生过程中是如何被激活的尚未完全阐明。在这里，我们确定了 NF-κB/LIN28A/let-7a 轴在促进人端粒酶逆转录酶 (hTERT) 表达以促进胃癌发生方面的关键作用。从机制上讲，LIN28A 表达被幽门螺杆菌诱导的 NF-κB 激活上调。反过来，LIN28A 抑制 let-7a 表达，形成 NF-κB/LIN28A/let-7a 轴以调节幽门螺杆菌感染后的基因表达。值得注意的是，我们首先发现 hTERT 作为 let-7a 的直接靶标，它通过与 mRNA 的 3'UTR 结合来抑制 hTERT 表达。因此，幽门螺杆菌触发的 let-7a 下调增强了 hTERT 蛋白翻译，导致端粒酶重新激活。此外，hTERT 增强 LIN28A 表达，形成 hTERT 与 NF-κB/LIN28A/let-7a 轴之间的正反馈调节，以维持 hTERT 在胃癌中的持续过表达。启示：NF-κB/LIN28A/Let-7a 轴对于胃癌发展过程中幽门螺杆菌感染时 hTERT 的过表达至关重要，并且可能作为抑制 hTERT 表达的潜在靶点用于胃癌的预防和治疗。