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.
©2020 American Association for Cancer Research.