H. pylori induces a novel NF-κB/Lin28A/let-7a/hTERT axis to promote gastric carcinogenesis.

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 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 39UTR 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 GC. Implications: NF-κB/Lin28A/Let-7a axis was crucial for the overexpression of hTERT upon H. pylori infection during GC development and may serve as a potential target to suppress hTERT expression for GC prevention and treatment.