Bussière Françoise I, Michel Valérie, Fernandes Julien, Costa Lionel, Camilo Vania, Nigro Giulia, De Reuse Hilde, Fiette Laurence, Touati Eliette
Institut Pasteur, Unit of Helicobacter Pathogenesis, CNRS ERL6002, 25-28 Rue du Dr Roux, 75724 Paris cedex 15, France.
Institut Pasteur, Unit of Molecular Microbial Pathogenesis, INSERM U1202, 25-28 Rue du Dr Roux, 75724 Paris cedex 15, France.
J Oncol. 2019 Dec 31;2019:5415761. doi: 10.1155/2019/5415761. eCollection 2019.
infection causes chronic gastritis and is the major risk factor of gastric cancer. induces a chronic inflammation-producing reactive oxygen species (ROS) which is a source of chromosome instabilities and contributes to the development of malignancy. also promotes DNA hypermethylation, known to dysregulate essential genes that maintain genetic stability. The maintenance of telomere length by telomerase is essential for chromosome integrity. Telomerase reverse transcriptase (TERT) is the catalytic component of telomerase activity and an important target during host-pathogen interaction. We aimed to investigate the consequences of on the regulation of gene expression and telomerase activity. , mRNA levels and telomerase activity were analysed in -infected human gastric epithelial cells. In addition, C57BL/6 and INS-GAS mice were used to investigate the influence of -induced inflammation on TERT levels. Our data demonstrated that, , inhibits gene expression and decreases the telomerase activity. The exposure of cells to lycopene, an antioxidant compound, restores TERT levels in infected cells, indicating that ROS are implicated in this downregulation. , fewer TERT-positive cells are observed in gastric tissues of infected mice compared to uninfected, more predominantly in the vicinity of large aggregates of lymphocytes, suggesting an inflammation-mediated regulation. Furthermore, appears to downregulate gene expression through DNA hypermethylation as shown by the restoration of transcript levels in cells treated with 5'-azacytidine, an inhibitor of DNA methylation. This was confirmed in infected mice, by PCR-methylation assay of the gene promoter. Our data unraveled a novel way for to promote genome instabilities through the inhibition of TERT levels and telomerase activity. This mechanism could play an important role in the early steps of gastric carcinogenesis.
感染会引发慢性胃炎，是胃癌的主要风险因素。它会诱导产生慢性炎症的活性氧（ROS），而ROS是染色体不稳定的一个来源，并促使恶性肿瘤的发展。它还会促进DNA高甲基化，已知这会使维持遗传稳定性的关键基因失调。端粒酶维持端粒长度对于染色体完整性至关重要。端粒酶逆转录酶（TERT）是端粒酶活性的催化成分，也是宿主 - 病原体相互作用过程中的一个重要靶点。我们旨在研究其对TERT基因表达调控和端粒酶活性的影响。在其感染的人胃上皮细胞中分析了TERT mRNA水平和端粒酶活性。此外，使用C57BL / 6和INS - GAS小鼠来研究其诱导的炎症对TERT水平的影响。我们的数据表明，它会抑制TERT基因表达并降低端粒酶活性。细胞暴露于抗氧化化合物番茄红素后，感染细胞中的TERT水平得以恢复，这表明ROS与这种下调有关。此外，与未感染的小鼠相比，在感染小鼠的胃组织中观察到TERT阳性细胞较少，更多地集中在大淋巴细胞聚集附近，提示存在炎症介导的调控。此外，如用DNA甲基化抑制剂5'-氮杂胞苷处理的细胞中TERT转录水平的恢复所示，它似乎通过DNA高甲基化下调TERT基因表达。通过对TERT基因启动子的PCR甲基化分析在感染小鼠中证实了这一点。我们的数据揭示了它通过抑制TERT水平和端粒酶活性促进基因组不稳定的一种新方式。这种机制可能在胃癌发生的早期阶段起重要作用。
