As one of the malignant tumors with a high incidence rate worldwide, the pathogenesis of gastric cancer has always been a hot topic in medical research. In recent years, more and more studies have shown that Helicobacter pylori infection is closely related to the occurrence of gastric cancer. However, the scientific community has not yet fully elucidated the question of how Helicobacter pylori induces gastric cancer and why gastric cancer can still occur even after eradication.

To this end, a research team led by Yang Shiming and Xiao Yufeng from the Second Affiliated Hospital of the Army Medical University is committed to exploring the mechanism of Helicobacter pylori-induced gastric cancer, especially the "hit-and-run" hypothesis. This hypothesis suggests that after H. pylori infection, even if it is later eradicated, some of the damage it causes to host cells or some of the changes it induces during infection may persist, thus continuing to drive the development of gastric cancer.

Research process and findings

The research team first focused on N6-methyladenosine (m0A), an important epigenetic modification of mRNA that regulates mRNA stability, translation and splicing, and is closely related to the occurrence and progression of cancer. Through the analysis of gastric cancer tissue samples, the researchers found that m0A levels of mRNA were significantly reduced in gastric cancer samples that were positive for virulence factor CagA, one of the most important carcinogenic factors in Helicobacter pylori. At the same time, H. pylori infection experiments also showed that m0A levels were also reduced in CagA-producing H. pylori-infected cells.

Further studies have found that FTO (an enzyme capable of removing m6A from mRNA) is highly expressed in CagA-positive gastric cancer, and this high expression is associated with poor prognosis in patients. The specific mechanism is that CagA activates the ERK signaling pathway, an important intracellular signaling pathway involved in the regulation of cell growth, differentiation, survival, apoptosis and other biological processes, which in turn promotes the expression of FTO. FTO removes m0A modifications on mRNA leads to increased expression of certain genes that promote the migration and invasion ability of gastric cancer cells. Therefore, FTO plays a role in promoting tumor progression in CagA-positive gastric cancer.

To test this mechanism, the research team conducted a number of experiments, including cell experiments, human database analysis, and mouse model experiments. They found that the expression levels of FTO were significantly higher in CagA-positive gastric cancer tissues, and that there was a correlation between mRNA levels of FTO and major clinicopathological features such as lymph node metastasis, distant metastases, and tumor stage. In addition, the study found that the survival rate of patients with high FTO expression was lower, suggesting that FTO may be a potential target for gastric cancer treatment.

The study also found that even eradication of H. pylori could not reverse the elevated levels of FTO and HBEGF. This suggests that the epigenetic changes caused by H. pylori infection are persistent and that the carcinogenic effects may persist even if H. pylori is eliminated.

After clarifying the above mechanism of action, the research team further explored potential therapeutic strategies. They combined meclofenamic acid, a non-steroidal anti-inflammatory drug (NSAID) and FTO inhibitor that has been approved by the US FDA, with antibiotics, and the results showed that m6A levels were increased, the expression of HBEGF (which is related to tumor progression, invasion and metastasis, and high expression of HBEGF may promote the growth and spread of cancer cells) was inhibited, and the migration and invasion ability of gastric cancer cells was also weakened. This suggests that meclofenamic acid in combination with antibiotics can fight CagA-positive gastric cancer, providing patients with a new treatment option.

This study provides a new perspective for understanding the relationship between Helicobacter pylori and gastric cancer, and also provides new ideas for the prevention and treatment of gastric cancer. In addition, given the prevalence of Helicobacter pylori infection, optimizing prevention strategies, such as early screening and eradication therapy, is also of practical significance to reduce the incidence of gastric cancer.

With the deepening of the understanding of the relationship between H. pylori and gastric cancer, we hope to develop more effective methods to prevent and treat this deadly disease in the future. The research by the Yang Shiming/Xiao Yufeng team is undoubtedly an important step towards this goal. In the future, we hope that more studies can further reveal the carcinogenic mechanism of H. pylori and provide a more solid scientific foundation for the prevention and treatment of gastric cancer.