May 29 of this year is the 18th "world intestinal health day". Since 2005, the world gastroenterology Organization (wgo) has designated May 29 as the world intestinal health day every year to remind people to pay attention to the warnings issued by the intestines and pay attention to their health.
One day 40 years ago, a young doctor from Australia picked up a bottle of "drink" after work and drank it. In the next few days, the symptoms of nausea, vomiting and heartburn made him miserable, but also made him ecstatic.
In 2005, Marshall, who was over 50 years old, was awarded the Nobel Prize in physiology or medicine for his discovery of Helicobacter pylori, the culprit of gastric ulcer. The story that he tried to poison himself spread like wildfire, and has been widely praised by the medical community.
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Helicobacter pylori (HP) has been proved to be the initiator of peptic ulcer, and is also regarded as an important pathogenic factor of gastric cancer. According to research statistics, the infection rate of HP in China is about 60%, and the infection rate of the elderly over 70 years old is 80%.
However, the mechanism of HP causing gastric cancer has been puzzling scientists. Recently, an article published in gastroenterology recently elaborated on the carcinogenic mechanism of HP. This study found that HP may promote the occurrence of gastric cancer through fibroblast growth factor (FGF).
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FGF was extracted from bovine tissue in the early stage and mainly secreted by brain tissue. As the name suggests, FGF is mainly used to promote fibroblast division and growth, and is widely used in the field of tissue repair and healing.
Clinically, FGF is often used for wound repair after medical and aesthetic surgery, and is also widely added to various beauty products. The healing of burns, ulcers and other wounds is also inseparable from the powerful role of FGF. Because of this function of turning decay into magic, FGF has been favored by the majority of beauty lovers.
However, the powerful mitogenic ability of FGF also accelerates the carcinogenesis of cells. The researchers first found that high abundance of FGFR4, a FGF receptor, was abnormally expressed in gastric cancer tissues, which can mediate the biological effects of FGF.
doi: 10.1053/j.gastro. 2022.05.016
The analysis of the public database shows that the high expression of FGFR4 in gastric cancer is associated with poor prognosis, specifically, the patients with high expression of FGFR4 have shorter overall survival and disease-free survival.
Further mouse experiments confirmed that HP infection could promote the expression of FGFR4 in gastric cancer cells. At the same time, HP also activated STAT3 molecule of gastric cancer cells and promoted the entry of phosphorylated STAT3 into the nucleus.
A conjecture emerged in the minds of researchers: HP up regulates the content of FGFR4 by activating STAT3 pathway. To test this hypothesis, they used STAT3 inhibitors in cell and mouse experiments, respectively. As expected, when STAT3 was inhibited in HP infected gastric cancer cells, the content of FGFR4 also decreased.
doi: 10.1053/j.gastro. 2022.05.016.
STAT3, as a classical transcription factor, often promotes the expression of downstream molecules by binding to the promoters of target genes. Therefore, the researchers further predicted that the promoter of FGFR4 had the ability to bind STAT3, which was verified by luciferase reporting experiment. After screening, a total of 6 binding sites entered the waiting list.
The binding sites were determined by chromatin immunoprecipitation (chip) assay. The results showed that two of the six candidate sites significantly bound Stat3. After STAT3 was activated by IL-6, the enrichment abundance of these two sites increased significantly, which further proved that HP induced STAT3 activation to up regulate the expression of FGFR4.
doi: 10.1053/j.gastro. 2022.05.016.
However, as the receptor of FGF, FGFR4 cannot function alone, and the participants of FGF are required to play a role. FGF has many subtypes, and the focus of follow-up work is to select specific subtype molecules.
After experiments and database analysis, the researchers focused on Fgf19. The content of Fgf19 in gastric cancer was higher than that in normal gastric tissue. After Hp infection, the expression of Fgf19 in gastric cancer cells increased further.
How does Fgf19 function? The research team stimulated tumor cells with Fgf19. They found that Fgf19 could promote the activation of STAT3 in cells, and this promoting effect was mediated by SRC molecules.
Previous studies have confirmed that HP infection can activate STAT3 and up regulate FGFR4. Upregulated FGFR4 binds to Fgf19 and in turn activates STAT3 again. Such a positive feedback loop enlarges the biological effect of HP.
doi: 10.1053/j.gastro. 2022.05.016.
But what effect does such a positive feedback loop have on the occurrence and development of gastric cancer? Using cytological experiments, researchers found that the existence of positive feedback loop promoted the growth of gastric cancer cells.
Cell cycle and apoptosis are the two research directions most related to cell growth. The positive feedback loop induced by HP significantly inhibited the apoptosis of gastric cancer cells. Inhibiting the key molecules of the loop can restrict the growth of gastric cancer cells and increase apoptosis.
So far, researchers have proposed the key mechanism of HP carcinogenesis: after infection with HP, tumor cells will produce a large amount of Fgf19, which activates the downstream pathway after binding with FGFR4 and promotes the growth of tumors. At the same time, Fgf19 can also make tumor cells produce more FGFR4, further amplifying the carcinogenic effect of Fgf19.
doi: 10.1053/j.gastro. 2022.05.016.
How HP promotes the expression of Fgf19 still needs further discussion, but the discovery of key molecules provides a new idea for the prevention and treatment of gastric cancer. Since the cup of "drink" 40 years ago, the true face of HP has gradually become clear in the relay of generations of scientific researchers.
reference material:
1. Chinese Medical Association, et al Guidelines for primary diagnosis and treatment of Helicobacter pylori infection (2019) Chinese Journal of general practitioners, 2020, 19 (5): 397-402 doi: 10.3760/cma. j.cn114798-20200223-00158.
2、Xing Zhang, et al. Induction of FGFR4 by H. pylori via STAT3 with a feedforward activation loop
involving SRC signaling in gastric cancer. Gastroenterology. 2022; S0016-5085(22)00505-4. doi: 10.1053/j.gastro. 2022.05.016.
Article source:
https://www.medsci.cn/article/show_article.do?id=171ce28101c5
