this year is May 29th The 18th “World Gut Health Day”, since 2005, the World Gastroenterology Organization (WGO) has designated May 29 as World Gut Health Day every year, aiming to remind people to pay attention to the warning issued by the intestine, pay attention to Healthy body.
One day 40 years ago, a young doctor from Australia picked up a bottle after work” Drinks” gulp down. In the days that followed, nausea, vomiting, and a burning stomach made him miserable, but also ecstatic.
In 2005, Marshall, who was over fifty, was awarded the Nobel Prize in Physiology or Medicine for his discoveries The culprit of gastric ulcer – Helicobacter pylori. In those days, the story of him experimenting with drugs also spread like wildfire, and it has been widely praised by the medical community to this day.
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FGF was extracted from bovine tissue in the early stage, mainly secreted by brain tissue. As the name suggests, the main function of FGF is to promote the division and growth of fibroblasts, and it is widely used in the field of tissue repair and healing.
Clinically, FGF is often used for wound repair after medical cosmetic surgery, and is also widely added in various cosmetic products. among. The recovery of burns, ulcers and other wounds is also inseparable from the powerful effect of FGF. It is precisely because of this magical function that FGF is favored by the majority of beauty lovers.
However, the strong mitogenic ability of FGF also accelerates the carcinogenesis of cells. The researchers first discovered that FGFR4, an FGF receptor, is abnormally expressed in high abundance in gastric cancer tissue, which can mediate the biological effects of FGF.
doi: 10.1053/j.gastro.2022.05.016.
Analysis of public databases shows that high expression of FGFR4 in gastric cancer is associated with poor prognosis, specifically the overall survival of patients with high expression of FGFR4 and shorter disease-free survival.
Further experiments in mice confirmed that Hp infection could promote the expression of FGFR4 in gastric cancer cells. At the same time, Hp also activated the STAT3 molecule of gastric cancer cells and promoted the nuclear entry of phosphorylated STAT3.
A conjecture came to the researchers’ minds: Hp upregulates FGFR4 by activating the STAT3 pathway. To test this conjecture, they used inhibitors of STAT3 in cell and mouse experiments, respectively. As expected, when STAT3 was inhibited in Hp-infected gastric cancer cells, the content of FGFR4 was also decreased.
doi: 10.1053/j.gastro.2022.05.016. >
STAT3, as a classic transcription factor, often promotes the expression of downstream molecules by binding to the promoter of target genes. Therefore, the researchers further predicted that the promoter of FGFR4 has the ability to bind STAT3 and use fluorescence The vegetase reporter experiment was used to verify it. Next, after screening, a total of 6 binding sites entered the candidate list.
binding sites were determined by chromatin co-immunoprecipitation(ChIP)experiments. The results showed that two of the six candidate sites were found Significantly binds STAT3. After activation of STAT3 with IL-6, the enrichment abundance of these two sites is significantly increased, which further proves thatHp induces the activation of STAT3 to upregulate the expression of FGFR4.
doi: 10.1053/j.gastro.2022.05.016.
However, as the receptor of FGF, FGFR4 cannot function alone, it needs the participation of FGF to function. And FGF has many subtypes, Selecting specific subtype molecules is the focus of follow-up work.
After experiments and database analysis, the researchers’ Eyes fixed on FGF19. FGF1 in gastric cancer The content of 9 was higher than that in normal gastric tissue, and the expression of FGF19 in gastric cancer cells further increased after Hp infection.
How does FGF19 function? The research team stimulated tumor cells with FGF19, and they found thatFGF19 promotes the activation of STAT3 in cells, and this promotion effect is mediated by SRC molecules.
Previous studies have confirmed that Hp infection can activate STAT3 and then upregulate FGFR4. Up-regulated FGFR4 binds FGF19, which in turn reactivates STAT3. Such a positive feedback loop continuously amplifies the biological effects 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, the researchers found that the presence of a 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 significantly inhibited the apoptosis of gastric cancer cells. Inhibition of key molecules of the loop can limit the growth of gastric cancer cells and increase apoptosis.
So far, researchers have proposed the key mechanism of H. pylori carcinogenesis: After infection with H. pylori , tumor cells will produce a large amount of FGF19, and the combination of FGFR4 activates downstream pathways and promotes tumor growth. At the same time, FGF19 also causes tumor cells to produce more FGFR4, further amplifying the oncogenic effect of FGF19.
doi: 10.1053/j.gastro.016.2022 >
How Hp promotes the expression of FGF19 still needs to be further explored, but the discovery of key molecules provides new ideas for the prevention and treatment of gastric cancer. Starting from the cup of “drink” 40 years ago, the true face of Hp is gradually becoming clear in the relay of generations of scientific researchers.
References:
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.
Writing | Guan ShuimuEditing | Swagpp
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