Major breakthrough in H. pylori research! This beauty factor is actually a cancer-causing accomplice

Since 2005, the World Gastroenterology Organization (WGO) has designated May 29 as World Gut Health Day to remind people to pay attention to the warnings from the intestines and to take care of their health.

One day, 40 years ago, a young doctor from Australia picked up a bottle of the "drink" and drank it down after work. In the days that followed, he suffered from nausea, vomiting and burning pain in his stomach, but he was also overjoyed.

In 2005, Marshall, who was already over 100 years old, was awarded the Nobel Prize in Physiology or Medicine for his discovery of the culprit of gastric ulcers—helicobacter pylori.

Helicobacter pylori (Hp), which has been proven to be the cause of peptic ulcers, is also regarded as an important causative factor of gastric cancer.

However, the mechanism by which Hp causes gastric cancer has been troubling scientists. A recent article published in Gastroenterology provides an update on the mechanism of Hp carcinogenesis. This study found that Hp may promote gastric cancer through fibroblast growth factor (FGF).

FGF was obtained early from bovine tissue and is mainly secreted by brain tissue. As the name implies, the main function of FGF is to promote fibroblast division and growth, and it is widely used in tissue repair and healing.

Clinically, FGF is often used for wound repair after medical and aesthetic surgery and is also widely added to various cosmetic products. The recovery of burns, ulcers and other wounds is also dependent on the powerful effect of FGF. Many beauty enthusiasts like FGF because of its feature.

However, the powerful pro-division ability of FGF also accelerates cellular carcinogenesis. Researchers first found that gastric cancer tissues abnormally express high abundance of FGFR4, an FGF receptor that mediates the biological effects of FGF.

Analysis of public databases illustrates that high expression of FGFR4 in gastric cancer is associated with poor prognosis, specifically that patients with high expression of FGFR4 have shorter overall and disease-free survival.

Further mouse experiments confirmed that Hp infection promoted FGFR4 expression in gastric cancer cells. Also, Hp activated STAT3 molecules in gastric cancer cells and promoted the entry of phosphorylated STAT3 into the nucleus.

A conjecture surfaced in the researchers' minds that Hp upregulates FGFR4 content by activating the STAT3 pathway. To test this conjecture, they used inhibitors of STAT3 in cellular and mouse experiments, respectively. As expected, inhibition of STAT3 in Hp-infected gastric cancer cells was followed by a reduction in FGFR4 levels.

STAT3, a classical transcription factor, often drives the expression of downstream molecules by binding to the promoters of target genes. Therefore, the researchers further predicted that the promoter of FGFR4 has the ability to bind STAT3 and verified it using luciferase reporter assays. A total of six binding sites were next screened and made it to the shortlist.

The binding sites were identified by chromatin immunoprecipitation (ChIP) assay. The results showed that two of the six candidate sites significantly bound STAT3, and the enrichment abundance of these two sites increased significantly after activation of STAT3 with IL-6, further demonstrating that Hp induced STAT3 activation to upregulate FGFR4 expression.

However, as an FGF receptor, FGFR4 does not function in isolation; it requires the presence of FGF to function. Because there are so many subtypes of FGF, the selection of specific subtype molecules became the focus of later research.

The researchers concentrated on FGF19 after conducting experiments and analyzing databases. FGF19 levels are higher in gastric cancer than in normal gastric tissues, and FGF19 expression in gastric cancer cells increases even more following Hp infection.

The researchers showed that FGF19 enhances intracellular STAT3 activation and that this action is mediated by SRC molecules after they stimulated tumor cells with FGF19.

Previous studies have demonstrated that Hp infection activates STAT3, which in turn upregulates FGFR4, and that the upregulated FGFR4 binds to FGF19, which in turn reactivates STAT3. This positive feedback loop amplifies the biological effects of Hp. Using cytological experiments, the researchers found that the presence of such positive feedback loop promoted the growth of gastric cancer cells.

The cell cycle and apoptosis are the two most relevant research directions for cell growth, and the positive feedback loop caused by Hp significantly inhibits apoptosis in gastric cancer cells. Key molecules that inhibit the loop can lead to restricted growth and increased apoptosis in gastric cancer cells.

So far, the researchers have postulated a crucial mechanism of Hp carcinogenesis: following Hp infection, tumor cells create significant levels of FGF19, which binds to FGFR4 and activates the downstream pathway, increasing tumor growth. At the same time, FGF19 stimulates tumor cells to create more FGFR4, enhancing FGF19's oncogenic effect.

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