Potential Effects of FGFR4 in the Helicobacter pylori–Induced Inflammatory Carcinoma Transformation

Abstract

In the pathogenesis of gastric cancer, Helicobacter pylori infection was the most important risk factor for noncardia gastric cancer. Recently, the US Department of Health and Human Services had again identified H pylori as a human carcinogen in its 15th Report on Carcinogens,1National Toxicology Program. https://ntp.niehs.nih.gov/go/roc15.Google Scholar which has sparked global concern. However, the exact mechanism by which H pylori induces gastric carcinogenesis remains unclear. In their article in Gastroenterology, Zhang et al2Zhang X. et al.Gastroenterology. 2022; 163: 620-636.e9Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar found a link between H pylori infection, inflammation, and fibroblast growth factor (FGF) receptor 4 (FGFR4) activation, where SRC mediated a feed-forward activation loop between FGFR4 and signal transducer and activator of transcription 3 (STAT3) in response to H pylori infection. Different from the previous concept of H pylori carcinogenicity, a recent study3Koizumi Y. et al.J Natl Cancer Inst. 2022; 114: 1149-1158Crossref PubMed Scopus (4) Google Scholar found that the survival time of gastric cancer patients with H pylori infection was longer than that for those without H pylori infection. Therefore, we want to highlight the possible shifting roles of H pylori–host interactions in gastritis cancer transformation. Cytotoxin-associated antigen A gene product (CagA) is one of the most important virulence factors of H pylori.4Hatakeyama M. Nat Rev Cancer. 2004; 4: 688-694Crossref PubMed Scopus (597) Google Scholar CagA is injected into gastric epithelial cells via a type IV secretion system, triggering the activation of inflammatory signaling pathways.5Lee K.S. et al.PLoS One. 2012; 7e30786Google Scholar It is well known that both H pylori strains (7.13 and J166) are CagA-positive H pylori and have been further confirmed in Western blot experiments reported by Zhang et al.2Zhang X. et al.Gastroenterology. 2022; 163: 620-636.e9Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar A previous study5Lee K.S. et al.PLoS One. 2012; 7e30786Google Scholar and Zhang et al demonstrated that CagA caused activation of STAT3 in response to H pylori infection. However, nuclear factor kappa B (NF-κB), a crucial determinant for chronic inflammation, could also be activated by CagA.6Brandt S. et al.Proc Natl Acad Sci U S A. 2005; 102: 9300-9305Crossref PubMed Scopus (404) Google Scholar Therefore, in the process of H pylori infection–induced activation of FGFR4 expression, are other important inflammation-related markers, such as NF-κB, also involved? Crosstalk between FGFR4, STAT3, and NF-κB has been previously noted in colorectal cancer and ovarian cancer.7Agarwal S. et al.Mol Oncol. 2022; 16: 1728-1745Crossref PubMed Scopus (2) Google Scholar,8Zaid T.M. et al.Clin Cancer Res. 2013; 19: 809-820Crossref PubMed Scopus (68) Google Scholar Moreover, it is not clear whether H pylori induced FGFR4 expression in a CagA-dependent manner. In addition, FGFs are associated with a variety of tumor biological processes, including drug resistance. Futibatinib, a novel FGFR1–4 inhibitor, had shown antitumor activity against FGFR-deregulated tumors.9Sootome H. et al.Cancer Res. 2020; 80: 4986-4997Crossref PubMed Scopus (59) Google Scholar Therefore, we should not ignore the role of FGFR4 in the chemoresistance of H pylori–induced gastric cancer. We speculate that it would be of great interest to examine whether FGFR4 modulates the function of H pylori in the resistance of tumors to therapy. The identification of FGFR4 uncovers the possibility of manipulating H pylori–induced inflammatory carcinoma transformation. We recommend that the detailed mechanistic link between H pylori infection and activation of FGFR4, as well as its correlation with chemotherapy resistance, should be comprehensively considered. Induction of Fibroblast Growth Factor Receptor 4 by Helicobacter pylori via Signal Transducer and Activator of Transcription 3 With a Feedforward Activation Loop Involving Steroid Receptor Coactivator Signaling in Gastric CancerGastroenterologyVol. 163Issue 3PreviewHelicobacter pylori infection is a key step driving a novel tumorigenic feedforward signaling loop linking infection, inflammation, and fibroblast growth factor receptor 4 activation in gastric cancer. Full-Text PDF ReplyGastroenterologyVol. 164Issue 3PreviewIn their recent correspondence, Jia et al1 summarized the key findings of our recently published work in which we reported the crosstalk between infection, inflammation (signal transducer and activator of transcription 3 [STAT3]), and activation of fibroblast growth factor receptor 4 (FGFR4) in response to Helicobacter pylori infection.2 As noted by the authors, “H pylori infection was classified as a class I carcinogen by the World Health Organization in 1994 and was identified again as a human carcinogen by the U.S. Full-Text PDF