Sanjana Nayak

Introduction. Gastric cancer is one of the leading causes of cancer-related death in the world, with the rate of incidence still high in East Asia¹. H. pylori infection is the main risk factor, with the likelihood for infection increasing with greater age, higher BMI, and male sex^2,3,4. H. pylori infection can deregulate signaling pathways, like the JAK/STAT pathway, in epithelial cells and fibroblasts^2,5. Deregulation of epithelial cells directly contributes to cancer development, while the deregulation of fibroblasts can contribute to a molecular microenvironment that allows for inflammation and cancer development^2,5. Studies have found that deregulation of the JAK/STAT pathway in gastric epithelial cells results in the overproduction of IL-8, a proinflammatory and tumor promoting factor⁶. Other studies show that the deregulation of the JAK/STAT pathway in fibroblasts results in an upregulation of several factors involved in the pathway, like TLRs (toll-like receptors) and STAT3⁵. The studies also indicate that deregulation results in an increase in Snail1 protein expression, an epithelial-mesenchymal transition-inducing transcription factor that promotes a microenvironment for cancer develoopment⁵. These findings could suggest potential targets for treatment of H. pylori infection and prevention of cancer. Methods. Primary human gastric epithelial cells were harvested from H. pylori-negative individuals⁶. Some cells were treated with a JAK/STAT inhibitor and H. pylori and others were kept as a control⁶. PCR and ELISA analysis was done⁶. In a similar animal study, gastric fibroblasts were harvested from a rat and infected with H. pylori⁵. Cellular RNA was isolated and reverse transcription was done to synthesize cDNA⁵. PCR was run to identify mRNA expression of TLRs and STAT3⁵. Western Blot analysis was done to identify protein expression of Snail1⁵. Results. The JAK/STAT inhibitor decreased H. pylori– induced IL-8 mRNA expression and protein secretion significantly when compared to that of uninhabited cells⁶. In comparison to uninfected cells, there was a significant increase in TLR2 and TLR4 expression 48 hours after infection⁵. There was also a significant increase in STAT3 mRNA expression⁵. Moreover, there was a significant increase in Snail1 mRNA and protein expression 72 hours after infection⁵. Conclusions. Studies have found that JAK/STAT deregulation can result in overproduction of IL-8 in epithelial cells, upregulation of pathway elements (TLRs and STAT3) in fibroblasts, and production of Snail1 by fibroblasts. The cancer development promoted by the changes in these elements could be inhibited by treatments like glutamine supplementation, which inhibits IL-8 production, and menadione, an antibiotic that inhibits components of the JAK/STAT pathway and IL-8^7,8.

1. Liu KS, Wong IO, Leung WK. Helicobacter pylori associated gastric intestinal metaplasia: Treatment and surveillance. World Journal of Gastroentrology. 2016 Jan 21;22(3):1311-20. doi: 10.3748/wjg.v22.i3.1311.
2. Negovan A, Iancu M, Fülöp E, Bănescu C. Helicobacter pylori and cytokine gene variants as predictors of premalignant gastric lesions. World Journal of Gastroenterology. 2019;25(30):4105-4124. doi:10.3748/wjg.v25.i30.4105.
3. Leja M, Grinberga‐Derica I, Bilgilier C, Steininger C. Review: Epidemiology of Helicobacter pylori infection infection. Helicobacter. 2019;24(S1). doi:10.1111/hel.12635.
4. Shen J, Zhai J, You Q, et al. Cancer-associated fibroblasts-derived VCAM1 induced by H. pylori infection facilitates tumor invasion in gastric cancer. Oncogene. 2020;39(14):2961-2974. doi:10.1038/s41388-020-1197-4.
5. Krzysiek-Maczka G, Targosz A, Szczyrk U, Strzalka M, Brzozowski T, Ptak-Belowska A. Involvement of epithelial-mesenchymal transition-inducing transcription factors in the mechanism of Helicobacter pylori-induced fibroblasts activation. Journal of Physiology and Pharmacology: an official journal of the Polish Physiological Society. 2019 Oct;70(5). doi: 10.26402/jpp.2019.5.08.
6. Tran CT, Garcia M, Garnier M, Burucoa C, Bodet C. Inflammatory signaling pathways induced by Helicobacter pylori in primary human gastric epithelial cells. Innate Immunity. 2016 Oct;23(2):165-174. doi:10.1177/1753425916681077.
7. Lee YM, Kim MJ, Kim Y, Kim H. Glutamine Deprivation Causes Hydrogen Peroxide-induced Interleukin-8 Expression via Jak1/Stat3 Activation in Gastric Epithelial AGS Cells. Journal of Cancer Prevention. 2015;20(3):179-184. doi:10.15430/jcp.2015.20.3.179.
8. Lee M, Yang J, Cho Y, et al. Inhibitory Effects of Menadione on Helicobacter pylori Growth and Helicobacter pylori-Induced Inflammation via NF-κB Inhibition. International Journal of Molecular Sciences. 2019;20(5):1169. doi:10.3390/ijms20051169.