Helicobacter pylori and Gastric Cancer: Adaptive Cellular Mechanisms Involved in Disease Progression

Abstract

Helicobacter pylori (H. pylori) infection is the major risk factor associated with the development of gastric cancer. The transition from normal mucosa to non-atrophic gastritis, triggered primarily by H. pylori infection, initiates precancerous lesions which may then progress to atrophic gastritis and intestinal metaplasia. Further progression to dysplasia and gastric cancer is generally believed to be attributable to processes that no longer require the presence of H. pylori. The responses that develop upon H. pylori infection are directly mediated through the action of bacterial virulence factors, which drive the initial events associated with transformation of infected gastric cells. Besides genetic and to date poorly defined environmental factors, alterations in gastric cell stress-adaptive mechanisms due to H. pylori appear to be crucial during chronic infection and gastric disease progression. Firstly, H. pylori infection promotes gastric cell death and reduced epithelial cell turnover in the majority of infected cells, resulting in primary tissue lesions associated with an initial inflammatory response. However, in the remaining gastric cell population, adaptive responses are induced that increase cell survival and proliferation, resulting in the acquisition of potentially malignant characteristics that may lead to precancerous gastric lesions. Thus, deregulation of these intrinsic survival-related responses to H. pylori infection emerge as potential culprits in promoting disease progression. This review will highlight the most relevant cellular adaptive mechanisms triggered upon H. pylori infection, including endoplasmic reticulum stress and the unfolded protein response, autophagy, oxidative stress, and inflammation, together with a subsequent discussion on how these factors may participate in the progression of a precancerous lesion. Finally, this review will shed light on how these mechanisms may be exploited as pharmacological targets, in the perspective of opening up new therapeutic alternatives for non-invasive risk control in gastric cancer.

UHMK 1 promotes gastric cancer progression through reprogramming nucleotide metabolism

“…Since ATF4 activation was found to be significantly associated with H. pylori ‐positive GC (Diaz et al , ), we examined whether H. pylori infection affected UHMK1 expression, NCOA3 phosphorylation at S1062/T1067, and ATF4 transcriptional activity in GC.…”

“…Helicobacter pylori infection and GC-associated UHMK1 mutation significantly enhance UHMK1 activity and NCOA3 phosphorylation at S1062/T1067 in GC Since ATF4 activation was found to be significantly associated with H. pylori-positive GC (Diaz et al, 2018), we examined whether H. pylori infection affected UHMK1 expression, NCOA3 phosphorylation at S1062/T1067, and ATF4 transcriptional activity in GC. Interestingly, in BGC823 cells treated with or without J166 or 7.13 (two Cag + H. pylori strains) (Soutto et al, 2015), the expression of UHMK1 mRNA and protein was significantly upregulated ( Fig 8A and B).…”

Epigenetic downregulation of MUC17 by H. pylori infection facilitates NF-κB-mediated expression of CEACAM1-3S in human gastric cancer

“…Helicobacter pylori infection is a high risk factor for development of precancerous lesions such as chronic atrophic gastritis (CAG), gastric intestinal metaplasia (IM), and cancer [39,40]. GC development triggered primarily by H. pylori infection is mediated through multistep mechanisms [41]. Data from TCGA database indicates that mutations were highly frequent in MUC17 gene, including inframe mutation, missense mutation and truncating mutation (data not shown).…”

Natural Products for the Prevention and Management of Helicobacter pylori Infection

“…Epidemiological research has indicated that increased fruit intake was indeed related to a decreased gastric cancer risk (Wang et al, 2017). Considering H. pylori is closely related to the development of gastric cancer (Diaz, Valderrama, Bravo, & Quest, 2018), anti-H. pylori properties might be one of the mechanisms by which fruits decrease the risk of gastric cancer.…”