A positive feedback loop between STAT3 and cyclooxygenase‐2 gene may contribute to Helicobacter pylori‐associated human gastric tumorigenesis

Abstract

Persistent infection with Helicobacter pylori (H. pylori) contributes to gastric diseases including chronic gastritis and gastric cancer. However, the pathogenesis of this carcinogenic bacterium has not been completely elucidated. Here, we report that H. pylori rapidly triggers STAT3 signaling and induces STAT3-dependent COX-2 expression both in vitro and in vivo. STAT3 upregulats COX-2 by binding to and increasing the activity of COX-2 promoter. COX-2 in turn regulates IL-6=STAT3 signaling under basal conditions and during H. pylori infection. These findings suggest that a positive feedback loop between STAT3 and COX-2 exists in the basal condition and H. pylori infectious condition. Immunohistochemical staining revealed that H. pylori-positive gastritis tissues exhibited markedly higher levels of pSTAT3Tyr705 than H. pylori-negative ones. High pSTAT3 Tyr705 levels are correlated with intestinal metaplasia and dysplasia, suggesting pSTAT3 Tyr705 may be useful in the early detection of gastric tumorigenesis. Additionally, a strong positive correlation between STAT3=pSTAT3 Tyr705 levels and COX-2 expression was identified in gastritis and gastric cancer tissues. Together, these findings provide new evidence for a positive feedback loop between STAT3 signaling and COX-2 in H. pylori pathogenesis and may lead to new approaches for early detection and effective therapy of gastric cancer.

Retrospective study on gastrointestinal tract tumors in humans in Zaria, Kaduna State, Nigeria

“…This is consistent with other evidence that most cancers are predominantly related to environmental causes rather than hereditary, although the two factors interact (Polk and Peek, 2010;Rugge et al, 2013;Uehara et al, 2013). Cancer is the second most common cause of mortality in the western world after cardiovascular disease (Xiong et al, 2014;Assumpção et al, 2015).…”

“…Some tumors with benign nomenclature are obviously malignant, for example; lymphoma, myeloma. Problems of classifying neuroendocrine tumors with diverse tissues of origin exists (Polk and Peek, 2010;Xiong et al, 2014). There exist also tumors of mixed cell phenotype which have posed a problem of histological classification, for example; tumors of salivary glands, teratomata also called "Monsters" (Irrazábal et al, 2014;Assumpção et al, 2015).…”

“…Carcinoma is the commonest malignant gastrointestinal tumor in the world, commonly in the 40 to 70 age groups with the highest prevalence in 55 to 65 age groups. Causes are excessive intake of smoked fish, probably because of benzopyrene a carcinogen resulting from the smoking process, nitrosamines, Helicobacter pylori infection, remnant stump of partial gastrectomy and a lack of fruit and vegetables (Polk and Peek, 2010;Rugge et al, 2013;Uehara et al, 2013;Xiong et al, 2014;Assumpção et al, 2015).…”

Docosahexaenoic acid inhibits Helicobacter pylori‐induced STAT3 phosphorylation through activation of PPARγ

“…Expression of STAT3 mutant in which tyrosine 705 is replaced by phenylalanine impairs tyrosine phosphorylation, nuclear translocation and the transcriptional activity in IL‐6‐stimulated cells . Moreover, H. pylori ‐positive gastritis tissues exhibited markedly higher levels of phosphorylation at the tyrosine residue 705 (P‐STAT3 Tyr705 ) than H. pylori ‐negative ones . However, roles for STAT3 in H. pylori ‐associated gastric carcinogenesis and underlying molecular mechanisms remain largely unveiled.…”

Exogenous hydrogen sulfide promotes hepatocellular carcinoma cell growth by activating the STAT3-COX-2 signaling pathway

“…Liu et al (49) observed that COX-2/prostaglandin E2 regulated JAK2/STAT3 signaling in colorectal cancer cells (49). Furthermore, Xiong et al (50) revealed that there is a positive feedback loop between the STAT3 and COX-2 genes that may contribute to Helicobacter pylori-associated human gastric tumorigenesis (50). However, the exact association The signal transducer and activator of transcription 3-cyclooxygenase-2 signaling pathway serves a function in the NaHS-induced production of VEGF in PLC/PRF/5 cells.…”