β-Catenin and p120 Mediate PPARδ-Dependent Proliferation Induced by Helicobacter pylori in Human and Rodent Epithelia

Nagy, Toni A.; Wroblewski, Lydia E.; Wang, Dingzhi; Piazuelo, M. Blanca; Delgado, Alberto; Romero–Gallo, Judith; Noto, Jennifer M.; Israel, Dawn A.; Ogden, Seth R.; Correa, Pelayo; Cover, Timothy L.; Peek, Richard M.

doi:10.1053/j.gastro.2011.05.004

Cited by 66 publications

(60 citation statements)

References 27 publications

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“…Studies from two independent groups revealed that loss of PPARδ by deletion of its exons 4-5 or exon 4 reduced intestinal adenoma burden in both Apc Min/+ and AOM-treated mice without exposure to DSS (22,23). A recent report described a role of PPARδ in Helicobacter pylori-associated gastric carcinogenesis, which represents another example of its effects in a proinflammatory pathway (24). These results suggest that PPARδ has proinflammatory and protumor effects.…”

Section: Discussionmentioning

confidence: 88%

Peroxisome proliferator-activated receptor δ promotes colonic inflammation and tumor growth

Wang¹,

Fu²,

Wei³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Although epidemiologic and experimental evidence strongly implicates chronic inflammation and dietary fats as risk factors for cancer, the mechanisms underlying their contribution to carcinogenesis are poorly understood. Here we present genetic evidence demonstrating that deletion of peroxisome proliferator-activated receptor δ (PPARδ) attenuates colonic inflammation and colitis-associated adenoma formation/growth. Importantly, PPARδ is required for dextran sodium sulfate induction of proinflammatory mediators, including chemokines, cytokines, COX-2, and prostaglandin E 2 (PGE 2 ), in vivo. We further show that activation of PPARδ induces COX-2 expression in colonic epithelial cells. COX-2-derived PGE 2 stimulates macrophages to produce proinflammatory chemokines and cytokines that are responsible for recruitment of leukocytes from the circulation to local sites of inflammation. Our results suggest that PPARδ promotes colonic inflammation and colitis-associated tumor growth via the COX-2-derived PGE 2 signaling axis that mediates cross-talk between tumor epithelial cells and macrophages.colorectal cancer | COX-2/PGE 2

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Section: Discussionmentioning

confidence: 88%

Peroxisome proliferator-activated receptor δ promotes colonic inflammation and tumor growth

Wang¹,

Fu²,

Wei³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…H. pylori activates β-catenin through inactivation of GSK-3β, or via an interaction between CagA and membrane-associated β-catenin, which promotes mitogenic signalling and proliferation. 91213 …”

Section: Introductionmentioning

confidence: 99%

Helicobacter pyloritargets cancer-associated apical-junctional constituents in gastroids and gastric epithelial cells

Wroblewski

Piazuelo

Chaturvedi

et al. 2014

Gut

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Objective Helicobacter pylori strains that express the oncoprotein CagA augment risk for gastric cancer. However, the precise mechanisms through which cag+ strains heighten cancer risk have not been fully delineated and model systems that recapitulate the gastric niche are critical for understanding pathogenesis. Gastroids are three-dimensional organ-like structures that provide unique opportunities to study host-H. pylori interactions in a preclinical model. We used gastroids to inform and direct in vitro studies to define mechanisms through which H. pylori modulates expression of the cancer-associated tight junction protein claudin-7. Design Gastroids were infected by luminal microinjection, and MKN28 gastric epithelial cells were cocultured with H. pylori wild-type cag+ strains or isogenic mutants. β-catenin, claudin-7 and snail localisation was determined by immunocytochemistry. Proliferation was assessed using 5-ethynyl-2′-deoxyuridine, and levels of claudin-7 and snail were determined by western blot and flow cytometry. Results Gastroids developed into a self-organising differentiation axis and H. pylori induced mislocalisation of claudin-7 and increased proliferation in a CagA- and β-catenin-dependent manner. In MKN28 cells, H pylori-induced suppression of claudin-7 was regulated by β-catenin and snail. Similarly, snail expression was increased and claudin-7 levels were decreased among H. pylori-infected individuals. Conclusions H. pylori increase proliferation in a strain-specific manner in a novel gastroid system. H. pylori also alter expression and localisation of claudin-7 in gastroids and human epithelial cells, which is mediated by β-catenin and snail activation. These data provide new insights into molecular interactions with carcinogenic potential that occur between H. pylori and epithelial cells within the gastric niche.

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“…In addition to activating MAPK, H. pylori infection also induces the expression of other inflammatory responsive genes including nuclear factor-κB (NF-κB) (8), cyclooxygenase-2 (COX-2) (9) and aquaporin 3 (AQP3) (10). H. pylori has been reported to stimulate the proliferation of gastric epithelial cells both in vitro and in vivo (5,11,12) and to alter intercellular tight junctions (13), thus facilitating the malignant transformation of the gastric mucosa.…”

Section: Introductionmentioning

confidence: 99%

Helicobacter pylori enhances CIP2A expression and cell proliferation via JNK2/ATF2 signaling in human gastric cancer cells

Zhao

Han

et al. 2014

International Journal of Molecular Medicine

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Abstract.Helicobacter pylori (H. pylori) infection plays an important role in the development of gastric carcinomas. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a novel human oncoprotein that functions as an important regulator of cell growth and malignant transformation. In the present study, we aimed to investigate the potential mechanisms by which H. pylori upregulates the expression of CIP2A and the functional impact of H. pylori-induced CIP2A in gastric cancer cells. We demonstrated that infection of MKN-45 cells with H. pylori led to a marked increase in the expression of CIP2A at the mRNA and protein levels. H. pylori-induced CIP2A was associated with increased cell proliferation. In addition, H. pylori was found to activate the JNK2 pathway. Importantly, both H. pylori-induced CIP2A production and cell proliferation were partially reversed by inhibition of JNK2 signaling. Similarly, the blockade of H. pylori-induced CIP2A expression by siRNA against CIP2A also inhibited cell proliferation. Thus, H. pylori appears to stimulate the expression of CIP2A and proliferation of gastric cancer cells via JNK2 signaling. These findings suggest that H. pylori-induced upregulation of CIP2A contributes to the development and progression of gastric cancer. Further in vivo studies are warranted to explore the biological role of CIP2A and its interaction with JNK2 signaling in gastric cancer.

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β-Catenin and p120 Mediate PPARδ-Dependent Proliferation Induced by Helicobacter pylori in Human and Rodent Epithelia

Cited by 66 publications

References 27 publications

Peroxisome proliferator-activated receptor δ promotes colonic inflammation and tumor growth

Peroxisome proliferator-activated receptor δ promotes colonic inflammation and tumor growth

Helicobacter pyloritargets cancer-associated apical-junctional constituents in gastroids and gastric epithelial cells

Helicobacter pylori enhances CIP2A expression and cell proliferation via JNK2/ATF2 signaling in human gastric cancer cells

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