Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2018

Open Access 01-12-2018 | Research

Helicobacter pylori CagA promotes epithelial mesenchymal transition in gastric carcinogenesis via triggering oncogenic YAP pathway

Authors: Nianshuang Li, Yan Feng, Yi Hu, Cong He, Chuan Xie, Yaobin Ouyang, Stephen C. Artim, Deqiang Huang, Yin Zhu, Zhijun Luo, Zhongming Ge, Nonghua Lu

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2018

Login to get access

Abstract

Background

Helicobacter pylori (H. pylori) delivers oncoprotein CagA into gastric epithelial cells via the T4SS and drives activation of multiple oncogenic signalling pathways. YAP, a core effector of the Hippo tumour suppressor pathway, is frequently overexpressed in human cancers, suggesting its potential tumor-promoting role. Although CagA is a casual factor in H. pylori induced gastric carcinogenesis, the link between CagA and YAP pathway has not been identified. In this work, we investigated the regulation of oncogenic YAP pathway by H. pylori CagA.

Methods

Expression of YAP and E-cadherin protein in human gastric biopsies were assessed by immunohistochemistry. H. pylori PMSS1 cagA− isogenic mutant strains were generated. Gastric epithelial cells were co-cultured with H. pylori wild-type cagA+ strains or isogenic mutants and were also treated by recombinant CagA expression. Immunofluorescence was performed for YAP localization. Immunoblot and quantitative PCR were performed for examining levels of YAP, downstream effectors and markers of epithelial-mesenchymal transition. Verteporfin and siRNA silencing were used to inhibit YAP activity.

Results

YAP is significantly upregulated in human gastric carcinogenesis. We generated PMSS1 CagA isogenic mutant strains with chloramphenicol resistance successfully. Our analysis indicated that H. pylori infection induced YAP and downstream effectors in gastric epithelial cells. Importantly, knockout of CagA in 7.13 and PMSS1 strains reduced the expression of YAP by H. pylori infection. Moreover, Inhibition of YAP suppressed H. pylori infection-induced Epithelial-mesenchymal transition (EMT).

Conclusion

Our results indicated that H. pylori CagA as a pathogenic protein promotes oncogenic YAP pathway, which contributes to EMT and gastric tumorigenesis. This study provided a novel mechanistic insight into why cagA+ H. pylori infection is associated with a higher risk for the development of gastric cancer.
Appendix
Available only for authorised users
Literature
1.
Malaty HM, El-Kasabany A, Graham DY, Miller CC, Reddy SG, Srinivasan SR, Yamaoka Y, Berenson GS. Age at acquisition of helicobacter pylori infection: a follow-up study from infancy to adulthood. Lancet. 2002;359(9310):931–5.CrossRef
2.
Weyermann M, Rothenbacher D, Brenner H. Acquisition of Helicobacter pylori infection in early childhood: independent contributions of infected mothers, fathers, and siblings. Am J Gastroenterol. 2009;104(1):182–9.CrossRef
3.
Wu MS, Chow LP, Lin JT, Chiou SH. Proteomic identification of biomarkers related to helicobacter pylori-associated gastroduodenal disease: challenges and opportunities. J Gastroenterol Hepatol. 2008;23(11):1657–61.CrossRef
4.
Fox JG, Wang TC. Inflammation, atrophy, and gastric cancer. J Clin Invest. 2007;117(1):60–9.CrossRef
5.
Cover TL, Peek RM Jr. Diet, microbial virulence, and helicobacter pylori-induced gastric cancer. Gut Microbes. 2013;4(6):482–93.CrossRef
6.
Fox JG, Wang TC. Dietary factors modulate helicobacter-associated gastric cancer in rodent models. Toxicol Pathol. 2014;42(1):162–81.CrossRef
7.
Parsonnet J, Friedman GD, Orentreich N, Vogelman H. Risk for gastric cancer in people with CagA positive or CagA negative helicobacter pylori infection. Gut. 1997;40(3):297–301.CrossRef
8.
Ohnishi N, Yuasa H, Tanaka S, Sawa H, Miura M, Matsui A, Higashi H, Musashi M, Iwabuchi K, Suzuki M, et al. Transgenic expression of helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse. Proc Natl Acad Sci U S A. 2008;105(3):1003–8.CrossRef
9.
Chaturvedi R, Asim M, Romero-Gallo J, Barry DP, Hoge S, de Sablet T, Delgado AG, Wroblewski LE, Piazuelo MB, Yan F, et al. Spermine oxidase mediates the gastric cancer risk associated with Helicobacter pylori CagA. Gastroenterology. 2011;141(5):1696–708 e1–2.CrossRef
10.
Odenbreit S, Puls J, Sedlmaier B, Gerland E, Fischer W, Haas R. Translocation of helicobacter pylori CagA into gastric epithelial cells by type IV secretion. Science. 2000;287(5457):1497–500.CrossRef
11.
Hatakeyama M. Helicobacter pylori CagA and gastric cancer: a paradigm for hit-and-run carcinogenesis. Cell Host Microbe. 2014;15(3):306–16.CrossRef
12.
Higashi H, Tsutsumi R, Muto S, Sugiyama T, Azuma T, Asaka M, Hatakeyama M. SHP-2 tyrosine phosphatase as an intracellular target of helicobacter pylori CagA protein. Science. 2002;295(5555):683–6.CrossRef
13.
Bourzac KM, Botham CM, Guillemin K. Helicobacter pylori CagA induces AGS cell elongation through a cell retraction defect that is independent of Cdc42, Rac1, and Arp2/3. Infect Immun. 2007;75(3):1203–13.CrossRef
14.
Yu FX, Zhao B, Guan KL. Hippo pathway in organ size control, tissue homeostasis, and Cancer. Cell. 2015;163(4):811–28.CrossRef
15.
Piccolo S, Dupont S, Cordenonsi M. The biology of YAP/TAZ: hippo signaling and beyond. Physiol Rev. 2014;94(4):1287–312.CrossRef
16.
Moroishi T, Hansen CG, Guan KL. The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer. 2015;15(2):73–9.CrossRef
17.
Li N, Xie C, Lu N. Crosstalk between hippo signalling and miRNAs in tumour progression. FEBS J. 2017;284(7):1045–55.CrossRef
18.
Zanconato F, Cordenonsi M, Piccolo S. YAP/TAZ at the roots of Cancer. Cancer Cell. 2016;29(6):783–803.CrossRef
19.
Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford SA, Gayyed MF, Anders RA, Maitra A, Pan D. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell. 2007;130(6):1120–33.CrossRef
20.
Zhou D, Zhang Y, Wu H, Barry E, Yin Y, Lawrence E, Dawson D, Willis JE, Markowitz SD, Camargo FD, et al. Mst1 and Mst2 protein kinases restrain intestinal stem cell proliferation and colonic tumorigenesis by inhibition of yes-associated protein (yap) overabundance. Proc Natl Acad Sci U S A. 2011;108(49):E1312–20.CrossRef
21.
Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6):1420–8.CrossRef
22.
Ye X, Weinberg RA. Epithelial-mesenchymal plasticity: a central regulator of Cancer progression. Trends Cell Biol. 2015;25(11):675–86.CrossRef
23.
Lei QY, Zhang H, Zhao B, Zha ZY, Bai F, Pei XH, Zhao S, Xiong Y, Guan KL. TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway. Mol Cell Biol. 2008;28(7):2426–36.CrossRef
24.
Overholtzer M, Zhang J, Smolen GA, Muir B, Li W, Sgroi DC, Deng CX, Brugge JS, Haber DA. Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci U S A. 2006;103(33):12405–10.CrossRef
25.
Lee DG, Kim HS, Lee YS, Kim S, Cha SY, Ota I, Kim NH, Cha YH, Yang DH, Lee Y, et al. Helicobacter pylori CagA promotes snail-mediated epithelial-mesenchymal transition by reducing GSK-3 activity. Nat Commun. 2014;5:4423.CrossRef
26.
Jiao S, Wang H, Shi Z, Dong A, Zhang W, Song X, He F, Wang Y, Zhang Z, Wang W, et al. A peptide mimicking VGLL4 function acts as a YAP antagonist therapy against gastric cancer. Cancer Cell. 2014;25(2):166–80.CrossRef
27.
Ge Z. And D.E. Taylor, H. pylori DNA transformation by natural competence and electroporation. Methods Mol Med. 1997;8:145–52.PubMed
28.
Li NS, Zou JR, Lin H, Ke R, He XL, Xiao L, Huang D, Luo L, Lv N, Luo Z. LKB1/AMPK inhibits TGF-beta1 production and the TGF-beta signaling pathway in breast cancer cells. Tumour Biol. 2016;37(6):8249–58.CrossRef
29.
Xie C, Xu LY, Yang Z, Cao XM, Li W, Lu NH. Expression of gammaH2AX in various gastric pathologies and its association with helicobacter pylori infection. Oncol Lett. 2014;7(1):159–63.CrossRef
30.
Yang Z, Xie C, Xu W, Liu G, Cao X, Li W, Chen J, Zhu Y, Luo S, Luo Z, et al. Phosphorylation and inactivation of PTEN at residues Ser380/Thr382/383 induced by helicobacter pylori promotes gastric epithelial cell survival through PI3K/Akt pathway. Oncotarget. 2015;6(31):31916–26.CrossRef
31.
Ohata H, Kitauchi S, Yoshimura N, Mugitani K, Iwane M, Nakamura H, Yoshikawa A, Yanaoka K, Arii K, Tamai H, et al. Progression of chronic atrophic gastritis associated with helicobacter pylori infection increases risk of gastric cancer. Int J Cancer. 2004;109(1):138–43.CrossRef
32.
Lamar JM, Stern P, Liu H, Schindler JW, Jiang ZG, Hynes RO. The hippo pathway target, YAP, promotes metastasis through its TEAD-interaction domain. Proc Natl Acad Sci U S A. 2012;109(37):E2441–50.CrossRef
33.
Fock KM, Ang TL. Epidemiology of helicobacter pylori infection and gastric cancer in Asia. J Gastroenterol Hepatol. 2010;25(3):479–86.CrossRef
34.
Barrozo RM, Cooke CL, Hansen LM, Lam AM, Gaddy JA, Johnson EM, Cariaga TA, Suarez G, Peek RM Jr, Cover TL, et al. Functional plasticity in the type IV secretion system of helicobacter pylori. PLoS Pathog. 2013;9(2):e1003189.CrossRef
35.
Jang S, Su H, Blum FC, Bae S, Choi YH, Kim A, Hong YA, Kim J, Kim JH, Gunawardhana N, et al. Dynamic Expansion and Contraction of cagA Copy Number in Helicobacter pylori Impact Development of Gastric Disease. MBio. 2017;8(1).
36.
Liu-Chittenden Y, Huang B, Shim JS, Chen Q, Lee SJ, Anders RA, Liu JO, Pan D. Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev. 2012;26(12):1300–5.CrossRef
37.
Loh JT, Shaffer CL, Piazuelo MB, Bravo LE, McClain MS, Correa P, Cover TL. Analysis of cagA in helicobacter pylori strains from Colombian populations with contrasting gastric cancer risk reveals a biomarker for disease severity. Cancer Epidemiol Biomark Prev. 2011;20(10):2237–49.CrossRef
38.
Naumann M, Sokolova O, Tegtmeyer N, Backert S. Helicobacter pylori: a paradigm pathogen for subverting host cell signal transmission. Trends Microbiol. 2017;25(4):316–28.CrossRef
39.
Barranco SC, Townsend CM Jr, Casartelli C, Macik BG, Burger NL, Boerwinkle WR, Gourley WK. Establishment and characterization of an in vitro model system for human adenocarcinoma of the stomach. Cancer Res. 1983;43(4):1703–9.PubMed
40.
Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178–96.CrossRef
41.
Wang Y, Pan P, Wang Z, Zhang Y, Xie P, Geng D, Jiang Y, Yu R, Zhou X. beta-catenin-mediated YAP signaling promotes human glioma growth, 2017. J Exp Clin Cancer Res. (36, 1):136.
42.
Mo JS, Meng Z, Kim YC, Park HW, Hansen CG, Kim S, Lim DS, Guan KL. Cellular energy stress induces AMPK-mediated regulation of YAP and the hippo pathway. Nat Cell Biol. 2015;17(4):500–10.CrossRef
Metadata
Title
Helicobacter pylori CagA promotes epithelial mesenchymal transition in gastric carcinogenesis via triggering oncogenic YAP pathway
Authors
Nianshuang Li
Yan Feng
Yi Hu
Cong He
Chuan Xie
Yaobin Ouyang
Stephen C. Artim
Deqiang Huang
Yin Zhu
Zhijun Luo
Zhongming Ge
Nonghua Lu
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2018
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-018-0962-5

Other articles of this Issue 1/2018

Journal of Experimental & Clinical Cancer Research 1/2018 Go to the issue

Research

MKRN2 inhibits migration and invasion of non-small-cell lung cancer by negatively regulating the PI3K/Akt pathway

Research

TIPE3 hypermethylation correlates with worse prognosis and promotes tumor progression in nasopharyngeal carcinoma

Research

3-O-acetyl-11-keto-β-boswellic acid exerts anti-tumor effects in glioblastoma by arresting cell cycle at G2/M phase

Research

GPR119 agonist enhances gefitinib responsiveness through lactate-mediated inhibition of autophagy

Research

M1-like tumor-associated macrophages activated by exosome-transferred THBS1 promote malignant migration in oral squamous cell carcinoma

Research

Protease-activated receptor-1 (PAR1) promotes epithelial-endothelial transition through Twist1 in hepatocellular carcinoma
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits