Helicobacter pylori promotes epithelial-mesenchymal transition in gastric cancer by downregulating programmed cell death protein 4 (PDCD4)

Han Yu; Jiping Zeng; Xiuming Liang; Wenfu Wang; Yabin Zhou; Yundong Sun; Shili Liu; Wenjuan Li; Chunyan Chen; Jihui Jia

doi:10.1371/journal.pone.0105306

Helicobacter pylori promotes epithelial-mesenchymal transition in gastric cancer by downregulating programmed cell death protein 4 (PDCD4)

PLoS One. 2014 Aug 21;9(8):e105306. doi: 10.1371/journal.pone.0105306. eCollection 2014.

Authors

Han Yu¹, Jiping Zeng², Xiuming Liang¹, Wenfu Wang¹, Yabin Zhou¹, Yundong Sun¹, Shili Liu¹, Wenjuan Li¹, Chunyan Chen¹, Jihui Jia¹

Affiliations

¹ Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China.
² Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China; Departments of Biochemistry, School of Medicine, Shandong University, Jinan, PR China.

Abstract

Helicobacter pylori, a Gram-negative, microaerophilic bacterium found in the stomach, is assumed to be associated with carcinogenesis, invasion and metastasis in digestive diseases. Cytotoxin-associated gene A (CagA) is an oncogenic protein of H. pylori that is encoded by a Cag pathogenicity island related to the development of gastric cancer. The epithelial-mesenchymal transition (EMT) is the main biological event in invasion or metastasis of epithelial cells. H. pylori may promote EMT in human gastric cancer cell lines, but the specific mechanisms are still obscure. We explored the underlying molecular mechanism of EMT induced by H. pylori CagA in gastric cancer. In our article, we detected gastric cancer specimens and adjacent non-cancerous specimens by immunohistochemistry and found increased expression of the EMT-related regulatory protein TWIST1 and the mesenchymal marker vimentin in cancer tissues, while programmed cell death factor 4 (PDCD4) and the epithelial marker E-cadherin expression decreased in cancer specimens. These changes were associated with degree of tissue malignancy. In addition, PDCD4 and TWIST1 levels were related. In gastric cancer cells cocultured with CagA expression plasmid, CagA activated TWIST1 and vimentin expression, and inhibited E-cadherin expression by downregulating PDCD4. CagA also promoted mobility of gastric cancer cells by regulating PDCD4. Thus, H. pylori CagA induced EMT in gastric cancer cells, which reveals a new signaling pathway of EMT in gastric cancer cell lines.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Antigens, Bacterial / metabolism
Apoptosis Regulatory Proteins / genetics
Apoptosis Regulatory Proteins / metabolism*
Bacterial Proteins / metabolism
Cadherins / genetics
Cadherins / metabolism
Cell Line, Tumor
Cell Movement / genetics
Epithelial-Mesenchymal Transition*
Female
Gene Expression
Helicobacter pylori* / metabolism
Humans
Immunohistochemistry
Male
Middle Aged
Models, Biological
Neoplasm Grading
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism*
Signal Transduction
Stomach Neoplasms / etiology*
Stomach Neoplasms / metabolism
Stomach Neoplasms / pathology*
Twist-Related Protein 1 / genetics
Twist-Related Protein 1 / metabolism
Vimentin / genetics
Vimentin / metabolism

Substances

Antigens, Bacterial
Apoptosis Regulatory Proteins
Bacterial Proteins
Cadherins
Nuclear Proteins
PDCD4 protein, human
RNA-Binding Proteins
TWIST1 protein, human
Twist-Related Protein 1
Vimentin
cagA protein, Helicobacter pylori

Grants and funding

This work was supported by the National Basic Research Program of China (no. 973 Program 2012CB911202), the National Natural Science Foundation of China (nos: 81171536, 81371781, 81272654, 81372680 and 81170514), the Medical Science and Technology Development Program of Shandong (no. 2013WS0209) and the Independent Innovation Foundation of Shandong University (no. 2012TS106). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.