DDR2 Induces Gastric Cancer Cell Activities via Activating mTORC2 Signaling and Is Associated with Clinicopathological Characteristics of Gastric Cancer.

Abstract

BACKGROUND/AIM:

Epithelial-mesenchymal transition (EMT) plays a role in cancer progression. Previous studies have suggested that discoidin domain receptor 2 (DDR2) is related to tumor progression and EMT. However, the role of DDR2 in regulating gastric cancer (GC) metastasis and in EMT has not been elucidated. In this study, we aimed to determine DDR2 expression and its clinical relation in GC and to investigate the effects of DDR2 on EMT and its underlying mechanisms.

METHODS:

DDR2 expression and the relation to patients' clinicopathological features were assayed by Western blot or immunohistochemical staining. The effects of DDR2 overexpression were investigated using in vivo tumorigenicity and xenograft models. The effects of DDR2 on EMT marker expression were assayed by Western blot and immunofluorescence. The possible role of the mTORC pathway in these processes was explored.

RESULTS:

DDR2 showed high expression in GC tissues and cells. DDR2 expression was negatively correlated with E-cadherin expression and positively correlated with N-cadherin and vimentin expression. High DDR2 expression is correlated with unfavorable pathoclinical features such as multiple tumor locations and intestinal-type GC. In xenograft models, DDR2 overexpression promoted tumor formation. Furthermore, DDR2 expression impacted on the invasion and motility of GC cells, accompanied by changes in EMT marker expression. Finally, our results revealed that DDR2 facilitates GC cell invasion and EMT through mTORC2 activation and AKT phosphorylation.

CONCLUSION:

DDR2 is upregulated and correlated with unfavorable clinical features of GC patients. DDR2 promotes tumor formation and invasion through facilitating EMT process via mTORC2 activation and AKT phosphorylation.

• Authors: Yu-Gang Wang, Ling Xu, Rong-Rong Jia, Qiong Wu, Ting Wang, Jue Wei, Jia-Li Ma, Min Shi, Zhao-Shen Li
• Journal: Digestive diseases and sciences (Dig Dis Sci) Vol. 61 Issue 8 Pg. 2272-2283 (08 2016) ISSN: 1573-2568 [Electronic] United States
• PMID: 27010547 (Publication Type: Journal Article)

Chemical References

• Antigens, CD
• CDH1 protein, human
• CDH2 protein, human
• Cadherins
• Multiprotein Complexes
• Vimentin
• DDR2 protein, human
• Discoidin Domain Receptor 2
• Mechanistic Target of Rapamycin Complex 2
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Animals
• Antigens, CD (metabolism)
• Blotting, Western
• Cadherins (metabolism)
• Cell Line, Tumor
• Cell Movement (genetics)
• Discoidin Domain Receptor 2 (genetics, metabolism)
• Epithelial-Mesenchymal Transition (genetics)
• Female
• Fluorescent Antibody Technique
• Gene Expression Regulation, Neoplastic
• Humans
• Immunohistochemistry
• Mechanistic Target of Rapamycin Complex 2
• Mice, Nude
• Multiprotein Complexes (metabolism)
• Neoplasm Invasiveness (genetics)
• Neoplasm Metastasis
• Neoplasm Transplantation
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• Real-Time Polymerase Chain Reaction
• Stomach Neoplasms (genetics, metabolism, pathology)
• TOR Serine-Threonine Kinases (metabolism)
• Vimentin (metabolism)