HER2-induced metastasis is mediated by AKT/JNK/EMT signaling pathway in gastric cancer

AIM To investigated the relationships between HER2, c-Jun N-terminal kinase(JNK) and protein kinase B(AKT) with respect to metastatic potential of HER2-positive gastric cancer(GC) cells.METHODS Immunohistochemistry was performed on tissue array slides containing 423 human GC specimens. Using HER2-po...

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Published in:	World journal of gastroenterology : WJG 2016-11, Vol.22 (41), p.9141-9153
Main Authors:	Choi, Yiseul, Ko, Young San, Park, Jinju, Choi, Youngsun, Kim, Younghoon, Pyo, Jung-Soo, Jang, Bo Gun, Hwang, Douk Ho, Kim, Woo Ho, Lee, Byung Lan
Format:	Article
Language:	eng
Subjects:	Basic Study Cell Line, Tumor Cell Movement - drug effects Enzyme Activation Epithelial-Mesenchymal Transition - drug effects Feedback, Physiological Humans JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors JNK Mitogen-Activated Protein Kinases - metabolism Neoplasm Metastasis Phosphorylation Protein Kinase Inhibitors - pharmacology Proto-Oncogene Proteins c-akt - antagonists & inhibitors Proto-Oncogene Proteins c-akt - metabolism Receptor, ErbB-2 - genetics Receptor, ErbB-2 - metabolism RNA Interference Signal Transduction - drug effects Stomach Neoplasms - enzymology Stomach Neoplasms - genetics Stomach Neoplasms - pathology Time Factors Transfection
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Summary:	AIM To investigated the relationships between HER2, c-Jun N-terminal kinase(JNK) and protein kinase B(AKT) with respect to metastatic potential of HER2-positive gastric cancer(GC) cells.METHODS Immunohistochemistry was performed on tissue array slides containing 423 human GC specimens. Using HER2-positve GC cell lines SNU-216 and NCI-N87, HER2 expression was silenced by RNA interference, and the activations of JNK and AKT were suppressed by SP600125 and LY294002, respectively. Transwell assay, Western blot, semi-quantitative reverse transcriptionpolymerase chain reaction and immunofluorescence staining were used in cell culture experiments. RESULTS In GC specimens, HER2, JNK, and AKT activations were positively correlated with each other. In vitro analysis revealed a positive regulatory feedback loop between HER2 and JNK in GC cell lines and the role of JNK as a downstream effector of AKT in the HER2/AKT signaling pathway. JNK inhibition suppressed migratory capacity through reversing EMT and dual inhibition of JNK and AKT induced a more profound effect on cancer cell motility.CONCLUSION HER2, JNK and AKT in human GC specimens are positively associated with each other. JNK and AKT, downstream effectors of HER2, co-operatively contribute to the metastatic potential of HER2-positive GC cells. Thus, targeting of these two molecules in combination with HER2 downregulation may be a good approach to combat HER2-positive GC.
ISSN:	1007-9327 2219-2840