Copyright
©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
HER2-induced metastasis is mediated by AKT/JNK/EMT signaling pathway in gastric cancer
Yiseul Choi, Young San Ko, Jinju Park, Youngsun Choi, Younghoon Kim, Jung-Soo Pyo, Bo Gun Jang, Douk Ho Hwang, Woo Ho Kim, Byung Lan Lee
Yiseul Choi, Jinju Park, Youngsun Choi, Woo Ho Kim, Byung Lan Lee, Department of Tumor Biology, Cancer Research Institute, Seoul National Universit, College of Medicine, Seoul 110-799, South Korea
Young San Ko, Douk Ho Hwang, Byung Lan Lee, Department of Anatomy, Seoul National University College of Medicine, Seoul 110-799, South Korea
Younghoon Kim, Woo Ho Kim, Department of Pathology, Seoul National University College of Medicine, Seoul 110-799, South Korea
Jung-Soo Pyo, Department of Pathology, Eulji University Hospital, Eulji University College of Medicine, Daejon 35233, South Korea
Bo Gun Jang, Department of Pathology, Jeju National University Hospital, Jeju 690-767, South Korea
Byung Lan Lee, Ischemic/Hypoxic Disease Institute Medical Research Center, Seoul National University College of Medicine, Seoul 110-799, South Korea
Author contributions: Choi Y, Ko YS and Park J performed the experiments; Choi Y, Ko YS, Park J, Choi Y, Kim Y, Pyo JS, Jang BG, Hwang DH, Kim WH and Lee BL participated in writing, editing and reviewing of this manuscript.
Supported by SNUH Research Fund, Grant NO 04-2016-0220; and the Education and Research Encouragement Fund of Seoul National University Hospital (2015).
Institutional review board statement: The study was revised and approved by the Institutional Review Board of Seoul National University College of Medicine.
Informed consent statement: Waived by the Institutional Review Board of Seoul National University College of Medicine because of the following reasons: Most of the patients already died or are not visiting hospital anymore. This study will not cause hazard or exposure of personal information and will be used only for academic purposes (IRB No. 1309-087-522).
Conflict-of-interest statement: All the authors have no conflict of interest related to the manuscript.
Data sharing statement: No additional data available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Byung Lan Lee, MD, PhD, Department of Anatomy, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, South Korea.
dslanat@snu.ac.kr
Telephone: +82-2-7408218 Fax: +82-2-7459528
Received: June 29, 2016
Peer-review started: June 29, 2016
First decision: July 29, 2016
Revised: August 12, 2016
Accepted: September 12, 2016
Article in press: September 12, 2016
Published online: November 7, 2016
Processing time: 130 Days and 0 Hours
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 transcription-polymerase 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.
Core tip: We investigated the significance of c-Jun N-terminal kinase (JNK) and its interaction with protein kinase B (AKT) in the HER2 signaling with respect to metastatic potential of HER2-positive gastric cancer (GC). In clinical GC samples, we found positive relationships between HER2, JNK and AKT. Inhibition studies using HER2-positive SNU-216 and NCI-N87 GC cell lines demonstrated that positive crosstalk exists between HER2 and JNK, and that JNK is a downstream signaling molecule of AKT. In addition, JNK and AKT increased EMT and co-operatively contributed to the metastatic potential of HER2-positive GC cell lines. Thus, HER2 signaling contributes to GC metastasis through activation of AKT/JNK/EMT pathway.
