Published online Nov 7, 2016. doi: 10.3748/wjg.v22.i41.9141
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
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.
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.
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.
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.