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

Abstract

AIMTo 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.METHODSImmunohistochemistry 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.RESULTSIn 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.CONCLUSIONHER2, 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.

JNK Pathway Mediates Low Oxygen Level Induced Epithelial–Mesenchymal Transition and Stemness Maintenance in Colorectal Cancer Cells

“…As PTEN has the highest expression in HT-29 [36], this causes the weakened Akt activation in HT-29 as shown in the result of this study. SP600125 surprisingly caused hypophosphorylation of Akt, especially for HT-29 and SW-480, in which Akt was previously considered as a possible upstream regulator of JNK in previous research [33]. This suggests a novel feedback mechanism of JNK-c-Jun-Akt for further promotion of EMT as a positive feedback mechanism and inhibition of autophagy through Akt-mTOR pathway as negative feedback mechanism by preventing simultaneous stimulation of autophagy through Akt-mTOR and JNK pathways.…”

“…Akt, which is usually seen as an activator of EMT and an inhibitor of autophagy through phosphoinositide 3-kinase (PI3K)-Akt-Snail/Slug and PI3K-Akt-mechanistic target of rapamycin (mTOR) pathways, respectively, has also been regarded as a possible up-stream regulator of the JNK pathway in gastric cancer cells [33,34]. Our results showed that SW-480 had the most prominent up-regulation of Akt phosphorylation under lower oxygen levels, while HT-29 was less activated.…”

Hypoxia-Induced Epithelial-Mesenchymal Transition in Cancers: HIF-1α and Beyond

“…Additionally, JNK activation of the proliferating cell nuclear antigen (PCNA) and DNA methyltransferase 1 associated protein 1 (DMAP1) domains of DNA methyltransferase 1 (DNMT1) can directly interact with Snail and suppress E-cadherin in colorectal cancer, glioma, and nasopharyngeal carcinoma cell lines (117)(118)(119). Furthermore, JNK may be associated with Snail and TWIST1 via c-Jun in multi-drug resistant epidermoid carcinoma and as a downstream effector of Akt in gastric cancer cells (120,121). Other researches also associated JNK with EMT induction in colorectal cancer (122) and non-small cell lung cancer cells (123).…”

Overexpression of Krüppel-Like Factor 4 Suppresses Migration and Invasion of Non-Small Cell Lung Cancer Through c-Jun-NH2-Terminal Kinase/Epithelial-Mesenchymal Transition Signaling Pathway

“…Previous studies have demonstrated that activated JNK promotes the invasion and metastasis of tumors by promoting the development of EMT (Zhao et al, 2018;Wang et al, 2018;Dong et al, 2018). Choi Y et al reported that JNK inhibition suppressed migratory capacity through reversing EMT in gastric cancer (Choi et al, 2016). JNK has also been reported to promote EMT in renal cell carcinoma (An et al, 2015).…”