A synergistic interaction between human epidermal growth factor receptor 2/neu and c-Jun N-terminal kinase promotes gastric cancer cell migration and invasion

Abstract

Purpose: Human epidermal growth factor receptor2 (HER2) is a crucial regulator of tumor progression, but the underlying molecular mechanisms remain unclear. Recent studies reported the association between HER2 and c-Jun N-terminal kinase (JNK) in breast cancer

however, little is studied in gastric cancer (GC). The present study investigated the relationship between HER2 and JNK in relation to the metastatic potential in GC cells. Methods: HER2-overexpressing human GC cell lines SNU-216 and NCI-N87 were used. JNK activation was suppressed by treatment with SP600125 and HER2 expression was silenced by RNA interference. Western blot and semi-quantitative reverse transcription-PCR were used to detect the expressions of pHER2, HER2, pJNK, JNK and epithelial mesenchymal transition (EMT) markers. Cell growth was determined by crystal violet assay. Cell migration and invasion were assessed by a Transwell assay. Results: In both GC cell lines, pharmacological inhibition of JNK using SP600125 reduced cancer cell growth, migration, invasion and actin cytoskeleton organization. It also upregulated E-cadherin and downregulated Snail and Vimentin. HER2 silencing by lentivirus-mediated HER2 shRNA transfection blocked JNK activation. On the other hand, JNK inhibition reduced HER2 expression at the protein and mRNA levels in GC cells. Moreover, JNK inhibition in HER2-silenced GC cells induced further decrease in GC cell growth, migration and invasion compared to HER2 silencing alone. Conclusions: The interaction between HER2 and JNK synergistically contributes to the GC cell growth and metastatic potential in HER2-overexpressing GC cells. Thus, JNK may be an attractive target for the treatment of GC patients with a HER2-overexpressing GC.