Hepatocyte growth factor increases the metastatic potential of nasopharyngeal carcinoma: role of Akt and JNK pathways

Abstract

Nasopharyngeal carcinoma (NPC) is one of the most common cancers in Southeast Asia. One of the hallmarks of NPC is its highly invasive potential and extensive metastasis. However, the molecular mechanism of tumor progression in NPC is largely unknown. Recent studies have shown that hepatocyte growth factor (HGF) is abundant in the interstitial tissues surrounding NPC and, Met, the high affinity receptor for HGF, is frequently overexpressed in metastatic tumors. In this study, we aimed to find out the role of Met overexpression on NPC invasiveness, and to identify the signaling cascades of HGF/Met in NPC that lead to cell invasion. Here we showed that Met inhibition by siRNA and K252a reduced the invasiveness of NPC in response to HGF. HGF-induced cellular invasion of NPC is associated with enhanced matrix metalloproteinases-9 expression and proteolytic activity. Treatment of the cells with specific inhibitors against Akt (LY294002 or wortmannin) and JNK (SP600125) signaling, but not those of ERK1/2 (PD98059) and p38 MAPK (SB203580), inhibited HGF-induced invasion and MMP-9 production in NPC cells. A significant role for Akt and JNK is further supported by the observation that expression of dominant negative forms of Akt and JNK likewise abolished HGF-mediated upregulation of MMP-9 and cell invasion. In conclusion, these results suggest, for the first time, that HGF/Met plays an important role in NPC progression and metastasis. Our study also indicates that the invasive phenotype is mediated through the Akt and JNK signaling pathways, which may provide insight into the prospect of developing targeted therapy for NPC.