Ahn So Yeong, Kim Jin, Kim Min A, Choi Jiwoon, Kim Woo Ho
Cancer Research Institute, College of Medicine, Seoul National University, Seoul, Republic of Korea.
Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea.
Anticancer Res. 2017 Mar;37(3):1127-1138. doi: 10.21873/anticanres.11426.
Increased expression of hepatocyte growth factor (HGF) and MET proto-oncogene (c-MET) is associated with poor prognosis in various cancer types. Recently, it was reported that the expression of HGF induces resistance to tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor, human epidermal receptor receptor 2, and b-raf proto-oncogene. Here, we investigated the effects of HGF overexpression in gastric cancer cells in the absence or presence of c-MET TKIs.
The effects of c-MET TKIs in gastric cancer cells with and without c-MET overexpression were determined in gastric cancer cell lines with various cell biology methods.
Compared to the control, cells with induced expression of HGF showed increase in anchorage-independent colony formation (p<0.001). The c-MET TKIs inhibited HGF/c-MET downstream signaling, cell proliferation, migration and invasion, and triggered cell-cycle arrest in Hs746T cells. However, HGF-transfected cells were less affected.
c-MET TKIs had inhibitory effects only on cells overexpressing c-MET. Furthermore, overexpression of HGF resulted in resistance to c-MET TKIs through an autocrine manner in gastric cancer cells.
肝细胞生长因子（HGF）和MET原癌基因（c-MET）表达增加与多种癌症类型的不良预后相关。最近，有报道称HGF的表达会诱导对靶向表皮生长因子受体、人表皮受体2和b-raf原癌基因的酪氨酸激酶抑制剂（TKIs）产生耐药性。在此，我们研究了在有无c-MET TKIs的情况下，HGF过表达对胃癌细胞的影响。
采用多种细胞生物学方法，测定c-MET TKIs对有无c-MET过表达的胃癌细胞的影响。
与对照组相比，诱导表达HGF的细胞在非锚定依赖性集落形成方面有所增加（p<0.001）。c-MET TKIs抑制Hs746T细胞中HGF/c-MET下游信号传导、细胞增殖、迁移和侵袭，并引发细胞周期停滞。然而，转染HGF的细胞受影响较小。
c-MET TKIs仅对过表达c-MET的细胞有抑制作用。此外，HGF的过表达通过自分泌方式导致胃癌细胞对c-MET TKIs产生耐药性。
