The aim of the present study was to investigate the effect of hepatocyte growth factor receptor (c-MET) inhibition on the viability of colon cancer cells and xenografts exposed to irradiation using short hairpin (sh)RNA or the c-MET inhibitor PHA665752. The underlying mechanisms were also investigated. Human colorectal adenocarcinoma HT-29 cells were infected with a lentivirus expressing shRNAs against c-MET and were irradiated at 0, 2, 4, 6 and 8 Gy. The viability of the cells was assessed by alamarBlue (R) assays. Mice bearing human colon carcinoma SW620 xenografts were randomly selected to receive 2.5% dimethyl sulfoxide (DMSO), 25 mg/kg PHA665752 intraperitoneally once every 2 days for 3 weeks, irradiation at 10 Gy, or 25 mg/kg PHA665752 intraperitoneally once every 2 days for 3 weeks followed 24 h later by irradiation at 10 Gy. The mean tumor volume (MTV) was measured. The apoptotic rate of cells was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assays, and double stranded break marker antibody -H2AX and hypoxia inducible factor (HIF)-1 expression was examined by immunohistochemistry. alamarBlue assays revealed that c-MET downregulation by shRNA markedly accentuated the irradiation-induced reduction in the viability of HT-29 cells compared with HT-29 cells irradiated at the same doses (P<0.05). A combination of irradiation and PHA665752 caused an additional reduction in the MTV (382.8 +/- 42.4 mm3; P<0.01 vs. irradiation and PHA665752, 998.0 +/- 180.6 and 844.8 +/- 190.0 mm3, respectively). TUNEL assays revealed that irradiation and PHA665752 alone caused significant apoptosis of the SW620 cells in the tumor xenografts (P<0.01 vs. DMSO). The apoptotic index in the tumor xenografts of mice treated with a combination of irradiation and PHA665752 was significantly increased compared with mice treated with either agent alone (P<0.01). The combination of irradiation and PHA665752 was also associated with a marked increase in -H2AX levels and a significant decrease in HIF-1 expression in the xenografts (P<0.01). In conclusion, c-MET inhibition sensitizes colorectal cancer cells to irradiation by enhancing the formation of DNA double strand breaks and possibly alleviating tumor hypoxia.
基金：
National Natural Science Foundation of China (NSFC) [81172332]
第一作者机构：[1]Hebei Gen Hosp, Dept Oncol 3, Shijiazhuang 050011, Hebei, Peoples R China
通讯作者：
通讯机构：[2]Hebei Med Univ, Hosp 4, Dept Surg 2, 169 Tianshan St, Shijiazhuang 050035, Hebei, Peoples R China[*1]Second Department of Surgery, The Fourth Hospital of Hebei Medical University, 169 Tianshan Street, Shijiazhuang, Hebei 050035, P.R. China
推荐引用方式(GB/T 7714)：
Jia Yitao,Dai Guangyao,Wang Jinxi,et al.c-MET inhibition enhances the response of the colorectal cancer cells to irradiation in vitro and in vivo[J].ONCOLOGY LETTERS.2016,11(4):2879-2885.doi:10.3892/ol.2016.4303.
APA：
Jia, Yitao,Dai, Guangyao,Wang, Jinxi,Gao, Xing,Zhao, Zhaolong...&Li, Zhongxin.(2016).c-MET inhibition enhances the response of the colorectal cancer cells to irradiation in vitro and in vivo.ONCOLOGY LETTERS,11,(4)
MLA：
Jia, Yitao,et al."c-MET inhibition enhances the response of the colorectal cancer cells to irradiation in vitro and in vivo".ONCOLOGY LETTERS 11..4(2016):2879-2885
