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中华结直肠疾病电子杂志 ›› 2018, Vol. 07 ›› Issue (03) : 237 -241. doi: 10.3877/cma.j.issn.2095-3224.2018.03.008

所属专题: 文献

论著

抑制MET对RAS突变型结肠癌细胞的抗肿瘤作用
宋娜1, 白茗1, 王凯1, 李艳荣1, 曲秀娟1, 刘云鹏1,()   
  1. 1. 110001 沈阳,中国医科大学附属第一医院肿瘤内科
  • 收稿日期:2017-05-29 出版日期:2018-06-25
  • 通信作者: 刘云鹏
  • 基金资助:
    国家自然科学基金青年科学基金项目(No.81401938); 辽宁省科学技术计划项目(No.2014226033,No.2014225013); 辽宁省中央引导地方科技发展专项资金(No.2016007010)

The antitumor effect of MET inhibition on RAS mutant colon cancer cells

Na Song1, Ming Bai1, Kai Wang1, Yanrong Li1, Xiujuan Qu1, Yunpeng Liu1,()   

  1. 1. Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China
  • Received:2017-05-29 Published:2018-06-25
  • Corresponding author: Yunpeng Liu
  • About author:
    Correspondence author: Liu Yunpeng, Email:
引用本文:

宋娜, 白茗, 王凯, 李艳荣, 曲秀娟, 刘云鹏. 抑制MET对RAS突变型结肠癌细胞的抗肿瘤作用[J/OL]. 中华结直肠疾病电子杂志, 2018, 07(03): 237-241.

Na Song, Ming Bai, Kai Wang, Yanrong Li, Xiujuan Qu, Yunpeng Liu. The antitumor effect of MET inhibition on RAS mutant colon cancer cells[J/OL]. Chinese Journal of Colorectal Diseases(Electronic Edition), 2018, 07(03): 237-241.

目的

探讨抑制MET对于RAS突变结肠癌的体内体外抗肿瘤作用。

方法

选取4种常见RAS突变型结肠癌细胞(HCT-116、DLD-1、Lovo和HCT-15),采用siRNA敲除MET蛋白表达,或者加入特异性MET抑制剂PHA-665752,采用MTT及集落形成实验观察抑制MET对结肠癌细胞增殖抑制的作用,应用Western Blotting检测PHA-665752对MET/AKT/ERK信号通路的作用。另外,应用HCT-116细胞系构建裸鼠皮下成瘤模型,给予PHA-665752腹腔注射,观察MET抑制剂对体内肿瘤的抑制作用。

结果

RAS突变的4种结肠癌细胞系均有MET蛋白表达。应用siRNA敲除MET蛋白表达对HCT-116和Lovo细胞的增殖抑制作用分别为19.6±4.5%和27.8±5.8%,而应用MET特异性抑制剂PHA-665752对两种细胞的增殖抑制作用呈剂量依赖性,细胞克隆形成实验证实PHA-665752可有效抑制细胞克隆形成。另外,应用HCT-116细胞构建裸鼠皮下成瘤模型,给予PHA-665752单药证实MET抑制剂可明显抑制HCT-116细胞的皮下移植瘤(第四周肿瘤体积:PHA-665752组为300±72 mm3,对照组为608±59 mm3t=5.731,P=0.005)。Western Blotting证实应用PHA-665752预处理能明显抑制HGF激活的p-MET、p-AKT和p-ERK。

结论

抑制MET对于RAS突变型结肠癌具有抗肿瘤作用,靶向MET可能成为RAS突变型结肠癌的有效治疗。

Objective

To explore The effect of MET inhibition on RAS mutant colon cancer in vivo and in vitro experiments.

Methods

Four kinds of common RAS mutant colon cancer cells (HCT-116, DLD-1, Lovo and HCT-15) were selected in this study. The MTT assay and colony formation assay were used to testify the growth inhibitory effect of MET inhibition by siRNA and MET inhibitor PHA-665752, and Western Blotting was used to test the effect of PHA-665752 on MET/AKT/ERK signalling. HCT-116 cells were used to construct the subcutaneous tumor model in nude mice, and PHA-665752 was injected intraperitoneally to observe the inhibitory effect in vivo.

Results

The four kinds of RAS mutant colon cancer cells all possessed MET expression. The growth inhibitory rate of MET inhibition by siRNA in HCT-116 and Lovo cells was 19.6±4.5% and 27.8±5.8%, respectively. The inhibitory effect of MET specific inhibitor PHA-665752 in HCT-116 and Lovo cells was dose dependent, and the colony formation assay confirmed that PHA-665752 could effectively inhibit the formation of cell clones. Furthermore, tumor growth with PHA-665752 was analyzed in vivo. HCT-116 xenografts showed antitumor response when treated with PHA-665752 (the tumor volume in the fourth week: 300±72 mm3 for PHA-665752 arms and 608±59 mm3 for the control arms, P=0.005). Western Blotting showed pretreatment with PHA-665752 significantly abrogated p-MET, p-AKT and p-ERK stimulated by HGF.

Conclusions

MET inhibition exhibited antitumor effect in RAS mutant colon cancer cells, suggesting targeting MET might become a potential targeted therapy.

图5 MET抑制剂PHA-665752对MET/AKT/ERK信号通路的作用。在Lovo细胞中应用PHA-665752预处理2小时后加入HGF,Western Blotting检测p-MET、p-AKT和p-ERK及本底的蛋白表达
[1]
Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial [J]. Lancet, 2013, 381 (9863): 303-312.
[2]
Gherardi E, Birchmeier W, Birchmeier C, et al. Targeting MET in cancer: rationale and progress [J]. Nat Rev Cancer, 2012, 12(2): 89-103.
[3]
Gayyed MF, Abd E-Maqsoud NM, El-Hameed El-Heeny AA, et al. c-MET expression in colorectal adenomas and primary carcinomas with its corresponding metastases [J]. J Gastrointest Oncol, 2015, 6(6): 618-627.
[4]
Gao H, Guan M, Sun Z, et al. High c-Met expression is a negative prognostic marker for colorectal cancer: a meta-analysis [J]. Tumour Biol, 2015, 36(2): 515-520.
[5]
Sun YL, Liu WD, Ma GY, et al. Expression of HGF and Met in human tissues of colorectal cancers: biological and clinical implications for synchronous liver metastasis [J]. Int J Med Sci, 2013, 10(5): 548-559.
[6]
Isella C, Mellano A, Galimi F, et al. MACC1 mRNA levels predict cancer recurrence after resection of colorectal cancer liver metastases [J]. Ann Surg, 2013, 257(6): 1089-1095.
[7]
Liska D, Chen CT, Bachleitner-Hofmann T, et al. HGF rescues colorectal cancer cells from EGFR inhibition via MET activation [J]. Clin Cancer Res, 2011, 17(3), 472-482.
[8]
Song N, Liu S, Zhang J, et al. Cetuximab-induced MET activation acts as a novel resistance mechanism in colon cancer cells [J]. Int J Mol Sci, 2014, 15(4): 5838-5851.
[9]
Kang YK, Muro K, Ryu MH, et al. A phase II trial of a selective c-Met inhibitor tivantinib (ARQ 197) monotherapy as a second- or third-line therapy in the patients with metastatic gastric cancer [J]. Invest New Drugs, 2014, 32(2): 355-361.
[10]
Sequist LV, von Pawel J, Garmey EG, et al. Randomized phase II study of erlotinib plus tivantinib versus erlotinib plus placebo in previously treated non-small-cell lung cancer [J]. J Clin Oncol, 2011, 29(24): 3307-3315.
[11]
De Roock W, Claes B, Bernasconi D, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis [J]. Lancet Oncol, 2010, 11(8), 753-762.
[12]
Corso S, Giordano S. Cell-autonomous and non-cell-autonomous mechanisms of HGF/MET-driven resistance to targeted therapies: from basic research to a clinical perspective [J]. Cancer Discov, 2013, 3(9): 978-992.
[13]
Dulak AM, Gubish CT, Stabile LP, et al. HGF-independent potentiation of EGFR action by c-Met [J]. Oncogene, 2011, 30(33): 3625-3635.
[14]
Varkaris A, Gaur S, Parikh NU, et al. Ligand-independent activation of MET through IGF-1/IGF-1R signaling [J]. Int J Cancer, 2013, 133(7): 1536-1546.
[15]
Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer [J]. N Engl J Med, 2014, 371(23): 2167-2177.
[16]
Scagliotti G, von Pawel J, Novello S, et al. Phase III Multinational, Randomized, Double-Blind, Placebo-Controlled Study of Tivantinib (ARQ 197) Plus Erlotinib Versus Erlotinib Alone in Previously Treated Patients With Locally Advanced or Metastatic Nonsquamous Non-Small-Cell Lung Cancer [J]. J Clin Oncol, 2015, 33(24): 2667-2674.
[17]
Eng C, Bessudo A, Hart LL, et al. A randomized, placebo-controlled, phase 1/2 study of tivantinib (ARQ 197) in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with wild-type KRAS who have received first-line systemic therapy [J]. Int J Cancer, 2016, 139(1): 177-186.
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