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Hepatocyte growth factor‑induced mesenchymal‑epithelial transition factor activation leads to insulin‑like growth factor 1 receptor inhibitor unresponsiveness in gastric cancer cells

  • Authors:
    • Rujiao Liu
    • Wenbo Tang
    • Xiaotian Han
    • Ruixuan Geng
    • Chenchen Wang
    • Zhe Zhang
  • View Affiliations / Copyright

    Affiliations: Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China, International Medical Services, Peking Union Medical College Hospital, Beijing 100000, P.R. China
    Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 5983-5991
    |
    Published online on: September 6, 2018
       https://doi.org/10.3892/ol.2018.9414
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Abstract

Insulin‑like growth factor 1 receptor (IGF‑1R) inhibitors have been developed as potential therapeutics for cancer treatment; however, the phase III trials have not produced promising overall survival rates. Therefore, understanding the mechanism underlying intrinsic resistance to IGF‑1R‑targeted agents is urgently required. A number of studies have revealed that activation of alternative receptor tyrosine kinases can mediate resistance to IGF‑1R‑targeted therapy. The present study investigated whether activated mesenchymal‑epithelial transition factor (MET; also known as c‑Met and hepatocyte growth factor receptor) confers resistance to an IGF‑1R inhibitor (NVP‑AEW541) of gastric cancer (GC) cells. NCI‑N87 and MGC‑803 cells were treated with varying concentrations and combinations of NVP‑AEW541, hepatocyte growth factor (HGF) and MET small interfering (si)‑RNA or crizotinib (a MET inhibitor). The effects of these agents on cell proliferation and pro‑apoptotic events were assessed by Cell Counting Kit‑8 assays and flow cytometry. Receptor activation and the downstream signaling pathway were examined using western blot analysis. Expression and/or activation of MET and IGF‑1R in 156 GC specimens were evaluated by immunohistochemistry. The results demonstrated that NVP‑AEW541 inhibited cell growth, with dephosphorylation of IGF‑1R and protein kinase B (AKT), in NCI‑N87 and MGC‑803 cells. Application of HGF activated MET and the downstream AKT signaling pathways, decreased apoptotic events and restored cell proliferation, which were reversed by MET inhibition via crizotinib or siRNA knockdown. Furthermore, combination therapy of NVP‑AEW541 and crizotinib exhibited an enhanced effectiveness in vitro. In addition, >40% of IGF‑1R overexpressed GC specimens showed MET expression and activation. In conclusion, HGF‑induced MET activation may represent a novel mechanism conferring unresponsiveness to IGF‑1R‑targeted agents in GC, and inhibition of MET may improve the efficacy of IGF‑1R inhibitors.
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Copy and paste a formatted citation
Spandidos Publications style
Liu R, Tang W, Han X, Geng R, Wang C and Zhang Z: Hepatocyte growth factor‑induced mesenchymal‑epithelial transition factor activation leads to insulin‑like growth factor 1 receptor inhibitor unresponsiveness in gastric cancer cells. Oncol Lett 16: 5983-5991, 2018.
APA
Liu, R., Tang, W., Han, X., Geng, R., Wang, C., & Zhang, Z. (2018). Hepatocyte growth factor‑induced mesenchymal‑epithelial transition factor activation leads to insulin‑like growth factor 1 receptor inhibitor unresponsiveness in gastric cancer cells. Oncology Letters, 16, 5983-5991. https://doi.org/10.3892/ol.2018.9414
MLA
Liu, R., Tang, W., Han, X., Geng, R., Wang, C., Zhang, Z."Hepatocyte growth factor‑induced mesenchymal‑epithelial transition factor activation leads to insulin‑like growth factor 1 receptor inhibitor unresponsiveness in gastric cancer cells". Oncology Letters 16.5 (2018): 5983-5991.
Chicago
Liu, R., Tang, W., Han, X., Geng, R., Wang, C., Zhang, Z."Hepatocyte growth factor‑induced mesenchymal‑epithelial transition factor activation leads to insulin‑like growth factor 1 receptor inhibitor unresponsiveness in gastric cancer cells". Oncology Letters 16, no. 5 (2018): 5983-5991. https://doi.org/10.3892/ol.2018.9414
Copy and paste a formatted citation
x
Spandidos Publications style
Liu R, Tang W, Han X, Geng R, Wang C and Zhang Z: Hepatocyte growth factor‑induced mesenchymal‑epithelial transition factor activation leads to insulin‑like growth factor 1 receptor inhibitor unresponsiveness in gastric cancer cells. Oncol Lett 16: 5983-5991, 2018.
APA
Liu, R., Tang, W., Han, X., Geng, R., Wang, C., & Zhang, Z. (2018). Hepatocyte growth factor‑induced mesenchymal‑epithelial transition factor activation leads to insulin‑like growth factor 1 receptor inhibitor unresponsiveness in gastric cancer cells. Oncology Letters, 16, 5983-5991. https://doi.org/10.3892/ol.2018.9414
MLA
Liu, R., Tang, W., Han, X., Geng, R., Wang, C., Zhang, Z."Hepatocyte growth factor‑induced mesenchymal‑epithelial transition factor activation leads to insulin‑like growth factor 1 receptor inhibitor unresponsiveness in gastric cancer cells". Oncology Letters 16.5 (2018): 5983-5991.
Chicago
Liu, R., Tang, W., Han, X., Geng, R., Wang, C., Zhang, Z."Hepatocyte growth factor‑induced mesenchymal‑epithelial transition factor activation leads to insulin‑like growth factor 1 receptor inhibitor unresponsiveness in gastric cancer cells". Oncology Letters 16, no. 5 (2018): 5983-5991. https://doi.org/10.3892/ol.2018.9414
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