Regulation of intestinal myofibroblasts by KRas-mutated colorectal cancer cells through heparin-binding epidermal growth factor-like growth factor

  • Authors:
    • Hideyoshi Kawasaki
    • Takuya Saotome
    • Tatsuya Usui
    • Takashi Ohama
    • Koichi Sato
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  • Published online on: March 22, 2017     https://doi.org/10.3892/or.2017.5520
  • Pages: 3128-3136
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Abstract

In colorectal cancer, gain-of-function mutations in KRas play a critical role in malignant transformation. Tumor growth in colorectal cancer is known to be promoted by the intestinal myofibroblasts (IMFs) that localize adjacent to the cancer cells, but the mechanisms of interaction between KRas-mutated cancer cells and the myofibroblasts remain unclear. Here, we investigated the effects of KRas-mutated cells on the behavior of myofibroblasts by using mouse primary IMFs and cells of an IMF cell line (LmcMF) and a mouse colon epithelial cell line (aMoC1). Conditioned medium (CM) was collected from aMoC1 cells overexpressing a control vector or KRasV12 vector (KRasV12-CM), and the effects of KRasV12-CM on IMFs were analyzed by performing proliferation assays, wound-healing assays, Boyden chamber assays, and western blotting. Whereas KRasV12-CM exerted little effect on the differentiation and proliferation of primary IMFs, the CM promoted migration of both primary IMFs and LmcMF cells. In KRasV12-overexpressing aMoC1 cells, mRNA expression of heparin-binding epidermal growth factor-like growth factor (HB-EGF) was higher than in mock-transfected aMoC1 cells, and HB-EGF promoted the migration of primary IMFs and LmcMF cells. Moreover, KRasV12-CM-induced IMF migration was suppressed by dacomitinib, an inhibitor of HB-EGF receptors. Notably, in LmcMF cells, both KRasV12-CM and HB-EGF activated extracellular signal-regulated kinase (ERK) and c-jun N-terminal kinase (JNK), whereas KRasV12-CM-induced migration of IMFs was suppressed following treatment with either an ERK inhibitor (FR180204) or a JNK inhibitor (SP600125). These results suggest that HB-EGF secreted from KRas-mutated colorectal cancer cells promotes IMF migration through ERK and JNK activation, which, in turn, could support cancer progression.
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May-2017
Volume 37 Issue 5

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Kawasaki H, Saotome T, Usui T, Ohama T and Sato K: Regulation of intestinal myofibroblasts by KRas-mutated colorectal cancer cells through heparin-binding epidermal growth factor-like growth factor. Oncol Rep 37: 3128-3136, 2017
APA
Kawasaki, H., Saotome, T., Usui, T., Ohama, T., & Sato, K. (2017). Regulation of intestinal myofibroblasts by KRas-mutated colorectal cancer cells through heparin-binding epidermal growth factor-like growth factor. Oncology Reports, 37, 3128-3136. https://doi.org/10.3892/or.2017.5520
MLA
Kawasaki, H., Saotome, T., Usui, T., Ohama, T., Sato, K."Regulation of intestinal myofibroblasts by KRas-mutated colorectal cancer cells through heparin-binding epidermal growth factor-like growth factor". Oncology Reports 37.5 (2017): 3128-3136.
Chicago
Kawasaki, H., Saotome, T., Usui, T., Ohama, T., Sato, K."Regulation of intestinal myofibroblasts by KRas-mutated colorectal cancer cells through heparin-binding epidermal growth factor-like growth factor". Oncology Reports 37, no. 5 (2017): 3128-3136. https://doi.org/10.3892/or.2017.5520