HGF-activated colonic fibroblasts mediates carcinogenesis of colonic epithelial cancer cells via PKC-cMET-ERK1/2-COX-2 signaling.

COX-2 is a major regulator in colorectal inflammation and cancer. Herein, we first report that primary cancer-associated colonic fibroblasts activated by HGF play a critical role in mediation of proliferation and invasiveness of human colonic epithelial cancer cells. We have discovered that the proliferation and invasiveness of colonic epithelial cancer cells are predominantly enhanced through activation of PKC-cMET-ERK1/2-COX-2 signaling by HGF in the co-cultured cancer-associated fibroblasts. This conclusion is supported by the fact, that a selective PKC inhibitor, BIM, inhibits ERK1/2 and COX-2 signalings, MEK/ERK1/2 inhibitor, PD98059, nullifies COX-2 signaling, and COX-2 inhibitor, NS-398, attenuates the proliferation and invasiveness potential of the colonic cancer cells. We have concluded that HCF-activated cancer associated fibroblasts play a critical role in carcinogenesis of colonic cancer.