Previous studies indicate that COX-2 and prostaglandin E(2) (PGE(2)) receptor subtypes are involved in intestinal carcinogenesis and activation of downstream pathways. In this report, we try to understand the association of PGE(2) receptor and K-ras cellular mechanism during the development of colorectal cancer. We collected 21 colorectal cancer patients and compared the protein expression of tumor tissues and normal mucosa tissues by using immunoblot. Furthermore, we transferred empty vector and pcDNA-K-ras into Ras-HT29 colon cancer cells. Result showed that phosphorylation of Akt and EP(1)/EP(4) were over-expressed in the colorectal tumor tissue. K-ras induces HT29 cells proliferation through the expressions of COX-2, EP1/EP4, pAkt, GSK3beta and increases Tcf transcriptional factor activation. Additionally, Ras protein was suppressed when treated with EP(4) inhibitor in Ras-HT29 cell. In cell cycle assay, K-ras mutation causing cell cycle S phase was prolonged with an increase in the G2/M phase ratio. In conclusion, we suggested that Ras overexpression leads to cell proliferation through activating Ras/PI3K/GSK3beta/EP(4) PGE(2) receptor signals and caused a feedback regulation of Ras by EP4 in colorectal tumor progression.