TGF-beta acts as a dual regulator of COX-2/PGE(2) tumor promotion depending of its cross-interaction with H-Ras and Wnt/beta-catenin pathways in colorectal cancer cells

摘要

Transforming growth factor-beta (TGF-beta) plays a dual role acting as tumor promoter or suppressor. Along with cyclooxygenase-2 (COX-2) and oncogenic Ras, this multifunctional cytokine is deregulated in colorectal cancer. Despite their individual abilities to promote tumor growth and invasion, the mechanisms of cross regulation between these pathways is still unclear. Here, we investigate the effects of TGF-beta, Ras oncogene and COX-2 in the colorectal cancer context. We used colon adenocarcinoma cell line HT-29 and Ras-transformed IEC-6 cells, both treated with prostaglandin E-2 (PGE(2)), TGF-beta or a combined treatment with these agents. We demonstrated that PGE(2) alters the subcellular localization of E-cadherin and beta-catenin and enhanced the tumorigenic potential in HT-29 cells. This effect was inhibited by TGF-beta, indicating a tumor suppressor role. Conversely, in Ras-transformed IEC-6 cells, TGF-beta induced COX-2 expression and increased invasiveness, acting as a tumor promoter. In IEC-6 Ras-transformed cells, TGF-beta increased nuclear beta-catenin and Wnt/beta-catenin activation, opposite to what was seen in the PGE(2) and TGF-beta joint treatment in HT-29 cells. Together, our findings show that TGF-beta increases COX-2 levels and induces invasiveness cooperating with Ras in a Wnt/beta-catenin activation-dependent manner. This shows TGF-beta dual regulation over COX-2/PGE(2) tumor promotion depending on the H-Ras and Wnt/beta-catenin pathways activation status in intestinal cancer cells.