PECAM-1 drives beta-catenin-mediated EndMT via internalization in colon cancer with diabetes mellitus

Background Diabetes mellitus (DM) is considered to be a risk factor in carcinogenesis and progression, although the biological mechanisms are not well understood. Here we demonstrate that platelet-endothelial cell adhesion molecule 1 (PECAM-1) internalization drives beta-catenin-mediated endothelial-mesenchymal transition (EndMT) to link DM to cancer. Methods The tumor microenvironment (TME) was investigated for differences between colon cancer with and without DM by mRNA-microarray analysis. The effect of DM on colon cancer was determined in clinical patients and animal models. Furthermore, EndMT, PECAM-1 and Akt/GSK-3 beta/beta-catenin signaling were analyzed under high glucose (HG) and human colon cancer cell (HCCC) supernatant (SN) or coculture conditions by western and immunofluorescence tests. Results DM promoted the progression and EndMT occurrence of colon cancer (CC). Regarding the mechanism, DM induced PECAM-1 defection from the cytomembrane, internalization and subsequent accumulation around the cell nucleus in endothelial cells, which promoted beta-catenin entry into the nucleus, leading to EndMT occurrence in CC with DM. Additionally, Akt/GSK-3 beta signaling was enhanced to inhibit the degradation of beta-catenin, which regulates the process of EndMT. Conclusions PECAM-1 defects and/or internalization are key events for beta-catenin-mediated EndMT, which is significantly boosted by enhanced Akt/GSK-3 beta signaling in the DM-associated TME. This contributes to the mechanism by which DM promotes the carcinogenesis and progression of CC.

Automated summary

Diabetes mellitus enhances the occurrence and progression of colon cancer through the internalization of platelet-endothelial cell adhesion molecule 1 (PECAM-1) and subsequent activation of beta-catenin-mediated endothelial-mesenchymal transition (EndMT).