糖尿病（DM）被认为是癌变和进展的危险因素，尽管其生物机制尚不明确。本研究首次揭示了血小板-内皮细胞黏附分子1（PECAM-1）的内化通过β-连环蛋白介导的内皮-间充质转化（EndMT）将DM与癌症联系起来。我们通过mRNA微阵列分析研究了肠癌中DM与非DM之间肿瘤微环境（TME）的差异。通过临床患者和动物模型确定了DM对结肠癌的影响。此外，通过Western blot和免疫荧光检测在高葡萄糖（HG）和人结肠癌细胞（HCCC）上清液（SN）或共培养条件下分析了EndMT、PECAM-1和Akt / GSK-3β / β-连环蛋白信号转导。DM促进结肠癌（CC）的进展和EndMT发生。关于机制，DM导致PECAM-1从细胞膜缺陷，内化并在内皮细胞周围进一步积累，促使β-连环蛋白进入细胞核，导致CC中的EndMT发生。此外，Akt / GSK-3β信号通路被增强以抑制β-连环蛋白的降解，从而调节EndMT的过程。PECAM-1的缺陷和/或内化是β-连环蛋白介导的EndMT的关键事件，这在DM相关TME中通过增强的Akt / GSK-3β信号传导显著增强。这有助于解释DM如何促进CC的癌变和进展的机制。 视频摘要。©2023。BioMed Central Ltd.，Springer Nature的一部分。

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 β-catenin-mediated endothelial-mesenchymal transition (EndMT) to link DM to cancer.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-3β/β-catenin signaling were analyzed under high glucose (HG) and human colon cancer cell (HCCC) supernatant (SN) or coculture conditions by western and immunofluorescence tests.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 β-catenin entry into the nucleus, leading to EndMT occurrence in CC with DM. Additionally, Akt/GSK-3β signaling was enhanced to inhibit the degradation of β-catenin, which regulates the process of EndMT.PECAM-1 defects and/or internalization are key events for β-catenin-mediated EndMT, which is significantly boosted by enhanced Akt/GSK-3β signaling in the DM-associated TME. This contributes to the mechanism by which DM promotes the carcinogenesis and progression of CC. Video Abstract.© 2023. BioMed Central Ltd., part of Springer Nature.