High glucose promotes aggressive progression of PR-negative endometrial cancer via CD146

BACKGROUND: Hyperglycemia is a risk factor for endometrial cancer (EC) progression, especially in the high-risk progesterone receptor‑negative (PR‑) subtype. A high‑glucose environment can induce epithelial‑mesenchymal transition (EMT) to promote tumor aggressiveness. However, the regulatory mechanism of EMT‑related molecules like CD146 in PR‑ EC under hyperglycemic conditions remains unclear, and its therapeutic potential is undefined. This study aimed to elucidate the role and mechanism of CD146 in this context. METHODS: This study integrated bioinformatics, cellular experiments, and clinical validation. Bioinformatics analysis of the TCGA database assessed CD146 expression in EC, focusing on the PR-low subgroup to evaluate its associations with prognosis, EMT, and glucose metabolism. A high-glucose-induced PR-negative JEC cell model was established for in vitro validation. Gene knockdown and overexpression assays elucidated CD146's functional role in high-glucose-driven EMT, invasion, and metastasis. Clinical tissue validation was performed using immunohistochemistry (IHC). Finally, drug sensitivity screening combined with molecular docking was employed to identify potential therapeutic compounds targeting CD146. RESULTS: The results showed that CD146 was markedly downregulated in endometrial cancer (EC) tissues, an effect exacerbated in PR‑negative EC cells under high‑glucose conditions. Low CD146 expression correlated with poor prognosis in PR‑negative EC patients. Mechanistically, CD146 suppression activated epithelial-mesenchymal transition (EMT), accompanied by enhanced cell migration and invasion. Functional studies demonstrated that CD146 knockout accelerated high‑glucose-induced EMT and malignant progression, whereas its overexpression attenuated this process. Immunohistochemical analysis confirmed significantly lower CD146 expression in EC tissues. Furthermore, drug sensitivity screening and molecular docking revealed that CD146‑low EC cells exhibit heightened sensitivity to the TGF‑β pathway inhibitor SB505124, suggesting its pharmacological inhibition as a promising therapeutic strategy for this EC subtype. CONCLUSION: In summary, high glucose may promote the progression of PR-negative EC by downregulating CD146 expression and inducing EMT, suggesting that CD146 represents a promising therapeutic target for precision treatment strategies in EC, particularly in patients with concurrent glucose metabolism dysregulation.