Metformin alleviates endometrial hyperplasia through the UCA1/miR‑144/TGF‑β1/AKT signaling pathway.

Abstract

The objective of the present study was to investigate the molecular mechanism underlying the role of metformin (Met) in reducing the risk of endometrial hyperplasia (EH). Reverse transcription‑quantitative polymerase chain reaction, western blot and immunohistochemistry (IHC) assays were used to study the effects of Met and tamoxifen on the expression levels of urothelial cancer associated 1 (UCA1), microRNA‑144 (miR‑144) and other factors along the transforming growth factor‑β1 (TGF‑β1)/protein kinase B (AKT) signaling pathway. In addition, MTT and flow cytometry assays were performed to detect the effect of Met on cell proliferation and apoptosis. Tamoxifen treatment increased the weight of the uterus and the level of UCA1, while decreasing the expression of miR‑144. In addition, treatment with tamoxifen (2.0 and 3.5µg) upregulated the protein expression levels of TGF‑β and p‑AKT, while downregulating the protein expression of active Caspase‑3 in a dose‑dependent manner. By contrast, Met reduced cell viability, promoted cell apoptosis, and reduced the expression levels of UCA1, TGF‑β and p‑AKT, while upregulating the expression of miR‑144 and active Caspase‑3 in a dose‑dependent manner. Furthermore, Met also reduced the weight of uterus. However, tamoxifen and Met did not exert any effect on the protein levels of total AKT and total Caspase‑3. The levels of TGF‑β and p‑AKT proteins in the EH group were much higher when compared with those in the sham group, while Met treatment reduced these protein levels to a certain extent. In addition, the expression of active Caspase‑3 in the EH group was much lower than that in the sham group, while Met treatment increased its level to a certain extent. In conclusion, the current study suggested that Met reduces the risk of EH by reducing the expression levels of UCA1, TGF‑β and p‑AKT, while increasing the levels of miR‑144 and active Caspase‑3 in a dose‑dependent manner.