BPA Exposure Enhances The Metastatic Aggression Of Ovarian Cancer Through The ERα/AKT/mTOR/HIF-1α Signaling Axis

Objective: Bisphenol A(BPA)is the most used environmental endocrine disruptor worldwide and can be commonly detected in humans and the environment.Recent years,BPA has attracted much attention as a cancer risk factor.Ovarian cancer(OC)is one of the common gynecologic malignancies with relatively high mortality and morbidity,but the pathogenic factors of OC remain unclear.Currently,there is evidence suggesting that the environmental endocrine disruptor BPA may contribute to the occurrence and development of ovarian cancer.While studies exploring its molecular mechanisms and in vivo effects in animals are relatively limited.This study aims to investigate the effects of BPA on the biological functions of ovarian cancer,both at the cellular and animal levels.And we seek to demonstrate the molecular mechanisms behind these effects.Our goal of this study is to provide a theoretical basis and experimental support for understanding the influence of environmental factors on the development of ovarian cancer.Methods: MTT,Ed U,cell scratch assay and Transwell chamber assay were used to detect the effects of different concentrations of BPA on the biological function of human ovarian cancer ES-2 and OVCAR-3.Colorimetry was used to detect the effects of BPA on the glycolytic products of ovarian cancer cells.Transcriptome sequencing,bioinformatics methods,RT-q PCR and Western Blot were used to analyze and detect the changes of related genes and signaling pathways in human ovarian cancer ES-2 and OVCAR-3 cells exposed to BPA.The effects of BPA exposure on ERα interacting proteins were analyzed by co-IP and mass spectrometry.The effect of BPA on tumor growth in vivo was detected by constructing nude mouse xenograft model H&E staining,IHC detection,RT-q PCR and Western Blot were used to verify the molecular mechanism of BPA promoting the growth of xenograft tumor in nude mice.Results:(1)BPA(1,10,100 μM)could significantly promote the proliferation,migration and invasion of human ovarian cancer cells at the concentration of 10 μM after 48 h of treatment.Meanwhile,BPA could significantly promote the glucose uptake,lactate release and intracellular ATP content of human ovarian cancer cells.(2)Bisphenol A(BPA)has been demonstrated to promote the transcriptional activity of glycolytic enzymes and increase the protein expression levels of the ERα/AKT/mTOR/HIF-1α signaling axis;inhibition of ERα expression results in decreased transcriptional activity of glycolytic enzymes and lower expression levels of the AKT/mTOR/HIF-1α signaling axis.Additionally,BPA exposure enhances the targeted binding of ERα to LDHA.(3)After the successful modeling of ovarian cancer xenografts in nude mice,there was no significant difference in body weight between each group and the control group,but there is a increase in the tumor volume of nude mice exposed to BPA.(4)Compared to the control group,BPA increased the positive expression of Ki67,ERα and LDHA protein in ovarian cancer xenografts.It promoted the expression levels of ERα,LDHA,AKT,HIF-1α,mTOR transcription and translation.In conclusion,BPA promoted the proliferation,migration and invasion of ovarian cancer cells and induced the process of cellular glycolysis in vitro,and promoted the growth of transplanted tumors in nude mice in vivo.The present study revealed that BPA affects ovarian cancer cells.The present study reveals the molecular mechanism by which BPA affects the development of ovarian cancer,improves the understanding of the risk of BPA,and provides new insights and theoretical evidence for the subsequent assessment of the carcinogenic effects of BPA.