ABSTRACT
Ovarian cancer is one of the most common gynecological malignant tumors with insidious onset, strong invasiveness, and poor prognosis. Metabolic alteration, particularly aerobic glycolysis, which is tightly regulated by transcription factors, is associated with the malignant behavior of OC. We screened FOXK2 in this study as a key transcription factor that regulates glycolysis in OC. FOXK2 is overly expressed in OC, and poor prognosis is predicted by overexpression. FOXK2 promotes OC cell proliferation both in vitro and in vivo and cell migration in vitro. Further studies showed that PDK2 directly binds to the forkhead-associated (FHA) domain of FOXK2 to phosphorylate FOXK2 at Thr13 and Ser30, thereby enhancing the transcriptional activity of FOXK2. FOXK2 transcriptionally regulates the expression of PDK2, thus forming positive feedback to sustain glycolysis in OC cells.
Subject(s)
Cell Proliferation , Forkhead Transcription Factors , Glycolysis , Ovarian Neoplasms , Pyruvate Dehydrogenase Acetyl-Transferring Kinase , Humans , Ovarian Neoplasms/pathology , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/genetics , Female , Glycolysis/genetics , Pyruvate Dehydrogenase Acetyl-Transferring Kinase/metabolism , Pyruvate Dehydrogenase Acetyl-Transferring Kinase/genetics , Forkhead Transcription Factors/metabolism , Forkhead Transcription Factors/genetics , Cell Line, Tumor , Phosphorylation , Animals , Cell Proliferation/genetics , Mice , Cell Movement/genetics , Gene Expression Regulation, Neoplastic , Feedback, Physiological , Mice, Nude , PrognosisABSTRACT
OBJECTIVE: The aim of this study was to investigate the expression and clinical significance of HIF-1α and DcR3 in endometriosis by analysing clinical case data. Tissue samples were collected for tissue chip analysis and staining, and human endometrial stromal cells were isolated and cultured for cell experiments. Additionally, experiments were conducted on collected peritoneal fluid to explore the association and role of HIF-1α and DcR3 in endometriosis. STUDY DESIGN: Patients who visited the Department of Obstetrics and Gynaecology at Central Hospital in Fengxian District, Shanghai, from January 2018 to December 2021 were recruited for this controlled study. Clinical data and tissue chip staining results were collected for multiple regression analysis on the clinical significance of HIF-1α and DcR3. Endometrial tissue, ovarian cysts, and pelvic fluid were collected, and human endometrial stromal cells were cultured. The impact of HIF-1α on DcR3 in different oxygen environments and its role in endometriosis were investigated through PCR, Western blotting, enzyme-linked immunosorbent assay, as well as adhesion and migration assays. RESULTS: In patients with endometriosis, the expression of DcR3 and HIF-1α was found to be upregulated and correlated in ectopic endometrium. The expression of DcR3 served as an indicator of the severity of endometriosis. Hypoxia induced the expression of DcR3, which was regulated by HIF-1α and promoted migration and adhesion. CONCLUSION: DcR3 can be used as a clinical indicator to assess the severity of endometriosis. The hypoxic environment in endometriosis enhances disease progression by regulating DcR3 through HIF-1α.