Molecular Mechanism Of DHRS2 Inhibiting Ovarian Cancer Progression Through Choline Metabolism

Objective: Dehydrogenase/reductase member 2(DHRS2)belongs to NADH/NADPH-dependent short-chain dehydrogenase/reductase family(SDR)member 2,and is widely involved in regulating the proliferation,migration and drug resistance of cancer cells.However,the underlying mechanism of its action has not been well elucidated.This project intends to explore the function and molecular mechanism of DHRS2 inhibiting the malignant progression of ovarian cancer from the perspective of tumor metabolism.Research methods and results: First,the expression characteristics of DHRS2 in ovarian cancer were analyzed using bioinformatics and clinical tissue samples,and the results showed that the expression of DHRS2 in ovarian cancer was lower than that in normal tissues.Then,the effects of overexpression of DHRS2 on gene transcription and metabolism in ovarian cancer cells were analyzed by transcriptomics and metabolomics.The results showed that overexpression of DHRS2 affected the activity of choline metabolic pathway in ovarian cancer cells.q-PCR was used to detect the effect of DHRS2 overexpression on choline metabolism-related metabolic enzymes(such as choline kinase α(CHKα),phospholipase D(PLD),phospholipase C(PLC)and phosphodiesterase 5/6(GDPD5/6)etc.)m RNA levels in ovarian cancer cells,identified CHKα as the most significant metabolic enzyme regulated by DHRS2 in the choline metabolic pathway.After transiently transfecting CHKα in DHRS2-overexpressing cells or culturing cells exogenously supplemented with choline,the inhibition of ovarian cancer cell proliferation and invasion by DHRS2 was reversed by CCK8,Transwell and Western blot detection,and the phosphorylation level of AKT ser473 was restored.In addition,RIP experiments demonstrated that direct binding of DHRS2 to CHKα m RNA reduced its stability.Finally,by constructing a small animal xenograft model and an intraperitoneal metastasis model,we found that DHRS2 inhibited ovarian cancer proliferation and metastasis in vivo.Conclusion: This project clarified the molecular mechanism by which DHRS2 reduced the stability of CHKα m RNA by post-transcriptional modification,and then inhibited the activity of AKT signaling pathway and choline metabolism pathway,thereby hindering the progression of ovarian cancer;and established molecular associations between metabolic enzymes,metabolites and malignant phenotypes of tumor cells.This study suggests that the targeted induction of DHRS2 expression can inhibit the choline metabolic pathway,which is expected to become a novel clinical intervention strategy for ovarian cancer.