Research On Mechanism Of Up-regulating HIF-1? Expression By Glucocorticoid And Its Possible Biological Significance In Ovarian Cancer Cells

BackgroundOvarian cancer is the most deadly malignant tumor in gynecology.Because of its occult disease,it lacks specific and reliable diagnostic indicators.It is often late in its discovery.Metastasis is the leading cause of death in patients with ovarian cancer.The study of the relationship between stress and tumor has received increasing attention.Stress,including psychological stress caused by a patient's tumor,is thought to promote tumor progression.Glucocorticoids(GC)are important stress hormones,have strong immunosuppressive,antiinflammatory,and maintain internal environmental stability,and can regulate cell metabolism,differentiation,proliferation under the mediation of its receptor(GR).And survive.In addition,GC is widely used clinically.In addition to the treatment of autoimmune diseases and inflammation,it is also used as an adjunct to chemotherapy or radiotherapy for solid tumors/cancers to reduce side effects of radiochemotherapy and increase patient tolerance.Although the study of the relationship between GC and tumors has received attention,the results have not been clear.Studies have confirmed that GC can inhibit the proliferation and progression of some solid tumors.Therefore,GC alone or in combination with cytotoxic drugs(such as 5-fluorouracil)for breast cancer and prostate cancer has achieved certain results.In contrast,recent studies on multiple tumors have shown that GC can enhance tumor cell resistance to radiotherapy and chemotherapy,reduce apoptosis induced by radiotherapy and chemotherapy,and promote tumor cell survival [16-19],and these effects plus GC immunosuppression The role is to help the occurrence and development of cancer.Therefore,the role of GC in tumors is not yet clear,and whether or not the effect of GC depends on the type of tumor needs further study.Hypoxia is one of the characteristics of the tumor's common microenvironment.Hypoxia can induce the expression of hypoxia-inducible factor HIF-1.HIF-1 is an important transcription factor composed of HIF-1? and HIF-1?,where the ? subunit is an oxygen regulatory subunit.Increased expression of HIF-1? is thought to be associated with a poor prognosis in patients with cancer in the clinic.Studies have shown that the expression of HIF-1? in ovarian cancer tissues is significantly higher than that in normal ovarian tissues;and the high expression level of HIF-1? in ovarian cancer tissues is positively correlated with the poor prognosis of ovarian cancer patients.In recent years,studies have suggested that the high expression of HIF-1? promotes the migration and invasion of many kinds of tumor cells,so HIF1-? has become a key predictor of the progression of several types of tumors.However,HIF-1? has little research on the invasion and migration of ovarian cancer cells.Existing studies also suggest that HIF-1? promotes the invasion and metastasis of ovarian cancer cells under hypoxia.MUC1 is a transmembrane mucin that is often overexpressed in epithelial tumors and interacts with multiple proteins on the membrane,activating intracellular PI-3K/AKT pathways,Wnt pathways,and multiple signal transduction pathways.Regulate cell invasion and metastasis.In recent years,MUC1 has been considered as a new hypoxia-inducible factor.It has been reported that there is an interaction between MUC1 and HIF-1?,but the exact mechanism of action is unclear.The small G protein Rho-activated protein kinase ROCK2 as a downstream signaling molecule can regulate cell cytoskeleton to regulate cell movement and is closely related to the metastasis of tumor cells.Some foreign scholars have discovered in their research that the Rho/ROCK pathway can regulate HIF-1? signal transduction.Our previous research in the Department of Disease and Health of our school found that GC can obviously promote the migration,invasion and metastasis of ovarian cancer cells both in vivo and in vitro,and GC can up-regulate the expression of MUC1 and ROCK2 in ovarian cancer cells.Based on this research,we further explored whether GC could affect the HIF-1? signaling pathway in ovarian cancer cells to promote the migration of ovarian cancer cells and explore its possible mechanism.We mainly observed that MUC1 and ROCK2 and GC increase HIF-1? protein and then The role of promoting the role of ovarian cancer cell migration.METHODSWe performed experiments at the cellular level.The ovarian cancer cell lines HO-8910 and SKOV3 were used as research subjects.During the experiment,cells were cultured in 1640 medium containing 10% hormone-removed serum to remove the effect of hormones in the cells on the cells,using 100 nM.DEX treats cells for different times.Western Blot method was used to detect the expression level of HIF-1? protein.The siRNA interference experiments interfered with the expression of HIF-1? and MUC1,respectively,and then Western Blot was used to verify the expression of MUC1,ROCK2,and HIF-1?.Transwell chamber was used to detect the vertical migration ability of ovarian cancer cells.RESULTS1.DEX can significantly up-regulate the expression of HIF-1? protein in ovarian cancer cells.Interfering with the expression of HIF-1? can significantly block the effect of DEX on the migration of ovarian cancer cells.2.DEX can up-regulate the expression of MUC1 in ovarian cancer cells.Interfering with the expression of MUC1 not only can significantly block the effect of DEX on the migration of ovarian cancer cells,but also can significantly block the effect of DEX on the up-regulation of HIF-1?.On the contrary,it interferes with HIF-1?.Does not affect DEXinduced MUC1 expression.3.Interference with HIF-1? does not affect the expression of ROCK2 by DEX.CONCLUSIONDEX can significantly increase the expression of HIF-1? protein in ovarian cancer cells,which is closely related to the up-regulation of MUC1 expression by Dex.DEX up-regulates MUC1 and then increases HIF-1? plays an important role in the promotion of DEX-mediated ovarian cancer cell migration.