The Mechanism Of KNDC1 Inhibits The Proliferation Of Epithelial Ovarian Cancer Cell

ObjectiveThe aim of our study is to screen and identify genes differentially expressed in normal ovarian epithelial tissue and epithelial ovarian cancer;to explore the expression pattern of KNDC1 in epithelial ovarian cancer patients and its clinical significance and further to observe the biological functions and molecular mechanisms of KNDC1 in epithelial ovarian cancer.MethodThe gene chip was used to screen genes differentially expressed in normal ovarian epithelial tissue and epithelial ovarian cancer.And the m RNA level of KNDC1 was reexamined using RT-qPCR.The association between the expression level of KNDC1 and progression-free survival of patients with epithelial ovarian cancer was analyzed by kmplot database.After epithelial ovarian cancer cell line stably knockdown KNDC1 was established,the MTS assay and animal tumor model were respectively used to investigate the changes of cell proliferation ability in vitro and in vivo.To investigate the molecular mechanisms of KNDC1 promoting the proliferation,western blot was employed to detect the effects of KNDC1 on ERK1/2 signaling pathways and AKT signaling pathways;luciferase reporter assay was performed to detect the activity of NF-?B after knockdown KNDC1.ERK1/2 signaling pathway inhibitor(U0126)was applied to confirm the ability of KNDC1 to inhibit the proliferation of epithelial ovarian cancer cells through ERK1/2 signaling pathway.Finally,epithelial ovarian cancer cellswere treated with 5-Aza-d C or TSA to determine the possible mechanism of KNDC1 downregulation in epithelial ovarian cancer.ResultHere,we observed,using gene chip scanning and RT-qPCR,that the expression of KNDC1 m RNA in epithelial ovarian cancer was significantly downregulated compared with normal ovarian epithelial tissue.Survival analysis showed that lower KNDC1 predicted a poor progression-free survival(PFS)for patients with epithelial ovarian cancer.The efficiency of knockdown of KNDC1 by lentivirus infection was verified by western blot,the results showed the expression of KNDC1 was significantly down-regulated.The MTS assay and animal tumor model showed that knockdown of KNDC1 enhanced the proliferation of epithelial ovarian cancer cells both in vitro and in vivo.Subsequent investigation revealed that knockdown of KNDC1 promoted the proliferation of epithelial ovarian cancer cells via induction ERK1/2 phosphorylation rather than p38 or JNK.At the same time,the activities of NF-?B and AKT signaling pathway were not affected after KNDC1 knockdown.ERK1/2 inhibitor can reverse cell proliferation induced by knockdown of KNDC1.Furthermore,we observed that TSA restored the KNDC1 m RNA and KNDC1 protein levels in epithelial ovarian cancer cells.ConclusionKNDC1 expression is significantly downregulated in epithelial ovarian cancer and low KNDC1 expression could consider as a predictor of poor prognosis in epithelial ovarian cancer patients.KNDC1 might function as a tumor suppressor in epithelial ovarian tumors,inhibiting the proliferation of epithelial ovarian cancer cells by suppressing ERK1/2 activity.Histone deacetylation at the KNDC1 promoter accounts for the downregulation of KNDC1 in epithelial ovarian cancer.