RESUMO
MicroRNA let-7b is a potent tumor suppressor and targets crucial oncogenes. Previous studies have shown that let-7b expression is suppressed in ovarian cancer; however, the regulatory mechanisms of let-7b in ovarian cancer are still not well defined. The cellular role and targets of let-7b in ovarian cancer remain elusive. In the present study, we showed that histone demethylase, KDM2B, directly suppressed let-7b expression by H3K36me2 demethylation. Moreover, let-7b inhibited EZH2 expression in ovarian cancer cells. Based on these results we know that let-7b antagonizes the enhancement of EZH2 expression caused by KDM2B overexpression, and its expression is negatively correlated with KDM2B and EZH2 expression. More importantly, proliferation, migration, and wound healing assays showed that let-7b inhibited ovarian cancer cell proliferation and migration in vitro. Additionally, let-7b overexpression neutralized KDM2B-promoted cell proliferation and migration. Furthermore, downregulation of let-7b increased the xenografted tumor volumes in nude mice that were transplanted with KDM2B-silenced cells. EZH2 silencing reversed the tumor growth enhancement mediated by inhibition of let-7b. Last, we show that let-7b expression is suppressed in ovarian carcinomas and its expression is negatively associated with the clinicopathological features of ovarian cancer, including histological type, histological grade, International Federation of Gynecology and Obstetrics (FIGO) stage, and lymph node metastatic status. In conclusion, in ovarian cancer, let-7b expression is epigenetically suppressed by high expression of KDM2B. The loss of let-7b upregulates the expression of EZH2, which promotes ovarian cancer growth in vitro and in vivo.
Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteínas F-Box/genética , Regulação Neoplásica da Expressão Gênica/genética , Histona Desmetilases com o Domínio Jumonji/genética , MicroRNAs/genética , Neoplasias Ovarianas/patologia , Adulto , Animais , Proliferação de Células/genética , Progressão da Doença , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Proteínas F-Box/metabolismo , Feminino , Xenoenxertos , Humanos , Histona Desmetilases com o Domínio Jumonji/metabolismo , Camundongos , Camundongos Nus , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismoRESUMO
The use of mRNAs as biomarkers serves to diagnose, treat, as well as aid the prognosis of cancer. The present study involved an analysis of mRNAs in the cell cycle at the G2 and G3 tumor grades for the prognosis of ovarian serous cystadenocarcinoma (OSC) using 364 clinical samples (G2:G3=42:322). Statistics aided the identification of NPFFR2, XPNPEP2 and CELA3B; the 3-mRNA model that allows for classification of patients into high- and low-risk groups using a median value of 0.9580745. The rates of survival varied (P=0.00149) and the independent detection of stratification of the risk of this disease was validated with success using the 3-mRNA signature, which was demonstrated to be more successful than the weight model. This approach was revealed to provide the prognosis of grade G2 and G3 in patients with OSC compared with factors used traditionally. Compared with traditional factors, this 3-mRNA model was demonstrated to be the only and independent prognostic factor for patients with G2 and G3 stage OSC. A literature survey was also performed in the present study in order to assess the role of the 3 genes and indirectly prove their effectiveness. The establishment of this new genetic model will enhance prospective prognosis and treatment for patients with OSC.