RESUMO
PURPOSE: Characterization of the genetic landscapes of familial ovarian cancer through integrated analysis of microRNA and mRNA by partial least squares (PLS) and Monte Carlo technique based on genome-wide association studies (GWAS). METHODS: The miRNA and mRNA transcriptional data in familial ovarian cancer were characterized from the Gene Expression Omnibus (GEO) database. The miRNA and mRNA expression profiles in peripheral blood lymphocytes (PBLs) of 74 familial ovarian cancer patients and 47 control subjects were analyzed with the integration of partial least squares (PLS) and Monte Carlo techniques. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were also performed. RESULTS: Total of 16 miRNA-mRNA pairs were identified with the target gene prediction results of miRNAs and mRNAs. An innovated miRNA-mRNA integrated network was constructed in which 6 downregulated miRNAs and 1 upregulated miRNAs were included. KEGG and GO pathway enrichment analysis revealed over-representation of dysregulated miRNAs in various biological processes especially in cancer pathology. Hsa-miR-34b played a pivotal role in this network and interacted with other miRNAs. Hsa-miR-136 and hsa-miR-335 were associated with p53 and Erk1/2 pathways and tumor suppressors, such as PTEN. CONCLUSIONS: The results from this research provide insights on miRNA-mRNA networks and offer new tools for studying transcriptional variants in familial ovarian cancer.
Assuntos
Biomarcadores Tumorais/genética , Linfócitos/metabolismo , MicroRNAs/genética , Neoplasias Epiteliais e Glandulares/epidemiologia , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , RNA Mensageiro/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Carcinoma Epitelial do Ovário , China/epidemiologia , Feminino , Estudos de Associação Genética , Marcadores Genéticos/genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , MicroRNAs/sangue , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/diagnóstico , Neoplasias Ovarianas/diagnóstico , Prevalência , RNA Mensageiro/sangue , Reprodutibilidade dos Testes , Fatores de Risco , Sensibilidade e Especificidade , Adulto JovemRESUMO
Stathmin 1 (STMN1) is a biomarker in several types of neoplasms. It plays an important role in cell cycle progression, mitosis, signal transduction and cell migration. In ovaries, STMN1 is predominantly expressed in granulosa cells (GCs). However, little is known about the role of STMN1 in ovary. In this study, we demonstrated that STMN1 is overexpressed in GCs in patients with polycystic ovary syndrome (PCOS). In mouse primary GCs, the overexpression of STMN1 stimulated progesterone production, whereas knockdown of STMN1 decreased progesterone production. We also found that STMN1 positively regulates the expression of Star (steroidogenic acute regulatory protein) and Cyp11a1 (cytochrome P450 family 11 subfamily A member 1). Promoter and ChIP assays indicated that STMN1 increased the transcriptional activity of Star and Cyp11a1 by binding to their promoter regions. The data suggest that STMN1 mediates the progesterone production by modulating the promoter activity of Star and Cyp11a1. Together, our findings provide novel insights into the molecular mechanisms of STMN1 in ovary GC steroidogenesis. A better understanding of this potential interaction between STMN1 and Star in progesterone biosynthesis in GCs will facilitate the discovery of new therapeutic targets in PCOS.
