engleski

Epigenetic (dys)regulation of Hedgehog-GLI signaling pathway in ovarian cancer by microRNA molecules

Ovarian carcinoma is the leading cause of death from gynecological malignancies in the Western world. Its high death rate is a result of the fact that most patients (>60%) are diagnosed in advanced stage of the disease. Our experience with ovarian cancer so far came out from the research on genetic (mutations and polymorphisms) and epigenetic (promoter methylation) mechanisms of Hedghog-Gli signaling pathway in the development of various types of ovarian malignancies. The purpose of this study was to find out which Hedgehog-Gli (Hh-Gli) signaling pathway genes could be potential targets of microRNA molecules (miRNAs) differentially expressed in high-grade serous ovarian cancer, which is the most malignant type and most difficult to detect at an earlier stage. We conducted a miRNA profiling on 8 fresh-frozen high-grade serous ovarian cancer tissue samples using Agilent SurePrint Human miRNA Microarray Kit 8x60K which contains probes for 2, 549 human miRNAs represented in miRBase database (Release 21.0). In addition, 8 healthy Fallopian tube samples were used as a control tissue to find differentially expressed miRNAs, since this type of tissue is presumed origin of high-grade serous ovarian cancer (Reade et al. J Obstet Gynaecol Can. 2014). Acquired miRNA expression data were analyzed using LIMMA and AgiMicroRna tools from R/Bioconductor software package. Resulting p-values were adjusted for multiple hypothesis testing based on false discovery rate by the Benjamini-Hochberg method. Furthermore, on-line DIANA Tools (diana.imis.athena-innovation.gr) were used to find which Hh-Gli pathway genes are experimentally proven or potential targets of observed differentially expressed miRNAs. Data filtration (IQR>0.1, FDR<0.1, logFC>0.58 and <-0.58) gave us a list of 55 miRNAs: 32 were up-and 23 were down-regulated in high-grade serous ovarian cancer. Out of 47 genes which are involved in Hh-Gli pathway in humans (according to the KEGG Pathway hsa04340), 35 are known targets for 27 over-expressed observed miRNAs, while 22 genes are known targets for 16 under-expressed miRNAs. In addition, 28 genes are potential targets for 26 up-regulated miRNAs while 24 are potential targets for 19 down-regulated miRNAs in high-grade serous ovarian carcinoma. Our results have highlighted several candidate miRNAs which we intend to verify and functionally connect to Hh-Gli pathway genes in our future research. Enlightening the interplay between miRNAs and Hh-Gli signaling pathway genes in serous ovarian carcinoma pathogenesis could give us new information for better therapeutic approaches and early prevention programs.

ovarian cancer ; microRNA ; microarrays ; Hedgehog-Gli signaling

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