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Looking for new markers:could microRNA molecules help for earlier diagnosis and better therapies? How (dys)regulation of Hedgehog-Gli signaling pathway contribute to ovarian cancer

High-grade serous ovarian cancer (HGSOC), the most common ovarian cancer, is urgent clinical problem (high mortality, no early signs of disease, diagnosis at an advanced stage), and its molecular background is still unknown. Signaling pathway Hedgehog-Gli (Hh-Gli) is involved in embryonal ovarian development, but its atypical activation can lead to different types of ovarian tumors. Our previous studies showed its aberrant activity: in benign ovarian tumors, but not in ovarian cancer, hypermethylation in a promoter of tumor suppressor gene PTCH1 in the CpG islands near the GLI-binding site (Sabol et al 2012, 2017 Int J Oncol, Musani et al 2013 Gene, Maurac et al 2012 Int J Gynecol Pathol). We and others claim that aberrant activity of Hh-Gli pathway in ovarian cancer is result of various genetic and epigenetic alterations. Our hypothesis is that changes in the expression of miRNA molecules related to the Hh-Gli signaling pathway contribute to the development of HGSOC. We did microRNA profiling of HGSOC (Agilent Human miRNA Microarray platform), with 2, 549 human miRNAs represented in miRBase database (Release 21.0) and healthy Fallopian tube samples as a control (Reade et al., J Obstet Gynaecol Can 2014). Data were analyzed (AgiMicroRna in R/Bioconductor), p-values by Benjamini-Hochberg method, and on-line analyses by DIANA Tools (diana.imis.athena-innovation.gr). Data filtration (IQR > 0.1, FDR < 0.1, logFC > 0.58 and < -0.58) gave 55 microRNAs: 32 up- and 23 down-regulated in HGSOC. Out of 47 genes involved in Hh-Gli pathway in humans (KEGG Pathway hsa04340), 35 are known targets for 27 over-expressed observed microRNAs, while 22 are known targets for 16 under-expressed microRNAs, 28 genes are potential targets for 26 up-regulated microRNAs while 24 are potential targets for 19 down-regulated microRNAs in HGSOC. Those results highlighted candidate microRNAs potentially targeting Hh-Gli signaling pathway genes, when additionally verified, could be better therapeutic and early prevention approaches.

microRNA ; Hedgehog-Gli signaling pathway ; ovarian cancer

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