engleski

The Role of ceRNAs in the regulation of BCL2 gene expression in high-grade serous ovarian cancer

Introduction High mortality from high-grade serous ovarian cancer (HGSOC) is caused by its late detection due to the absence of early symptoms and lack of early detection tests. The Hedgehog-GLI (Hh-Gli) signaling pathway is involved in ovarian embryonic development and its atypical activation can lead to different types of ovarian tumors. Our microarray-based transcriptome profiling on smaller number of HGSOC tissue samples and healthy Fallopian tubes, from which most of HGSOC originate, has shown that expression of BCL2, one of the Hh-Gli pathway members, was significantly decreased in HGSOC. On the contrary, the expression of two miRNAs that target BLC2, miR-21- 5p and miR-96-5p, was increased in HGSOC. Furthermore, the expression of two lncRNAs that can also bind those two miRNAS, MALAT1 and XIST1, was also decreased. We hypothesize that BCL2 expression could be regulated by a network of endogenous competitive RNA molecules (ceRNAs), which compete for binding available miRNAs and thus regulate the expression of miRNA target- genes. Material and Methods On an expanded set of 62 HGSOC and 19 healthy Fallopian tube tissue samples, we determined by qPCR the expression of BCL2, its transcription factors GLI1 and GLI2, miR-21-5p, miR-96-5p, MALAT1 and XIST1. Based on the obtained expressions we conducted a correlation analysis to build a network of potential ceRNAs. We also performed the ROC curve analysis to determine a diagnostic value of studied RNAs for distinguishing between cancer and healthy tissue. Results and Discussions The qPCR results confirmed results obtained with microarrays: BCL2, MALAT1 and XIST were significantly down-regulated, while miR-21-5p and miR-96-5p were up-regulated in HGSOC. In addition, GLI1 was also decreased in HGSOC. The BCL2 expression was in an expected correlation with the expressions of all other studied RNAs: negative between BLC2 and miRNAs expression, and positive between BCL2 and lncRNAs or GLi1/2. Positive correlation between BCL2 and GLI1 expression was stronger than for GLI2, potentially meaning that GLI1 is more important regulator of BCL2 transcription in HGSOC. Regarding the lncRNAs and miRNAs, there was only a significant negative correlation between XIST and miR-96-5p. Expression of BCL2 and XIST showed the highest area under ROC curve (AUC), thus potentially having an excellent diagnostic value. Conclusion Based on our expression analyses, it seems that BCL2—miR-96-5p— XIST axis could be an epigenetic cause of a decreased BCL2 gene expression in high-grade serous ovarian cancer.

ovarian cancer ; BCL2 ; microRNA ; lncRNA ; gene expression ; qRT-PCR

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