A miR-433 mediated mechanism of chemoresistance in high grade serous ovarian cancer (HGSOC).

Tara Byrne, Weiner-Gorzel Karolina, Michael Gallagher, Daniel Sharpe, Stephanie Annett, Sharon O'Toole, John O'Leary, Laura Nelson, W. Glenn McCluggage, James Beirne, Tracy Robson, Amanda McCann, Fiona Furlong

Research output: Contribution to conferencePoster

Abstract

Higher expression of the miR-433 microRNA (miRNA) is associated with poorer survival outcomes in patients with HGSOC that may be overcome by a greater understanding of the functional role of this miRNA. We previously described miR-433 as a critical cell cycle regulator and mediator of cellular senescence. Downregulation of the mitotic arrest deficiency 2 (MAD2) protein by miR-433 led to increased cellular resistance to paclitaxel in epithelial ovarian cancer cells (EOC). Furthermore immunohistochemical (IHC) analysis of MAD2 expression in patients with HGSOC showed that loss of MAD2 was significantly associated with poorer patient survival. Higher miR-433 expression is also associated with an increased resistance to the platins which is unrelated to loss of MAD2 expression. In silico analysis of the miR-433 target proteins in the TCGA database identified the association between a number of miR-433 targets and poorer patient survival. IHC analysis of the miR-433 target, histone deacetylase 6 (HDAC6), confirmed that its expression was significantly associated with a decrease in patient overall survival. The knock-down of HDAC6 by siRNA in EOC cells did not attenuate apoptotic responses to paclitaxel or platin although lower endogenous HDAC6 expression was associated with more resistant EOC cell lines. In vitro analysis revealed that EOC cells which survived chemotherapeutic kill with high doses of paclitaxel expressed higher miR-433 and concomitant decreased expression of the miR-433 targets. These cells were more chemoresistant compared to the parental cell line and repopulated as 3d organoid cultures in non-adherent stem cell selective conditions; thus indicating that the cells which survive chemotherapy were viable, capable of regrowth and had an increased potential for pluripotency. In conclusion, our data suggests that chemotherapy is not driving the transcriptional upregulation of miR-433 but rather selecting a population of cells with high miR-433 expression that may contribute to chemoresistant disease and tumour recurrence.
Original languageEnglish
Publication statusAccepted - 09 Oct 2015
Event2nd Ovarian Cancer Forum of Ireland - South West Acute Hospital, Co. Fermanagh, Enniskillen, United Kingdom
Duration: 09 Oct 201510 Oct 2015

Conference

Conference2nd Ovarian Cancer Forum of Ireland
CountryUnited Kingdom
CityEnniskillen
Period09/10/201510/10/2015

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