An active RUNX1-ID1/ID3 axis governs differentiation and chemoresistance of cancer stem cell population in epithelial ovarian cancer cells

作     者：AJIT CDHADVE PRITHA RAY 

作者机构：Imaging Cell Signaling&Therapeutics LaboratoryAdvanced Centre for TreatmentResearch and Education in CancerTata Memorial CentreNavi Mumbai410210India Homi Bhabha National InstituteMumbai400094India 

出 版 物：《BIOCELL》 (生物细胞（英文）)

年 卷 期：2022年第46卷第1期

页      面：75-86页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：Advanced Centre for Treatment  Research and Education in Cancer-Tata Memorial Centre and Advanced Centre for Treatment  Research and Education in Cancer-Tata Memorial Centre  (ABT-199) 

主　　题：Cancer stem cells Differentiation RUNX1 ID1 ID2 BCL2 Chemoresistance Ovarian cancer 

摘      要：Progression,relapse,and therapy resistance are the most challenging features of cancer therapy that have been postulated to be driven by Cancer Stem Cell(CSC)population.This enigmatic subpopulation of cancer cells has therefore emerged as promising therapeutic candidate.We earlier reported enrichment of CSC-like side population(SP)with increasing resistance towards Cisplatin and Paclitaxel either alone or in combination in epithelial ovarian cancer(EOC)cells.This SP population is a small proportion of the total population of cancer cells characterised with high expression of drug transporters,a unique feature of stem cells and thereby can be isolated through their efflux properties of DNA binding dyes.While the bulk non-SP(NSP)population of the cancer cells lack overexpression of the drug transporters and thus can be identified as the dye containing population.In this study,we show that increased expression of Runt related transcription factor 1(RUNX1)maintains undifferentiated state of CSC-like SP cells through upregulation of inhibitors of DNA binding/differentiation genes(ID1 and ID3)in late cisplatinpaclitaxel resistant cells.Higher RUNX1 expression was found to correlate with decreased median overall survival and disease-free survival in The Cancer Genome Atlas(TCGA)data set of high grade serous ovarian cancer(HGSOC)patients.The protein-protein interaction network analysis of 397 upregulated genes in RUNX1-high samples of TCGA data show significant enrichment of pathways known to negatively regulate CSC differentiation.Intriguingly RUNX1 inhibition not only induces CSC differentiation but also downregulates anti-apoptotic protein BCL2 in both SP and NSP cells and potentiates cytotoxic effects of Cisplatin-Paclitaxel in chemoresistant EOC cells.Inhibition of BCL2 through Venetoclax treatment,a small molecule BH3 mimic,sensitized these cells to platinum taxol treatment.Altogether,our data reveal new regulatory roles by RUNX1 to modulate CSC differentiation via ID1 and ID3 and to promote chemoresistance through BCL2 upregulation.