Aminoflavone upregulates putative tumor suppressor miR-125b-2-3p to inhibit luminal A breast cancer stem cell-like properties  

作　　者：Nicole Mavingire Petreena Campbell Tiantian Liu Jonathan Wooten Salma Khan Xin Chen Jason Matthews Charles Wang Eileen Brantley 

机构地区：[1]Department of Basic Sciences,Loma Linda University School of Medicine,Loma Linda,CA 92350,USA [2]Center for Genomics,Loma Linda University School of Medicine,Loma Linda,CA 92350,USA [3]Center for Health Disparities and Molecular Medicine,Loma Linda University School of Medicine,Loma Linda,CA 92350,USA [4]Department of Nutrition,University of Oslo,Oslo 0372,Norway [5]Department of Pharmacology and Toxicology,University of Toronto,Toronto,Ontario M5S 1A8,Canada [6]Frederick National Laboratory for Cancer Research,PO Box B,Bldg.432,Room 232 Frederick,MD 21702-1201,USA

出　　处：《Precision Clinical Medicine》2022年第2期72-86,共15页精准临床医学（英文）

基　　金：supported in part by funds from the Department of Basic Sciences Loma Linda University Health(LLUH)School of Medicine;the Grants for Research and School Partnerships award(LLUH intramural grant);the Grants to Promote Collaborative and Translational Research Award(LLUH intramural grant);NIH/National Institute of General Medical Sciences grant(award number 2R25GM060507);the National Institutes of Health(NIH)(Grant No.S10OD019960)。

摘　　要：Metastatic breast cancer is incurable and often due to breast cancer stem cell(CSC)-mediated self-renewal.We previously determined that the aryl hydrocarbon receptor(AhR)agonist aminoflavone(AF)inhibits the expression of the CSC biomarkerα6-integrin(ITGA6)to disrupt the formation of luminal(hormone receptor-positive)mammospheres(3D breast cancer spheroids).In this study,we performed miRNA-sequencing analysis of luminal A MCF-7 mammospheres treated with AF to gain further insight into the mechanism of AF-mediated anti-cancer and anti-breast CSC activity.AF significantly induced the expression of>70 microRNAs(miRNAs)including miR125b-2–3p,a predicted stemness gene regulator.AF-mediated miR125b-2–3p induction was validated in MCF-7 mammospheres and cells.miR125b-2–3p levels were low in breast cancer tissues irrespective of subtype compared to normal breast tissues.While miR125b-2–3p levels were low in MCF-7 cells,they were much lower in AHR100 cells(MCF-7 cells made unresponsive to AhR agonists).The miR125b-2–3p mimic decreased,while the antagomiR125b-2–3p increased the expression of stemness genes ITGA6 and SOX2 in MCF-7 cells.In MCF-7 mammospheres,the miR125b-2–3p mimic decreased only ITGA6 expression although the antagomiR125b-2–3p increased ITGA6,SOX2 and MYC expression.AntagomiR125b-2–3p reversed AF-mediated suppression of ITGA6.The miR125b-2–3p mimic decreased proliferation,migration,and mammosphere formation while the antagomiR125b-2–3p increased proliferation and mammosphere formation in MCF-7 cells.The miR125b-2–3p mimic also inhibited proliferation,mammosphere formation,and migration in AHR100 cells.AF induced AhR-and miR125b2-3p-dependent anti-proliferation,anti-migration,and mammosphere disruption in MCF-7 cells.Our findings suggest that miR125b-2–3p is a tumor suppressor and AF upregulates miR125b-2–3p to disrupt mammospheres via mechanisms that rely at least partially on AhR in luminal A breast cancer cells.

关 键 词：breast cancer cancer stem cells therapeutic targeting miR125b-2-3p aminoflavone aryl hydrocarbon receptor mammospheres 

分 类 号：R73[医药卫生—肿瘤]