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

引用

Precision Clinical Medicine 2022年第2期5卷 72-86页

作者： Nicole Mavingire Petreena Campbell Tiantian Liu jonathan wooten Salma Khan Xin Chen Jason Matthews Charles Wang Eileen Brantley Department of Basic Sciences Loma Linda University School of MedicineLoma LindaCA 92350USA Center for Genomics Loma Linda University School of MedicineLoma LindaCA 92350USA Center for Health Disparities and Molecular Medicine Loma Linda University School of MedicineLoma LindaCA 92350USA Department of Nutrition University of OsloOslo 0372Norway Department of Pharmacology and Toxicology University of TorontoTorontoOntario M5S 1A8Canada Frederick National Laboratory for Cancer Research PO Box BBldg.432Room 232 FrederickMD 21702-1201USA

Metastatic breast cancer is incurable and often due to breast cancer stem cell(CSC)-mediated *** 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 *** significantly induced the expression of>70 microRNAs(miRNAs)including miR125b-2–3p,a predicted stemness gene ***-mediated miR125b-2–3p induction was validated in MCF-7 mammospheres and ***125b-2–3p levels were low in breast cancer tissues irrespective of subtype compared to normal breast *** 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 *** MCF-7 mammospheres,the miR125b-2–3p mimic decreased only ITGA6 expression although the antagomiR125b-2–3p increased ITGA6,SOX2 and MYC ***125b-2–3p reversed AF-mediated suppression of *** miR125b-2–3p mimic decreased proliferation,migration,and mammosphere formation while the antagomiR125b-2–3p increased proliferation and mammosphere formation in MCF-7 *** miR125b-2–3p mimic also inhibited proliferation,mammosphere formation,and migration in AHR100 *** induced AhR-and miR125b2-3p-dependent anti-proliferation,anti-migration,and mammosphere disruption in MCF-7 *** 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

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