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

ABSTRACT: 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 biomarker α6-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.

SUBMITTER: Mavingire N

PROVIDER: S-EPMC9172653 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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

Mavingire Nicole N Campbell Petreena P Liu Tiantian T Wooten Jonathan J Khan Salma S Chen Xin X Matthews Jason J Wang Charles C Brantley Eileen E

Precision clinical medicine 20220328 2

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 biomarker α6-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 in ...[more]

PMID: 35694715

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Project description:ObjectivePeriodontitis is a chronic inflammatory infectious disease caused by the deposition of dental plaque on the tooth surface, leading to adverse systemic consequences. Accumulating evidence shows that dysregulated microRNAs (miRNAs) are associated with the disease severity of periodontitis. Herein, we report two novel miRNAs, miR-30b-3p and miR-125b-1-3p, in the context of periodontitis and their relationships with disease severity of periodontitis.MethodsThe miRNA profiles of gingival crevicular fluid (GCF) samples were used to screen differentially expressed miRNAs (DEmiRNAs) between periodontitis patients and periodontally healthy individuals. Clinical human GCF samples were collected from 80 patients diagnosed with periodontitis (PD +) for the first time and 100 periodontally healthy individuals (PD-). The severity of periodontitis was categorized into mild/moderate (MPD) and severe (SPD) groups. The expressions of miR-30b-3p and miR-125b-1-3p were determined by quantitative real-time PCR. The levels of IL-1β, IL-6, and TNF-α were determined by ELISA methods.ResultsWe applied GEO2R bioinformatics tool to analyze the raw data of the GSE89081 dataset and identified miR-30b-3p (|logFC|= 1.987) and miR-125b-1-3p (|logFC|= 1.878) between periodontitis patients and periodontally healthy individuals. It was found that PPD, CAL, BOP, and the relative expression levels of miR-30b-3p and miR-125b-1-3p were all higher in the PD + group than the PD- group, in the SPD group than the MPD group (P < 0.05). The periodontitis patients with high-miR-30b-3p expression exhibited increased PPD, CAL, and BOP compared to those low-miR-30b-3p expression, while high-miR-125b-1-3p expression group showed significant differences on PPD and BOP from low-miR-125b-1-3p expression group (P < 0.05). Pearson correlation analysis demonstrated a significantly positive correlation between the levels of inflammatory cytokines, miR-30b-3p expression, and miR-125b-1-3p expression (P < 0.001). Results of ROC curves showed AUC of 0.878 and 0.927, sensitivity of 0.843 and 0.855, and specificity of 0.791 and 0.801, respectively, when miR-30b-3p and miR-125b-1-3p expression levels were used to diagnose periodontitis.ConclusionThese data unveiled that miR-30b-3p and miR-125b-1-3p expressions may be associated with the pathogenesis of periodontitis.

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

Publications

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

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