Glabridin inhibits cancer stem cell-like properties of human breast cancer cells: An epigenetic regulation of miR-148a/SMAd2 signaling

Abstract

In breast cancer, the cancer stem cells (CSCs) are thought to be the main cause of metastasis and recurrence. Targeting of CSCs or cancer cells with stem cell-like properties has become a new approach for the treatment of breast cancer. Glabridin (GLA), a phytochemical from the root of Glycyrrhiza glabra, exhibited effective antitumor properties in various human cancer cells. However, the roles of GLA in the regulation of CSC-like properties and the underlying molecular mechanisms remain unclear. Here, we reported that GLA attenuated the CSC-like properties through microRNA-148a (miR-148a)/transforming growth factor beta (TGFβ)-SMAD2 signal pathway in vitro and in vivo. In MDA-MB-231 and Hs-578T breast cancer cell lines, GLA enhanced the expression of miR-148a through DNA demethylation. By targeting of the SMAD2-3'-UTR, miR-148a blocked the expression/activation of SMAD2, and in turn, restored the epithelial characteristics, adhesive abilities, and CSC-like properties. Furthermore, in mouse xenograft models, we also confirmed that GLA attenuated the tumor growth, mesenchymal characteristics, and CSCs-like properties via demethylation-activated miR-148a. Our findings suggested a potential treatment strategy to reduce the CSCs-like properties, and therefore enhance the effectiveness of breast cancer therapy.

Virtual Screening of potential inhibitors from Herbs for the treatment of Breast Cancer

“…Furthermore, SER1755 has Pi-Donor hydrogen bond with the ligand. In mouse xenograft models, this glabridin compound was found to attenuated the tumor growth, mesenchymal characteristics, and cancer stem cells-like properties via demethylation-activated miR-148a [22].…”

MicroRNAs, a subpopulation of regulators, are involved in breast cancer progression through regulating breast cancer stem cells (Review)

“…The glabridin (GLA)/miR-148a/SMAD2 axis serves a critical role in modulating CSC-like properties, such as the formation of mammospheres and colonies. GLA-upregulated miR-148a results in a repression of clone formation, as miR-148a is able to inhibit endogenous TGF-β/SMAD2 signaling in BC cells (49). It was identified that miR-99a directly inhibits the mTOR signaling pathway in breast cancer SP cells, which results in the suppression of tumorigenicity in vivo (35).…”

The repressive effect of miR-148a on Wnt/β-catenin signaling involved in Glabridin-induced anti-angiogenesis in human breast cancer cells

“…Glabridin(GLA), an isoflavane compound in licorice roots, has attracted extensive attention because of its various biological properties, including the anti-proliferative [16], anti-stem cell-like [17], and anti-cancer activities [18]. The results of a previous research had shown that GLA suppressed angiogenesis through FAK/Rho signaling in human non–small cell lung cancer A549 cells and human breast cancer MDA-MB-231 cells [19, 20].…”

“…Our previous data also detected that repressed NF-kB/IL-6/STAT-3 signal pathway might be responsible for the inhibition of GLA on the angiogenic ability of human breast cancer MDA-MB-231 cells [21]. Recent studies suggest GLA can upregulate miR-148a, suppress the activation of TGF-β/SMAD2 signaling, and attenuate CSC-like functions in HCC and breast cancer cells [17, 22]. In the following study, we hypothesized that in breast cancer cells, GLA partially inhibited angiogenesis through the Wnt/β-catenin signaling pathway and that miR-148a was involved in this process.…”