Simvastatin inhibits stem cell proliferation in human leiomyoma via TGF-β3 and Wnt/β-Catenin pathways.
Simvastatin inhibits stem cell proliferation in human leiomyoma via TGF-β3 and Wnt/β-Catenin pathways.
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DOI：
10.1111/jcmm.17211
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发表时间：
2022-03
影响因子：
5.3
通讯作者：
Borahay MA
中科院分区：
文献类型：
--
作者：
Afrin S;Ali M;El Sabeh M;Yang Q;Al-Hendy A;Borahay MA
子宫平滑肌瘤（UL）是最常见的妇科肿瘤，影响估计70%至80%的妇女。平滑肌瘤是由子宫肌层干细胞转化为平滑肌瘤干细胞（或肿瘤起始细胞）而形成的。这些细胞经历自我更新和分化为成熟细胞，两者分别是维持肿瘤干细胞龛和肿瘤生长所必需的。Wnt/β-catenin和TGF-β/SMAD通路在UL中过度活跃，促进干细胞自我更新，干细胞和成熟细胞之间的相互作用，细胞增殖，细胞外基质（ECM）积累并驱动总体UL生长。最近的证据表明，辛伐他汀，一种抗高血压药物，可能具有抗平滑肌瘤的特性。在此，我们研究了辛伐他汀对UL干细胞的影响。我们使用DyeCycle Violet染色和Stro‐1/CD 44表面标记通过流式细胞术分离平滑肌瘤干细胞。我们发现辛伐他汀抑制UL干细胞的增殖并诱导其凋亡。此外，它还抑制了干性标志物Nanog、Oct 4和Sox 2的表达。辛伐他汀显著降低了关键ECM蛋白、胶原1和纤连蛋白的产生。最后，它抑制UL干细胞中TGF-β1、2和3、SMAD 2、SMAD 4、Wnt 4、β-连环蛋白、LRP 6、AXIN 2和细胞周期蛋白D1的基因和/或蛋白质表达，所有这些都是TGF-β3/SMAD 2和Wnt 4/β-连环蛋白途径的关键驱动因素。因此，我们已经确定了一种新的干细胞靶向抗平滑肌瘤辛伐他汀作用。需要进一步的研究来在体内复制这些发现。
Uterine leiomyoma (UL) is the most common gynaecologic tumour, affecting an estimated 70 to 80% of women. Leiomyomas develop from the transformation of myometrial stem cells into leiomyoma stem (or tumour‐initiating) cells. These cells undergo self‐renewal and differentiation to mature cells, both are necessary for the maintenance of tumour stem cell niche and tumour growth, respectively. Wnt/β‐catenin and TGF‐β/SMAD pathways, both overactive in UL, promote stem cell self‐renewal, crosstalk between stem and mature cells, cellular proliferation, extracellular matrix (ECM) accumulation and drive overall UL growth. Recent evidence suggests that simvastatin, an antihyperlipidemic drug, may have anti‐leiomyoma properties. Herein, we investigated the effects of simvastatin on UL stem cells. We isolated leiomyoma stem cells by flow cytometry using DyeCycle Violet staining and Stro‐1/CD44 surface markers. We found that simvastatin inhibits proliferation and induces apoptosis in UL stem cells. In addition, it also suppressed the expression of the stemness markers Nanog, Oct4 and Sox2. Simvastatin significantly decreased the production of the key ECM proteins, collagen 1 and fibronectin. Finally, it inhibited genes and/or proteins expression of TGF‐β1, 2 and 3, SMAD2, SMAD4, Wnt4, β‐Catenin, LRP6, AXIN2 and Cyclin D1 in UL stem cells, all are key drivers of the TGF‐β3/SMAD2 and Wnt4/β‐Catenin pathways. Thus, we have identified a novel stem cell‐targeting anti‐leiomyoma simvastatin effect. Further studies are needed to replicate these findings in vivo.
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影响因子：
5.8
作者：
Lee, BS;Nowak, RA
通讯作者：
Nowak, RA
影响因子：
4.8
作者：
Borahay, Mostafa A.;Kilic, Gokhan S.;Boehning, Darren
通讯作者：
Boehning, Darren
影响因子：
4.3
作者：
通讯作者：
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辛伐他汀可以改善子宫平滑肌瘤细胞的机械转导改变。
影响因子：
9.8
作者：
Afrin S;Islam MS;Patzkowsky K;Malik M;Catherino WH;Segars JH;Borahay MA
通讯作者：
Borahay MA
影响因子：
4.8
作者：
El Sabeh M;Afrin S;Singh B;Miyashita-Ishiwata M;Borahay M
通讯作者：
Borahay M