ZEB1-repressed microRNAs inhibit autocrine signaling that promotes vascular mimicry of breast cancer cells.
ZEB1-repressed microRNAs inhibit autocrine signaling that promotes vascular mimicry of breast cancer cells.
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DOI：
10.1038/onc.2017.356
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发表时间：
2018-02-22
期刊：
影响因子：
8
通讯作者：
Sears RC
中科院分区：
文献类型：
--
作者：
Langer EM;Kendsersky ND;Daniel CJ;Kuziel GM;Pelz C;Murphy KM;Capecchi MR;Sears RC
在正常肿瘤生长期间和响应于一些治疗，肿瘤细胞经历急性或慢性营养素和氧的剥夺并诱导肿瘤血管化。虽然这主要通过萌芽血管生成发生，但也已显示肿瘤细胞通过血管拟态（VM）和/或内皮转分化直接促进血管形成。然而，肿瘤细胞采用内皮表型的外在和内在机制还不清楚。在这里，我们表明，血清戒断诱导间充质乳腺癌细胞进行VM和上皮间充质转化（EMT）调节，锌指E-box结合同源框1（ZEB 1），或ZEB 1抑制的microRNA（miRNA），miR-200 c，miR-183，miR-96和miR-182的过表达的敲低抑制这一过程。我们发现分泌蛋白纤连蛋白1（FN 1）和丝氨酸蛋白酶抑制剂（serepase inhibitor，serpin）家族E成员2（SERPINE 2）是VM在该系统中所必需的。这些分泌的因子在间充质细胞中响应于血清戒断而上调，并且VM抑制miRNA的过表达消除了这种上调。有趣的是，这些分泌蛋白的受体，低密度脂蛋白受体相关蛋白1（LRP 1）和整合素β 1（ITGB 1），也是VM抑制miRNA的靶点，这表明刺激VM的自分泌信号受ZEB 1抑制的miRNA簇的调节。总之，这些数据提供了对VM调节的机制性见解，并表明在EMT期间被抑制的miRNA除了抑制肿瘤细胞的迁移和干细胞样特性之外，还抑制了乳腺癌细胞响应营养缺乏微环境而采用的内皮表型。
During normal tumor growth and in response to some therapies, tumor cells experience acute or chronic deprivation of nutrients and oxygen and induce tumor vascularization. While this occurs predominately through sprouting angiogenesis, tumor cells have also been shown to directly contribute to vessel formation through vascular mimicry (VM) and/or endothelial transdifferentiation. The extrinsic and intrinsic mechanisms underlying tumor cell adoption of endothelial phenotypes, however, are not well understood. Here we show that serum withdrawal induces mesenchymal breast cancer cells to undergo VM and that knockdown of the epithelial-to-mesenchymal transition (EMT) regulator, Zinc finger E-box binding homeobox 1 (ZEB1), or overexpression of the ZEB1-repressed microRNAs (miRNAs), miR-200c, miR-183, miR-96 and miR-182 inhibits this process. We find that secreted proteins Fibronectin 1 (FN1) and serine protease inhibitor (serpin) family E member 2 (SERPINE2) are essential for VM in this system. These secreted factors are upregulated in mesenchymal cells in response to serum withdrawal, and overexpression of VM-inhibiting miRNAs abrogates this upregulation. Intriguingly, the receptors for these secreted proteins, low-density lipoprotein receptor-related protein 1 (LRP1) and Integrin beta 1 (ITGB1), are also targets of the VM-inhibiting miRNAs, suggesting that autocrine signaling stimulating VM is regulated by ZEB1-repressed miRNA clusters. Together, these data provide mechanistic insight into the regulation of VM and suggest that miRNAs repressed during EMT, in addition to suppressing migratory and stem-like properties of tumor cells, also inhibit endothelial phenotypes of breast cancer cells adopted in response to a nutrient-deficient microenvironment.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
DOI：
10.1007/978-1-61779-885-6_4
发表时间：
2012-01-01
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Dyballa, Nadine;Metzger, Sabine
通讯作者：
Metzger, Sabine
影响因子：
5.3
作者：
Farrell, Amy S.;Pelz, Carl;Sears, Rosalie C.
通讯作者：
Sears, Rosalie C.
影响因子：
11.2
作者：
Fayard, Berengere;Bianchi, Fabrizio;Monard, Denis
通讯作者：
Monard, Denis
影响因子：
12.3
作者：
Herschkowitz JI;Simin K;Weigman VJ;Mikaelian I;Usary J;Hu Z;Rasmussen KE;Jones LP;Assefnia S;Chandrasekharan S;Backlund MG;Yin Y;Khramtsov AI;Bastein R;Quackenbush J;Glazer RI;Brown PH;Green JE;Kopelovich L;Furth PA;Palazzo JP;Olopade OI;Bernard PS;Churchill GA;Van Dyke T;Perou CM
通讯作者：
Perou CM