miR-9 and miR-200 Regulate PDGFRβ-Mediated Endothelial Differentiation of Tumor Cells in Triple-Negative Breast Cancer
miR-9 and miR-200 Regulate PDGFRβ-Mediated Endothelial Differentiation of Tumor Cells in Triple-Negative Breast Cancer
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DOI：
10.1158/0008-5472.can-16-0140
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发表时间：
2016-09-15
期刊：
影响因子：
11.2
通讯作者：
Iorio, Marilena V.
中科院分区：
文献类型：
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作者：
D'Ippolito, Elvira;Plantamura, Ilaria;Iorio, Marilena V.
癌细胞组织成内皮样细胞系结构，以支持新生血管和促进实体瘤是进展和不良结局的标志。在三阴性乳腺癌（TNBC）中，PDGFR β已被确定为该过程的关键参与者，并被认为是乳腺癌治疗的有希望的靶点。因此，我们旨在研究mirna作为抑制PDGFR β介导的TNBC血管生成特性的治疗方法的作用，重点关注miR-9和miR-200。在MDA-MB-231和MDA-MB-157 TNBC细胞系中，miR-9和miR-200分别促进和抑制体外血管样结构的形成。内源性miR-9表达的诱导，在PDGFR β信号的配体依赖性刺激下，促进了TNBC细胞的血管发芽，部分是通过直接抑制STARD13。相反，miR-200的异位表达通过直接抑制ZEB1间接降低PDGFR β的蛋白水平来抑制这种发芽。值得注意的是，体内miR-9抑制或miR-200c恢复，无论是通过生成MDA-MB-231稳定克隆还是在MDA-MB-231异种移植小鼠的瘤周递送，都大大减少了血管腔隙的数量。最后，免疫组化和免疫荧光分析在TNBC标本中表明PDGFR β的表达表明肿瘤细胞参与血管腔隙。总之，我们的研究结果表明，miR-9和miR-200在TNBC血管生成能力的调节中发挥相反的作用，分别作为PDGFR β的促进剂和抑制剂。此外，我们的数据支持在治疗上利用miR-9和miR-200抑制TNBC中血管腔隙形成过程的可能性。(c) 2016年aacr。
Organization of cancer cells into endothelial-like cell-lined structures to support neovascularization and to fuel solid tumors is a hallmark of progression and poor outcome. In triple-negative breast cancer (TNBC), PDGFR beta has been identified as a key player of this process and is considered a promising target for breast cancer therapy. Thus, we aimed at investigating the role of miRNAs as a therapeutic approach to inhibit PDGFR beta-mediated vasculogenic properties of TNBC, focusing on miR-9 and miR-200. In MDA-MB-231 and MDA-MB-157 TNBC cell lines, miR-9 and miR-200 promoted and inhibited, respectively, the formation of vascular-like structures in vitro. Induction of endogenous miR-9 expression, upon ligand-dependent stimulation of PDGFR beta signaling, promoted significant vascular sprouting of TNBC cells, in part, by direct repression of STARD13. Conversely, ectopic expression of miR-200 inhibited this sprouting by indirectly reducing the protein levels of PDGFR beta through the direct suppression of ZEB1. Notably, in vivo miR-9 inhibition or miR-200c restoration, through either the generation of MDA-MB-231-stable clones or peritumoral delivery in MDA-MB-231 xenografted mice, strongly decreased the number of vascular lacunae. Finally, IHC and immunofluorescence analyses in TNBC specimens indicated that PDGFR beta expression marked tumor cells engaged in vascular lacunae. In conclusion, our results demonstrate that miR-9 and miR-200 play opposite roles in the regulation of the vasculogenic ability of TNBC, acting as facilitator and suppressor of PDGFR beta, respectively. Moreover, our data support the possibility to therapeutically exploit miR-9 and miR-200 to inhibit the process of vascular lacunae formation in TNBC. (C) 2016 AACR.