乳腺癌细胞中YAP过表达通过激活血管内皮细胞中的YAP信号促进血管生成。

IF 2.6 4区 医学 Q3 CELL BIOLOGY
Analytical Cellular Pathology Pub Date : 2022-10-03 eCollection Date: 2022-01-01 DOI:10.1155/2022/5942379
Yu Yan, Qiang Song, Li Yao, Liang Zhao, Hui Cai
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引用次数: 3

摘要

目的:YAP信号通路在人乳腺癌中发生改变并与致癌有关。然而,YAP信号在调节乳腺肿瘤血管生成中的作用仍不明确。肿瘤血管生成是通过癌细胞和血管内皮细胞的激活来协调的。YAP信号通路是否能够调节癌细胞与内皮细胞之间的细胞间相互作用基本上是未知的。方法:体外观察YAP对肿瘤血管生成、血管内皮细胞迁移和增殖的影响。使用Western blotting、免疫荧光染色和免疫组织化学分析评估参与YAP、G13-RhoA和PI3K/Akt信号通路的蛋白和磷酸化蛋白的表达。此外,我们还利用异种肿瘤移植小鼠在体内评价了YAP对乳腺癌血管生成的影响。结果:我们在这里发现,YAP过表达的乳腺癌细胞(CM-YAP+)的条件培养基可以促进血管生成,同时增加人脐静脉内皮细胞(HUVECs)的管形成、迁移和增殖。在huves中下调YAP可逆转CM-YAP+诱导的血管生成。CM-YAP+通过去磷酸化YAP和增加核易位,时间依赖性地激活huvec中的YAP。我们还发现G13-RhoA和PI3K/Akt信号通路都是CM-YAP+诱导的YAP激活所必需的。结缔组织生长因子(CTGF)和血管生成素-2 (ang2)在HUVECs中作为YAP的下游,促进血管生成。此外,皮下肿瘤裸鼠模型表明,过表达YAP的肿瘤在体内显示出更多的新生血管。结论:乳腺癌细胞与内皮细胞之间的YAP-YAP相互作用可促进肿瘤血管生成,支持YAP是开发新的乳腺癌治疗策略的潜在标志物和靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

YAP Overexpression in Breast Cancer Cells Promotes Angiogenesis through Activating YAP Signaling in Vascular Endothelial Cells.

YAP Overexpression in Breast Cancer Cells Promotes Angiogenesis through Activating YAP Signaling in Vascular Endothelial Cells.

YAP Overexpression in Breast Cancer Cells Promotes Angiogenesis through Activating YAP Signaling in Vascular Endothelial Cells.

YAP Overexpression in Breast Cancer Cells Promotes Angiogenesis through Activating YAP Signaling in Vascular Endothelial Cells.

Purpose: The YAP signaling pathway is altered and implicated as oncogenic in human mammary cancers. However, roles of YAP signaling that regulate the breast tumor angiogenesis have remained elusive. Tumor angiogenesis is coordinated by the activation of both cancer cells and vascular endothelial cells. Whether the YAP signaling pathway can regulate the intercellular interaction between cancer cells and endothelial cells is essentially unknown.

Methods: The effects of YAP on tumor angiogenesis, migration, and proliferation of vascular endothelial cells were evaluated in vitro. Expression of proteins and phosphorylating proteins involved in YAP, G13-RhoA, and PI3K/Akt signaling pathways was evaluated using the Western blotting, immunofluorescence staining, and immunohistochemistry analysis. In addition, the effects of YAP on breast cancer angiogenesis were evaluated in vivo by tumor xenograft mice.

Results: We showed here that conditioned media from YAP overexpressed breast cancer cells (CM-YAP+) could promote angiogenesis, accompanied by increased tube formation, migration, and proliferation of human umbilical vein endothelial cells (HUVECs). Down regulation of YAP in HUVECs reversed CM-YAP+ induced angiogenesis. CM-YAP+ time-dependently activated YAP in HUVECs by dephosphorylating YAP and increasing nuclear translocation. We also identified that both G13-RhoA and PI3K/Akt signaling pathway were necessary for CM-YAP+ induced activation of YAP. Besides, connective tissue growth factor (CTGF) and angiopoietin-2 (ANG-2) acted as down-stream of YAP in HUVECs to promote angiogenesis. In addition, subcutaneous tumors nude mice model demonstrated that tumors overexpressed YAP revealed more neovascularization in vivo.

Conclusion: YAP-YAP interaction between breast cancer cells and endothelial cells could promote tumor angiogenesis, supporting that YAP is a potential marker and target for developing novel therapeutic strategies against breast cancer.

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来源期刊
Analytical Cellular Pathology
Analytical Cellular Pathology ONCOLOGY-CELL BIOLOGY
CiteScore
4.90
自引率
3.10%
发文量
70
审稿时长
16 weeks
期刊介绍: Analytical Cellular Pathology is a peer-reviewed, Open Access journal that provides a forum for scientists, medical practitioners and pathologists working in the area of cellular pathology. The journal publishes original research articles, review articles, and clinical studies related to cytology, carcinogenesis, cell receptors, biomarkers, diagnostic pathology, immunopathology, and hematology.
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