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内皮细胞中脂肪细胞增强结合蛋白 1 的上调促进结直肠癌中的肿瘤血管生成。

Upregulation of adipocyte enhancer-binding protein 1 in endothelial cells promotes tumor angiogenesis in colorectal cancer.

机构信息

Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.

Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan.

出版信息

Cancer Sci. 2020 May;111(5):1631-1644. doi: 10.1111/cas.14360. Epub 2020 Apr 11.

DOI:10.1111/cas.14360
PMID:32086986
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7226196/
Abstract

Tumor angiogenesis is an important therapeutic target in colorectal cancer (CRC). We aimed to identify novel genes associated with angiogenesis in CRC. Using RNA sequencing analysis in normal and tumor endothelial cells (TECs) isolated from primary CRC tissues, we detected frequent upregulation of adipocyte enhancer-binding protein 1 (AEBP1) in TECs. Immunohistochemical analysis revealed that AEBP1 is upregulated in TECs and stromal cells in CRC tissues. Quantitative RT-PCR analysis showed that there is little or no AEBP1 expression in CRC cell lines, but that AEBP1 is well expressed in vascular endothelial cells. Levels of AEBP1 expression in Human umbilical vein endothelial cells (HUVECs) were upregulated by tumor conditioned medium derived from CRC cells or by direct coculture with CRC cells. Knockdown of AEBP1 suppressed proliferation, migration, and in vitro tube formation by HUVECs. In xenograft experiments, AEBP1 knockdown suppressed tumorigenesis and microvessel formation. Depletion of AEBP1 in HUVECs downregulated a series of genes associated with angiogenesis or endothelial function, including aquaporin 1 (AQP1) and periostin (POSTN), suggesting that AEBP1 might promote angiogenesis through regulation of those genes. These results suggest that upregulation of AEBP1 contributes to tumor angiogenesis in CRC, which makes AEBP1 a potentially useful therapeutic target.

摘要

肿瘤血管生成是结直肠癌（CRC）的重要治疗靶点。我们旨在鉴定与 CRC 血管生成相关的新基因。使用从原发性 CRC 组织中分离的正常和肿瘤内皮细胞（TEC）的 RNA 测序分析，我们在 TEC 中检测到脂肪细胞增强结合蛋白 1（AEBP1）频繁上调。免疫组织化学分析显示 AEBP1 在 CRC 组织中的 TEC 和基质细胞中上调。定量 RT-PCR 分析显示 CRC 细胞系中 AEBP1 的表达很少或没有，但血管内皮细胞中 AEBP1 表达良好。CRC 细胞来源的肿瘤条件培养基或与 CRC 细胞直接共培养可上调人脐静脉内皮细胞（HUVEC）中 AEBP1 的表达水平。AEBP1 的敲低抑制了 HUVEC 的增殖、迁移和体外管形成。在异种移植实验中，AEBP1 的敲低抑制了肿瘤发生和微血管形成。HUVEC 中 AEBP1 的耗竭下调了一系列与血管生成或内皮功能相关的基因，包括水通道蛋白 1（AQP1）和骨膜蛋白（POSTN），这表明 AEBP1 可能通过调节这些基因促进血管生成。这些结果表明，AEBP1 的上调有助于 CRC 中的肿瘤血管生成，这使得 AEBP1 成为一个有潜在用途的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fbca/7226196/080edb5eb609/CAS-111-1631-g006.jpg
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