Lu Xiangdong, Zhou Bin, Cao Minmin, Shao Qin, Pan Yukai, Zhao Tao
Jiangyin People's Hospital, Jiangyin, Jiangsu Province, 214400, P.R. China.
Technol Cancer Res Treat. 2021 Jan-Dec;20:15330338211045506. doi: 10.1177/15330338211045506.
C-terminal tensin-like (CTEN) belongs to the tensin gene family, which encodes proteins that localize to focal adhesions and modulate integrin function. Accumulating studies have reported that CTEN expression can be upregulated or downregulated in different types of cancers, suggesting that CTEN has both oncogenic and tumor suppressor functions. In this study, by analyzing the expression level of CTEN in the human breast cancer (BRCA) samples from the clinically annotated genomic database, The Cancer Genome Atlas, we found that CTEN was downregulated in different BRCA subclasses, including luminal, human epidermal growth factor receptor 2 positive and triple-negative BRCA. Consistently, the protein level of CTEN was also reduced in BRCA based on the Proteomic Tumor Analysis Consortium. In contrast, vascular endothelial growth factor A (VEGFA), a signal protein that stimulates the formation of blood vessels, was upregulated in BRCA. CTEN overexpression in human umbilical vein endothelial cells and MCF7 significantly suppressed the expression of VEGFA, inhibited cell proliferation, migration, and tube formation in vitro. Mechanistically, CTEN bind to casitas B-lineage lymphoma (c-Cbl), an E3 ubiquitin-protein ligase, and decreased the β-catenin expression. In turn, the downregulation of β-catenin reduced the expression of VEGFA. Rescuing β-catenin expression effectively ameliorated the effect of CTEN overexpression in cell proliferation, migration, and tube formation. In conclusion, CTEN inhibited tumor angiogenesis by targeting VEGFA through c-Cbl-mediated down-regulation of β-catenin and may serve as a tumor suppressor in BRCA.
C 末端张力蛋白样蛋白（CTEN）属于张力蛋白基因家族，该家族编码的蛋白质定位于粘着斑并调节整合素功能。越来越多的研究报道，CTEN 的表达在不同类型的癌症中可上调或下调，这表明 CTEN 具有致癌和肿瘤抑制双重功能。在本研究中，通过分析来自临床注释基因组数据库“癌症基因组图谱”的人类乳腺癌（BRCA）样本中 CTEN 的表达水平，我们发现 CTEN 在不同的 BRCA 亚类中表达下调，包括管腔型、人表皮生长因子受体 2 阳性和三阴性 BRCA。同样，基于蛋白质组肿瘤分析联盟的数据，BRCA 中 CTEN 的蛋白水平也降低。相反，血管内皮生长因子 A（VEGFA），一种刺激血管形成的信号蛋白，在 BRCA 中上调。在人脐静脉内皮细胞和 MCF7 中过表达 CTEN 显著抑制了 VEGFA 的表达，在体外抑制了细胞增殖、迁移和管腔形成。机制上，CTEN 与 E3 泛素蛋白连接酶 casitas B 系淋巴瘤（c-Cbl）结合，并降低了β-连环蛋白的表达。反过来，β-连环蛋白的下调降低了 VEGFA 的表达。挽救β-连环蛋白的表达有效改善了 CTEN 过表达对细胞增殖、迁移和管腔形成的影响。总之，CTEN 通过 c-Cbl 介导的β-连环蛋白下调靶向 VEGFA 抑制肿瘤血管生成，可能在 BRCA 中作为肿瘤抑制因子发挥作用。
