ACE2 通过抑制 VEGFa/VEGFR2/ERK 通路抑制乳腺癌血管生成。
ACE2 inhibits breast cancer angiogenesis via suppressing the VEGFa/VEGFR2/ERK pathway.
机构信息
Breast Disease Center, The First Affiliated Hospital, Sun Yat-Sen University, No.58 of Zhongshan 2nd road, Yuexiu district, Guangzhou, 510080, China.
Guangdong Key Engineering Laboratory for Diagnosis and Treatment of Vascular Disease, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China.
出版信息
J Exp Clin Cancer Res. 2019 Apr 25;38(1):173. doi: 10.1186/s13046-019-1156-5.
BACKGROUND
Breast cancer angiogenesis is key for metastasis and predicts a poor prognosis. Angiotensin-converting enzyme 2 (ACE2), as a member of the renin-angiotensin system (RAS), was reported to restrain the progression of hepatocellular carcinoma (HCC) and non-small cell lung cancer (NSCLC) through inhibiting angiogenesis. However, the relationship between ACE2 and breast cancer angiogenesis remains unclear.
METHODS
The prognosis and relative gene selection were analysed using the GEPIA, GEO, TCGA and STRING databases. ACE2 expression in breast cancer tissue was estimated by reverse transcription-quantitative polymerase chain reaction (qPCR). Breast cancer cell migration, proliferation and angiogenesis were assessed by Transwell migration, proliferation, tube formation, and wound healing assays. The expression of vascular endothelial growth factor A (VEGFa) was detected by qPCR and Western blotting. The phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2), mitogen-activated protein kinase 1/2 (MEK1/2), and extracellular signal-regulated protein kinase 1/2 (ERK1/2) was examined by Western blotting. Breast cancer metastasis and angiogenesis in vivo were measured using a zebrafish model.
RESULTS
ACE2 was downregulated in breast cancer patients. Patients with higher ACE2 expression had longer relapse-free survival (RFS). In vitro, ACE2 inhibited breast cancer migration. Meanwhile, ACE2 in breast cancer cells inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, tube formation and migration. In the zebrafish model, ACE2 inhibited breast cancer cell metastasis, as demonstrated by analyses of the number of disseminated foci and the metastatic distance. Neo-angiogenesis was also decreased by ACE2. ACE2 downregulated the expression of VEGFa in breast cancer cells. Furthermore, ACE2 in breast cancer cells inactivated the phosphorylation of VEGFR2, MEK1/2, and ERK1/2 in HUVECs.
CONCLUSIONS
Our findings suggest that ACE2, as a potential resister to breast cancer, might inhibit breast cancer angiogenesis through the VEGFa/VEGFR2/ERK pathway.
TRIAL REGISTRATION
Retrospectively registered.
背景
乳腺癌血管生成是转移的关键，可预测不良预后。血管紧张素转换酶 2（ACE2）作为肾素-血管紧张素系统（RAS）的一员，据报道可通过抑制血管生成来抑制肝细胞癌（HCC）和非小细胞肺癌（NSCLC）的进展。然而，ACE2 与乳腺癌血管生成之间的关系尚不清楚。
方法
使用 GEPIA、GEO、TCGA 和 STRING 数据库分析预后和相对基因选择。通过逆转录定量聚合酶链反应（qPCR）估计乳腺癌组织中的 ACE2 表达。通过 Transwell 迁移、增殖、管形成和划痕愈合试验评估乳腺癌细胞迁移、增殖和血管生成。通过 qPCR 和 Western blot 检测血管内皮生长因子 A（VEGFa）的表达。通过 Western blot 检测血管内皮生长因子受体 2（VEGFR2）、丝裂原活化蛋白激酶 1/2（MEK1/2）和细胞外信号调节激酶 1/2（ERK1/2）的磷酸化。使用斑马鱼模型测量乳腺癌转移和血管生成。
结果
ACE2 在乳腺癌患者中表达下调。ACE2 表达较高的患者无复发生存期（RFS）较长。体外，ACE2 抑制乳腺癌迁移。同时，乳腺癌细胞中的 ACE2 抑制人脐静脉内皮细胞（HUVEC）增殖、管形成和迁移。在斑马鱼模型中，ACE2 抑制乳腺癌细胞转移，通过分析播散灶的数量和转移距离来证明。新生血管形成也因 ACE2 而减少。ACE2 下调乳腺癌细胞中 VEGFa 的表达。此外，乳腺癌细胞中的 ACE2 使 HUVEC 中 VEGFR2、MEK1/2 和 ERK1/2 的磷酸化失活。
结论
我们的研究结果表明，ACE2 作为乳腺癌的潜在抑制剂，可能通过 VEGFa/VEGFR2/ERK 通路抑制乳腺癌血管生成。
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