B7-H3 promotes colorectal cancer angiogenesis through activating the NF-κB pathway to induce VEGFA expression
B7-H3 promotes colorectal cancer angiogenesis through activating the NF-κB pathway to induce VEGFA expression
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B7-H3通过激活NF-κB通路诱导VEGFA表达促进结直肠癌血管生成
DOI：
10.1038/s41419-020-2252-3
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发表时间：
2020-01-23
影响因子：
9
通讯作者：
Chen, Weichang
中科院分区：
文献类型：
--
作者：
Wang, Ruoqin;Ma, Yanchao;Chen, Weichang
肿瘤血管生成是癌症的标志，并且参与实体瘤的肿瘤发生。B7-H3是一种免疫检查点分子，在多种肿瘤的增殖、转移和肿瘤发生中起着关键作用;然而，关于B7-H3在调节结直肠癌（CRC）血管生成中的生物学功能和分子机制知之甚少。在这项研究中，我们首先证明，B7-H3的表达显着上调，并与血小板内皮细胞粘附分子-1（CD 31）水平在组织样本中的CRC患者。此外，一系列体外和体内实验表明，来自B7-H3敲低CRC细胞的条件培养基显著抑制人脐静脉内皮细胞（HUVECs）的迁移、侵袭和管形成，而B7-H3过表达具有相反的效果。此外，B7-H3通过上调VEGFA表达促进肿瘤血管生成。重组VEGFA消除了来自shB 7-H3 CRC细胞的条件培养基对HUVEC血管生成的抑制作用，而VEGFA siRNA或VEGFA中和抗体逆转了来自B7-H3过表达CRC细胞的条件培养基对HUVEC血管生成的作用。此外，我们证实B7-H3通过激活NF-κB通路上调VEGFA表达和血管生成。总的来说，我们的研究结果确定了B7-H3/NF-κB/VEGFA轴在促进CRC血管生成中的作用，这是一种有希望的CRC治疗方法。
Tumor angiogenesis is a hallmark of cancer and is involved in the tumorigenesis of solid tumors. B7-H3, an immune checkpoint molecule, plays critical roles in proliferation, metastasis and tumorigenesis in diverse tumors; however, little is known about the biological functions and molecular mechanism underlying B7-H3 in regulating colorectal cancer (CRC) angiogenesis. In this study, we first demonstrated that the expression of B7-H3 was significantly upregulated and was positively associated with platelet endothelial cell adhesion molecule-1 (CD31) level in tissue samples from patients with CRC. In addition, a series of in vitro and in vivo experiments showed that conditioned medium from B7-H3 knockdown CRC cells significantly inhibited the migration, invasion, and tube formation of human umbilical vein endothelial cells (HUVECs), whereas overexpression of B7-H3 had the opposite effect. Furthermore, B7-H3 promoted tumor angiogenesis by upregulating VEGFA expression. Recombinant VEGFA abolished the inhibitory effects of conditioned medium from shB7-H3 CRC cells on HUVEC angiogenesis, while VEGFA siRNA or a VEGFA-neutralizing antibody reversed the effects of conditioned medium from B7-H3-overexpressing CRC cells on HUVEC angiogenesis. Moreover, we verified that B7-H3 upregulated VEGFA expression and angiogenesis by activating the NF-κB pathway. Collectively, our findings identify the B7-H3/NF-κB/VEGFA axis in promoting CRC angiogenesis, which serves as a promising approach for CRC treatment.