OC-2在肿瘤生长、转移和血管生成中发挥着至关重要的作用，但OC-2如何调节血管生成因子的分子机制尚不清楚。我们发现OC-2在HepG2、COLO、MCF-7、SKOV3细胞和直肠癌组织中高表达，且血管生成因子水平与OC-2呈正相关。然后OC-2 KD在体外和体内抑制肿瘤生长、转移和血管生成过程。 ChIP-Seq显示，鉴定出OC-2的228个靶基因，它们与肿瘤生长、转移、血管生成和信号转导相关； OC-2 在启动子区域与 ZKSCAN3 结合。荧光素酶检测显示ZKSCAN3被鉴定为OC-2的靶基因，VEGFA被鉴定为ZKSCAN3的靶基因； OC-2通过激活ZKSCAN3转录程序促进VEGFA表达。重要的是，OC-2 KD 下调 VEGFA 分泌，从而抑制 HUVEC 的肿瘤血管生成。除VEGFA外，OC-2与其他血管生成因子HIF-1α、FGF2、EGFL6和HGF呈正相关。同时，ERK1/2和Smad1信号通路可能与OC-2驱动肿瘤侵袭性的功能有关。我们发现OC-2可能通过ERK1/2、Smad1信号通路调节肿瘤生长、转移、血管生成，并通过激活ZKSCAN3转录程序调节VEGFA表达促进肿瘤血管生成，这表明OC-2是开发新型抗肿瘤药物的一个令人信服的靶点基于血管生成的药物。版权所有 © 2024。由 Elsevier Inc. 出版。

OC-2 plays a vital role in tumor growth, metastasis and angiogenesis, but molecular mechanism how OC-2 regulates angiogenic factors is unclear. We found that OC-2 was highly expressed in HepG2, COLO, MCF-7, SKOV3 cells and rectum carcinoma tissues, and angiogenic factors levels were positively related to OC-2. Then OC-2 KD inhibited the tumor growth, metastasis and angiogenesis process in vitro and vivo. ChIP-Seq showed that 228 target genes of OC-2 were identified and they were associated with tumor growth, metastasis, angiogenesis and signal transduction; OC-2 bound to ZKSCAN3 at promoter region. Luciferase assays showed that ZKSCAN3 was identified as target gene of OC-2 and VEGFA was identified as target gene of ZKSCAN3; OC-2 promoted VEGFA expression via activating ZKSCAN3 transcriptional program. Importantly, OC-2 KD down-regulated VEGFA secretion to suppress tumor angiogenesis of HUVECs. Besides VEGFA, OC-2 was positively correlated with other angiogenic factors HIF-1α, FGF2, EGFL6 and HGF. Meanwhile, ERK1/2 and Smad1 signaling pathways might be related to function of OC-2 driving tumor aggressiveness. We revealed that OC-2 might regulate tumor growth, metastasis, angiogenesis via ERK1/2, Smad1 signaling pathways and regulate VEGFA expression for tumor angiogenesis via activating ZKSCAN3 transcriptional program, indicating that OC-2 was a convincing target to develop novel anti-tumor drugs based on angiogenesis.Copyright © 2024. Published by Elsevier Inc.