ETS variant 5 promotes colorectal cancer angiogenesis by targeting platelet-derived growth factor BB
ETS variant 5 promotes colorectal cancer angiogenesis by targeting platelet-derived growth factor BB
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ETS 变体 5 通过靶向血小板衍生生长因子 BB 促进结直肠癌血管生成
DOI：
10.1002/ijc.32071
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发表时间：
2019-07-01
影响因子：
6.4
通讯作者：
Zhao, Ren
中科院分区：
文献类型：
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作者：
Cheng, Xi;Jin, Zhijian;Zhao, Ren
ETS转录因子在肿瘤细胞的侵袭、分化和血管生成中起重要作用。在这项研究中，我们初步证明ETS易位变体5（ETV 5）在结直肠癌（CRC）中异常上调，与CRC肿瘤大小、淋巴转移和肿瘤淋巴结转移（TNM）分期呈正相关，并表明CRC患者的生存期和无病生存期较短。体内外实验表明，ETV 5的下调可显著抑制结直肠癌细胞的增殖。此外，ETV 5的过表达可以在体外和体内刺激CRC血管生成，这与RNA-seq结果一致。然后，我们通过血管生成抗体微阵列鉴定了血小板衍生生长因子BB（PDGF-BB）作为ETV 5的直接靶点，其在ETV 5介导的CRC血管生成中起重要作用。此外，PDGF-BB可以通过PDGFR-β/Src/STAT 3途径激活CRC细胞中的VEGFA表达，并且似乎与CRC组织中的ETV 5正相关。最后，我们发现ETV 5可以直接结合到PDGF-BB的启动子区，并通过ChIP和荧光素酶检测调节其表达。总的来说，我们的研究表明，转录因子ETV 5可以刺激CRC恶性肿瘤和促进CRC血管生成直接针对PDGF-BB。这些研究结果表明，EVT 5可能是一个潜在的新的诊断和预后标志物在CRC和靶向ETV 5可能是一个潜在的治疗选择，抑制CRC血管生成。
ETS transcription factors play important roles in tumor cell invasion, differentiation and angiogenesis. In this study, we initially demonstrated that ETS translocation variant 5 (ETV5) is abnormally upregulated in colorectal cancer (CRC), is positively correlated with CRC tumor size, lymphatic metastasis and tumor node metastasis (TNM) stage and indicates shorter survival and disease-free survival in CRC patients. In vitro and in vivo experiments revealed that the downregulation of ETV5 could significantly suppress CRC cell proliferation. Moreover, overexpression of ETV5 could stimulate CRC angiogenesis in vitro and in vivo, which is consistent with RNA-seq results. Then, we identified platelet-derived growth factor BB (PDGF-BB) as a direct target of ETV5 that plays an important role in ETV5-mediated CRC angiogenesis through an angiogenesis antibody microarray. Additionally, PDGF-BB could activate VEGFA expression via the PDGFR-beta/Src/STAT3 pathway in CRC cells and appeared to be positively correlated with ETV5 in CRC tissues. Finally, we revealed that ETV5 could bind directly to the promoter region of PDGF-BB and regulate its expression through ChIP and luciferase assays. Overall, our study suggested that the transcription factor ETV5 could stimulate CRC malignancy and promote CRC angiogenesis by directly targeting PDGF-BB. These findings suggest that EVT5 may be a potential new diagnostic and prognostic marker in CRC and that targeting ETV5 might be a potential therapeutic option for inhibiting CRC angiogenesis.