Roquin2 suppresses breast cancer progression by inhibiting tumor angiogenesis via selectively destabilizing proangiogenic factors mRNA.
Roquin2 suppresses breast cancer progression by inhibiting tumor angiogenesis via selectively destabilizing proangiogenic factors mRNA.
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Roquin2通过选择性去稳定促血管生成因子mRNA抑制肿瘤血管生成来抑制乳腺癌进展。
DOI：
10.7150/ijbs.59891
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发表时间：
2021
影响因子：
9.2
通讯作者：
Li A
中科院分区：
文献类型：
--
作者：
Zhou M;Lu W;Li B;Yuan X;Liu M;Han J;Liu X;Li A
肿瘤血管生成是肿瘤生长和转移的重要环节。肿瘤血管生成的启动是由促血管生成和抗血管生成基因表达程序之间的平衡转变决定的。Roquin 2是一种锌指RNA结合蛋白，在介导炎症基因如TNF、IL 6和PTGS 2的表达中具有重要作用，这些炎症基因也是重要的血管生成因子。在这项研究中，我们证明了Roquin 2作为一种有效的肿瘤血管生成调节剂，通过选择性地使促血管生成基因转录物（包括内皮糖蛋白（ENG）、内皮素-1（EDN 1）、血管内皮生长因子B（VEGFB）和血小板衍生生长因子C（PDGFC））的mRNA不稳定来抑制乳腺肿瘤诱导的血管生成。Roquin 2通过其ROQ结构域识别并结合这些mRNA的3 '非翻译区（3' UTR）中的茎环结构以使mRNA不稳定。此外，我们发现Roquin 2在乳腺癌细胞和组织中的表达减少，并且与乳腺癌患者的预后不良相关。Roquin 2的过表达在体外和体内抑制乳腺肿瘤诱导的血管生成，而Roquin 2的沉默则增强肿瘤血管生成。Roquin 2的腺病毒体内诱导显着抑制乳腺肿瘤的生长，转移和血管生成。综上所述，我们的研究结果表明Roquin 2是一种新的乳腺癌抑制因子，通过选择性下调促血管生成基因的表达来抑制肿瘤血管生成。
Tumor angiogenesis is an essential step in tumor growth and metastasis. The initiation of tumor angiogenesis is dictated by a shift in the balance between proangiogenic and antiangiogenic gene expression programs. Roquin2 is a zinc-finger RNA-binding protein with important roles in mediating the expression of inflammatory genes, such as TNF, IL6 and PTGS2, which are also important angiogenic factors. In this study, we demonstrate that Roquin2 functions as a potent tumor angiogenesis regulator that inhibits breast tumor-induced angiogenesis by selectively destabilizing mRNA of proangiogenic gene transcripts, including endoglin (ENG), endothelin-1 (EDN1), vascular endothelial growth factor B (VEGFB) and platelet derived growth factor C (PDGFC). Roquin2 recognizes and binds the stem-loop structure in the 3'untranslated region (3'UTR) of these mRNAs via its ROQ domain to destabilize mRNA. Moreover, we found that Roquin2 expression was reduced in breast cancer cells and tissues, and associated with poor prognosis in breast cancer patients. Overexpression of Roquin2 inhibited breast tumor-induced angiogenesis in vitro and in vivo, whereas silencing Roquin2 enhanced tumor angiogenesis. In vivo induction of Roquin2 by adenovirus significantly suppressed breast tumor growth, metastasis and angiogenesis. Taken together, our results identify that Roquin2 is a novel breast cancer suppressor that inhibits tumor angiogenesis by selectively downregulating the expression of proangiogenic genes.
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