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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Roquin2 通过选择性破坏促血管生成因子 mRNA 抑制肿瘤血管生成来抑制乳腺癌进展

肿瘤血管生成是肿瘤生长和转移的重要步骤。肿瘤血管生成的起始是由促血管生成和抗血管生成基因表达程序之间平衡的转变决定的。Roquin2 是一种锌指 RNA 结合蛋白，在介导炎症基因如TNF、IL6和PTGS2的表达中具有重要作用，这些基因也是重要的血管生成因子。在这项研究中，我们证明 Roquin2 可作为一种有效的肿瘤血管生成调节剂，通过选择性地破坏促血管生成基因转录物（包括内皮糖蛋白( ENG ) 、内皮素-1 ( EDN1 )）的 mRNA 来抑制乳腺肿瘤诱导的血管生成。、血管内皮生长因子B（VEGFB）和血小板衍生生长因子C（PDGFC）。Roquin2 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，从而使 mRNA 不稳定。此外，我们发现 Roquin2 在乳腺癌细胞和组织中的表达降低，并且与乳腺癌患者的不良预后相关。Roquin2 的过表达在体外和体内抑制了乳腺肿瘤诱导的血管生成，而沉默 Roquin2 增强了肿瘤血管生成。体内腺病毒对 Roquin2 的诱导显着抑制了乳腺肿瘤的生长、转移和血管生成。总之，我们的研究结果表明，Roquin2 是一种新型乳腺癌抑制剂，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。