TARBP2 promotes tumor angiogenesis and metastasis by destabilizing antiangiogenic factor mRNAs.
TARBP2 promotes tumor angiogenesis and metastasis by destabilizing antiangiogenic factor mRNAs.
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TARBP2 通过破坏抗血管生成因子 mRNA 的稳定性来促进肿瘤血管生成和转移
DOI：
10.1111/cas.14820
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发表时间：
2021-03
期刊：
影响因子：
5.7
通讯作者：
Li A
中科院分区：
文献类型：
--
作者：
Zhou M;Lu W;Li B;Liu X;Li A
肿瘤血管生成是实体瘤进一步生长和转移的关键步骤。然而，其监管机制仍不明确。在这里，我们发现，TARBP 2，一种RNA结合蛋白，通过靶向其3′非翻译区（3′ UTR）降解抗血管生成因子（包括血小板反应蛋白1/2（THBS 1/2），金属蛋白酶组织抑制剂1（TIMP 1）和丝氨酸蛋白酶抑制剂家族F成员1（SERPINF 1））的mRNA，在体外和体内促进肿瘤诱导的血管生成中发挥作用。TARBP 2的过表达促进肿瘤细胞诱导的血管生成，而其敲低抑制肿瘤血管生成。临床队列分析显示，TARBP 2的高表达水平与肺癌和乳腺癌患者的不良生存相关。从机制上讲，TARBP 2与位于抗血管生成转录物3′UTR的茎环结构发生物理相互作用，导致dsRNA结合结构域1/2（dsRBD 1/2）使mRNA不稳定。值得注意的是，人肿瘤组织中TARBP 2的表达水平与抗血管生成因子的表达呈负相关，包括THBS 1/2和脑特异性血管生成抑制因子1（BAI 1）。此外，在一组人肺癌样品中，TARBP 2表达与肿瘤血管生成密切相关。总的来说，我们的研究结果强调，TARBP 2是一种新的肿瘤血管生成调节因子，可以通过选择性下调抗血管生成基因的表达来促进肿瘤血管生成。我们证明了TARBP 2能够通过选择性地使抗血管生成因子基因的mRNA不稳定，通过结合位于3′ UTR中的茎环结构来促进肿瘤血管生成。令人惊讶的是，我们的基础研究结果也通过分析人类乳腺癌和肺癌的临床样本和数据得到了证实。因此，TARBP 2可能是抗血管生成肿瘤治疗的有用的分子靶点。
Tumor angiogenesis is a crucial step in the further growth and metastasis of solid tumors. However, its regulatory mechanism remains unclear. Here, we showed that TARBP2, an RNA‐binding protein, played a role in promoting tumor‐induced angiogenesis both in vitro and in vivo through degrading the mRNAs of antiangiogenic factors, including thrombospondin1/2 (THBS1/2), tissue inhibitor of metalloproteinases 1 (TIMP1), and serpin family F member 1 (SERPINF1), by targeting their 3′untranslated regions (3′UTRs). Overexpression of TARBP2 promotes tumor cell–induced angiogenesis, while its knockdown inhibits tumor angiogenesis. Clinical cohort analysis revealed that high expression level of TARBP2 was associated with poor survival of lung cancer and breast cancer patients. Mechanistically, TARBP2 physically interacts with the stem‐loop structure located in the 3′UTR of antiangiogenic transcripts, leading to mRNA destabilization by the dsRNA‐binding domains 1/2 (dsRBDs1/2). Notably, the expression level of TARBP2 in human tumor tissue is negatively correlated with the expression of antiangiogenic factors, including THBS1/2, and brain‐specific angiogenesis inhibitor 1 (BAI1). Moreover, TARBP2 expression is strongly associated with tumor angiogenesis in a group of human lung cancer samples. Collectively, our results highlight that TARBP2 is a novel tumor angiogenesis regulator that could promote tumor angiogenesis by selectively downregulating antiangiogenic gene expression. We demonstrated that TARBP2 was able to promote tumor angiogenesis through selectively destabilizing the mRNAs of antiangiogenic factor genes via binding to the stem‐loop structure located in the 3′UTRs. Strikingly, our basic research findings have also been confirmed by analyzing the clinical samples and data from human breast and lung cancers. Thus, TARBP2 is likely to be a useful molecular target for antiangiogenic tumor therapy.
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影响因子：
11.2
作者：
Lu W;Ning H;Gu L;Peng H;Wang Q;Hou R;Fu M;Hoft DF;Liu J
通讯作者：
Liu J
影响因子：
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作者：
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通讯作者：
Gatignol, Anne
影响因子：
3.6
作者：
Sand, Michael;Skrygan, Marina;Bechara, Falk G.
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Bechara, Falk G.
影响因子：
16.6
作者：
Essig K;Kronbeck N;Guimaraes JC;Lohs C;Schlundt A;Hoffmann A;Behrens G;Brenner S;Kowalska J;Lopez-Rodriguez C;Jemielity J;Holtmann H;Reiche K;Hackermüller J;Sattler M;Zavolan M;Heissmeyer V
通讯作者：
Heissmeyer V
影响因子：
3.7
作者：
Lipert B;Wilamowski M;Gorecki A;Jura J
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Jura J