The RNA binding protein SORBS2 suppresses metastatic colonization of ovarian cancer by stabilizing tumor-suppressive immunomodulatory transcripts.
The RNA binding protein SORBS2 suppresses metastatic colonization of ovarian cancer by stabilizing tumor-suppressive immunomodulatory transcripts.
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RNA结合蛋白SORBS2通过稳定肿瘤抑制免疫调节转录本来抑制卵巢癌的转移定植
DOI：
10.1186/s13059-018-1412-6
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发表时间：
2018-03-16
期刊：
影响因子：
12.3
通讯作者：
Zhou S
中科院分区：
文献类型：
--
作者：
Zhao L;Wang W;Huang S;Yang Z;Xu L;Yang Q;Zhou X;Wang J;Shen Q;Wang C;Le X;Feng M;Zhou N;Lau WB;Lau B;Yao S;Yi T;Wang X;Zhao X;Wei Y;Zhou S
卵巢癌是女性最致命的妇科恶性肿瘤之一。目前，卵巢癌的早期检测策略和治疗方案远不能令人满意，导致晚期诊断率高和疾病复发。需要针对卵巢癌进展中的关键过程的新的治疗途径。虽然各种非编码RNA已被证明可调节卵巢癌转移进展，但RNA结合蛋白（RBP）在此过程中的功能作用尚不明确。在这项研究中，我们确定，RBP sorbin和SH 3域包含2（SORBS 2）是一个有效的抑制卵巢癌转移定植。机制研究表明，SORBS 2结合WFDC 1（WAP四-二硫键核心结构域1）和IL-17 D（白细胞介素-17 D）的3′非翻译区（UTR），这两种分泌分子显示出作为转移抑制因子。WFDC 1或IL-17 D的表达增强可有效抑制SORBS 2耗竭介导的癌症转移促进。通过增强这些基因转录物的稳定性，SORBS 2抑制卵巢癌的侵袭性，并影响单核细胞向骨髓源性抑制细胞和M2样巨噬细胞的极化，从而引发肿瘤抑制性免疫微环境。我们的数据说明了一种新的转录后网络，通过SORBS 2介导的转录稳定性将肿瘤微环境中的癌症进展和免疫调节联系起来。本文的在线版本（10.1186/s13059-018-1412-6）包含补充材料，可供授权用户使用。
Ovarian cancer constitutes one of the most lethal gynecologic malignancies for females. Currently, early detection strategies and therapeutic options for ovarian cancer are far from satisfactory, leading to high diagnosis rates at late stages and disease relapses. New avenues of therapy are needed that target key processes in ovarian cancer progression. While a variety of non-coding RNAs have been proven to regulate ovarian cancer metastatic progression, the functional roles of RNA-binding proteins (RBPs) in this process are less well defined. In this study, we identify that the RBP sorbin and SH3 domain containing 2 (SORBS2) is a potent suppressor of ovarian cancer metastatic colonization. Mechanistic studies show that SORBS2 binds the 3′ untranslated regions (UTRs) of WFDC1 (WAP four-disulfide core domain 1) and IL-17D (Interleukin-17D), two secreted molecules that are shown to act as metastasis suppressors. Enhanced expression of either WFDC1 or IL-17D potently represses SORBS2 depletion-mediated cancer metastasis promotion. By enhancing the stability of these gene transcripts, SORBS2 suppresses ovarian cancer invasiveness and affects monocyte to myeloid-derived suppressor cell and M2-like macrophage polarization, eliciting a tumor-suppressive immune microenvironment. Our data illustrate a novel post-transcriptional network that links cancer progression and immunomodulation within the tumor microenvironment through SORBS2-mediated transcript stabilization. The online version of this article (10.1186/s13059-018-1412-6) contains supplementary material, which is available to authorized users.
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影响因子：
8.8
作者：
O'Sullivan T;Saddawi-Konefka R;Gross E;Tran M;Mayfield SP;Ikeda H;Bui JD
通讯作者：
Bui JD
影响因子：
8.8
作者：
Saddawi-Konefka R;Seelige R;Gross ET;Levy E;Searles SC;Washington A Jr;Santosa EK;Liu B;O'Sullivan TE;Harismendy O;Bui JD
通讯作者：
Bui JD
影响因子：
64.5
作者：
Jiménez-Sánchez A;Memon D;Pourpe S;Veeraraghavan H;Li Y;Vargas HA;Gill MB;Park KJ;Zivanovic O;Konner J;Ricca J;Zamarin D;Walther T;Aghajanian C;Wolchok JD;Sala E;Merghoub T;Snyder A;Miller ML
通讯作者：
Miller ML
影响因子：
7
作者：
Robin JD;Ludlow AT;Batten K;Gaillard MC;Stadler G;Magdinier F;Wright WE;Shay JW
通讯作者：
Shay JW
影响因子：
14.9
作者：
Cook KB;Kazan H;Zuberi K;Morris Q;Hughes TR
通讯作者：
Hughes TR