miR-181a Targets RGS16 to Promote Chondrosarcoma Growth, Angiogenesis, and Metastasis.
miR-181a Targets RGS16 to Promote Chondrosarcoma Growth, Angiogenesis, and Metastasis.
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miR-181a 靶向 RGS16 促进软骨肉瘤生长、血管生成和转移
DOI：
10.1158/1541-7786.mcr-14-0697
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发表时间：
2015-09
期刊：
影响因子：
--
通讯作者：
Terek RM
中科院分区：
文献类型：
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作者：
Sun X;Charbonneau C;Wei L;Chen Q;Terek RM
软骨肉瘤是成人最常见的原发性恶性骨肿瘤，目前尚无有效的系统治疗方法，且患者生存率低。microRNA（miR）表达的改变与肿瘤发生有关;然而，其在软骨肉瘤中的作用尚未确定。miR-181 a在高级别软骨肉瘤中过表达，受缺氧上调，并增加VEGF表达。本研究的目的是确定miR-181 a调节VEGF的机制，确定miR-181 a过表达是否促进肿瘤进展，并评估基于阿托莫西汀的软骨肉瘤治疗方法。在异种移植小鼠模型中，miR-181 a的治疗性抑制降低了体外VEGF和MMP 1的表达，以及血管生成、MMP 1活性、肿瘤生长和肺转移，均超过50%。miR-181 a的靶点是G蛋白信号传导16（RGS 16）的调节剂，其是CXC趋化因子受体4（CXCR 4）信号传导的负调节剂。CXCR 4信号在软骨肉瘤中增加，其表达也因缺氧而增加，并且与血管生成和转移相关;然而，受体阻断剂仅部分有效。RGS 16表达在miR-181 a抑制后恢复，并部分解释了miR-181 a抑制的抗血管生成和抗转移作用。这些数据确定miR-181 a作为oncomiR，其通过涉及通过抑制RGS 16增强CXCR 4信号传导的新机制促进软骨肉瘤进展。含义：靶向miR-181 a可以抑制肿瘤血管生成、生长和转移，从而提示基于miR-181 a的软骨肉瘤治疗的可能性。Mol Cancer Res; 13（9）; 1347-57.©2015 AACR.
Chondrosarcoma is the most common primary malignant bone tumor in adults, has no effective systemic treatment, and patients with this disease have poor survival. Altered expression of microRNA (miR) is involved in tumorigenesis; however, its role in chondrosarcoma is undetermined. miR-181a is overexpressed in high-grade chondrosarcoma, is upregulated by hypoxia, and increases VEGF expression. Here, the purpose was to determine the mechanism of miR-181a regulation of VEGF, determine whether miR-181a overexpression promotes tumor progression, and to evaluate an antagomir-based approach for chondrosarcoma treatment. Therapeutic inhibition of miR-181a decreased expression of VEGF and MMP1 in vitro, and angiogenesis, MMP1 activity, tumor growth, and lung metastasis, all by more than 50%, in a xenograft mouse model. A target of miR-181a is a regulator of G-protein signaling 16 (RGS16), a negative regulator of CXC chemokine receptor 4 (CXCR4) signaling. CXCR4 signaling is increased in chondrosarcoma, its expression is also increased by hypoxia, and is associated with angiogenesis and metastasis; however, receptor blockade is only partially effective. RGS16 expression is restored after miR-181a inhibition and partially accounts for the antiangiogenic and antimetastatic effects of miR-181a inhibition. These data establish miR-181a as an oncomiR that promotes chondrosarcoma progression through a new mechanism involving enhancement of CXCR4 signaling by inhibition of RGS16. Implications: Targeting miR-181a can inhibit tumor angiogenesis, growth, and metastasis, thus suggesting the possibility of antagomir-based therapy in chondrosarcoma. Mol Cancer Res; 13(9); 1347–57. ©2015 AACR.