TSP-1 is downregulated and inversely correlates with miR-449c expression in Cushing's disease
TSP-1 is downregulated and inversely correlates with miR-449c expression in Cushing's disease
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TSP-1 在库欣病中下调并与 miR-449c 表达呈负相关
DOI：
10.1111/jcmm.14297
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发表时间：
2019
影响因子：
5.3
通讯作者：
Sun Qingfang
中科院分区：
文献类型：
--
作者：
Ren Jie;Gu Changwei;Yang Yong;Xue Jun;Sun Yuhao;Jian Fangfang;Chen Dongjiang;Bian Liuguan;Sun Qingfang
库欣病是由垂体促肾上腺皮质激素腺瘤引起的，其发病机制有待进一步研究。分泌型血管抑制因子血小板反应蛋白-1（TSP-1）是一种粘附性糖蛋白，介导细胞与细胞和细胞与基质的相互作用，与血小板聚集、血管生成和肿瘤发生相关。我们发现TSP-1在人垂体促肾上腺皮质激素细胞肿瘤中的表达显著低于正常腺垂体。本研究旨在阐明TSP-1在调节垂体腺瘤肿瘤功能中的作用。在小鼠AtT 20垂体促肾上腺皮质激素肿瘤细胞系中强制过表达TSP-1可降低促肾上腺皮质激素前体激素阿黑皮素原（POMC）转录和促肾上腺皮质激素（ACTH）分泌。功能研究表明，垂体腺瘤细胞中TSP-1过表达抑制增殖、迁移和侵袭。我们已经证明TSP-1是miR-449 c的直接靶点。进一步的研究表明，miR-449 c活性通过直接抑制TSP-1表达而增强肿瘤发生。沿着TSP-1低表达的lncTHBS 1低表达与库欣病患者中miR-449 c高表达相关。此外，RNA免疫沉淀将miR-449 c与lncTHBS 1相关联，表明lncTHBS 1可能是miR-449 c的负调节因子。总之，这项研究表明，lncTHBS 1可能作为miR-449 c的竞争性内源性RNA发挥作用，这可能抑制库欣病的发展。
The pathogenesis of Cushing's disease, which is caused by pituitary corticotroph adenoma, remains to be studied. Secreted angioinhibitory factor thrombospondin‐1 (TSP‐1) is an adhesive glycoprotein that mediates cell‐to‐cell and cell‐to‐matrix interactions and is associated with platelet aggregation, angiogenesis and tumorigenesis. We have found that the expression of TSP‐1 is significantly lower in human pituitary corticotroph tumours compared with normal adenohypophysis. This study aims to elucidate the role of TSP‐1 in regulating the tumour function of pituitary adenomas. Forced overexpression of TSP‐1 in a murine AtT20 pituitary corticotroph tumour cell line decreased corticotroph precursor hormone proopiomelanocortin (POMC) transcription and adrenocorticotropic hormone (ACTH) secretion. Functional studies showed that TSP‐1 overexpression in pituitary adenoma cells suppressed proliferation, migration and invasion. We have demonstrated that TSP‐1 is a direct target of miR‐449c. Further study showed that miR‐449c activity enhanced tumorigenesis by directly inhibiting TSP‐1 expression. Low expression of lncTHBS1, along with low expression of TSP‐1, was associated with the high expression of miR‐449c in Cushing's disease patients. Furthermore, RNA‐immunoprecipitation associates miR‐449c with lncTHBS1 suggesting that lncTHBS1 might be a negative regulator of miR‐449c. Taken together, this study has demonstrated that lncTHBS1 might function as competing endogenous RNA for miR‐449c, which could suppress the development of Cushing's disease.