circOMA1-Mediated miR-145-5p Suppresses Tumor Growth of Nonfunctioning Pituitary Adenomas by Targeting TPT1
circOMA1-Mediated miR-145-5p Suppresses Tumor Growth of Nonfunctioning Pituitary Adenomas by Targeting TPT1
复制标题
circOMA1 介导的 miR-145-5p 通过靶向 TPT1 抑制无功能垂体腺瘤的肿瘤生长。
DOI：
10.1210/jc.2018-01851
复制
发表时间：
2019-06-01
影响因子：
5.8
通讯作者：
Wang, Haijun
中科院分区：
文献类型：
--
作者：
Du, Qiu;Hu, Bin;Wang, Haijun
背景：无功能垂体腺瘤（nfpa）是垂体功能低下和不孕症的主要原因。然而，nfpa的发病机制在很大程度上仍然未知。先前的研究已经证明了mirna在垂体腺瘤进展中的关键作用。越来越多的证据表明，环状rna （circRNAs）可能介导miRNA的转录活性，为研究nfpa的发病机制提供了新的见解。目的：探讨环状rna - mirna - mrna轴在nfpa肿瘤发生中的调控作用及其活性。设计：体外和体内研究miR-145-5p在nfpa中的功能。我们探索了其中的机械细节，并确定了miR-145-5p的潜在靶点。最后，mir -145-5p相关环状rna在功能上被识别和确认。结果：miR-145-5p在NFPA样本中显著降低，且与NFPA侵袭性呈负相关。过表达miR-145-5p抑制NFPA细胞增殖和侵袭性，促进细胞凋亡。进一步的结果证实，翻译控制肿瘤蛋白（TPT1）是miR-145-5p的靶点，并介导miR-145-5p的作用。miR-145-5p下调TPT1及其下游因子Mcl-1和Bcl-xL，上调Bax。此外，circOMA1 （hsa_circRNA_0002316）被证明可以海绵miR-145-5p，其对NFPA细胞的抑制作用被circOMA1过表达所消除。circOMA1沉默通过下调TPT1表现出与miR-145-5p过表达相似的抑制作用。我们发现circOMA1可以进一步上调Mcl-1和Bcl-xL，下调Bax。结论：circOMA1通过作为肿瘤抑制因子miR-145-5p的海绵调节TPT1信号通路，促进NFPA进展，揭示了防止NFPA发生的治疗靶点。
Context: Nonfunctioning pituitary adenomas (NFPAs) are the major cause of hypopituitarism and infertility. However, the pathogenesis of NFPAs remains largely unknown. Previous studies have demonstrated the crucial role of miRNAs in the progression of pituitary adenomas. Increasing evidence has indicated that circular RNAs (circRNAs) might mediate miRNA transcriptional activity, providing new insights to study the pathogenesis of NFPAs.Objectives: To explore the regulation and activity of the circRNA-miRNA-mRNA axis in the tumorigenesis of NFPAs.Design: The function of miR-145-5p in NFPAs was investigated in vitro and in vivo. The mechanical details were explored and potential targets of miR-145-5p were identified. Finally, miR-145-5p-associated circRNAs were functionally recognized and confirmed.Results: miR-145-5p was markedly decreased in NFPA samples and correlated negatively with NFPA invasiveness. Overexpression of miR-145-5p suppressed NFPA cell proliferation and invasiveness and promoted apoptosis. Further results confirmed that translationally controlled tumor protein (TPT1) is a target of miR-145-5p and mediated the effect of miR-145-5p. TPT1 and its downstream factors Mcl-1 and Bcl-xL were downregulated, and Bax was upregulated by miR-145-5p. Moreover, circOMA1 (hsa_circRNA_0002316) was demonstrated to sponge miR-145-5p, whose suppression on NFPA cells was abrogated by circOMA1 overexpression. circOMA1 silencing exhibited a similar inhibitory effect with miR-145-5p overexpression by downregulating TPT1. We found that circOMA1 could further upregulate Mcl-1 and Bcl-xL and downregulate Bax.Conclusions: circOMA1 promotes NFPA progression by acting as the sponge of tumor suppressor miR-145-5p to regulate the TPT1 signaling pathway, revealing a therapeutic target in preventing the tumorigenesis of NFPAs.