CircNR3C2 promotes HRD1-mediated tumor-suppressive effect via sponging miR-513a-3p in triple-negative breast cancer.
CircNR3C2 promotes HRD1-mediated tumor-suppressive effect via sponging miR-513a-3p in triple-negative breast cancer.
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在三阴性乳腺癌中，CircNR3C2 通过海绵 miR-513a-3p 促进 HRD1 介导的肿瘤抑制作用。
DOI：
10.1186/s12943-021-01321-x
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发表时间：
2021-02-02
期刊：
影响因子：
37.3
通讯作者：
Su D
中科院分区：
文献类型：
--
作者：
Fan Y;Wang J;Jin W;Sun Y;Xu Y;Wang Y;Liang X;Su D
E3泛素连接酶Hrd1(HMG-CoA还原酶降解蛋白1，别名突触素，以SYVN1为正式基因标志)在乳腺癌中表达下调，并发挥肿瘤抑制作用，但Hrd1在不同乳腺癌亚型中的确切表达谱尚不清楚。最近的研究表明，环状RNA(CircRNAs)在肿瘤进展中扮演着miRNA海绵的调节角色，为肿瘤相关基因的转录后调控提供了一个新的视角。使用公共微阵列/RNA测序数据集和乳腺癌组织/细胞系来检测Hrd1蛋白和mRNA的表达。根据公开的RNA测序结果，使用在线数据库和浓缩/聚类分析来预测可能控制Hrd1表达的CircRNA/miRNA的特定组合。通过免疫印迹、免疫沉淀和体外泛素化实验，通过Hrd1介导的Vimentin蛋白酶体降解来评价CircNR3C2在体外和体内的功能获得和挽救实验，以评估CircNR3C2对乳腺癌进展的抑制作用。Hrd1在三阴性乳腺癌(TNBC)中的表达明显低于其他亚型，并且与Vimentin呈负相关，通过诱导Vimentin的多泛素化介导的蛋白酶体降解抑制乳腺癌细胞的增殖、迁移、侵袭和EMT(上皮-间充质转化)过程。CircNR3C2(HsA_CIRC_0071127)在TNBC中的表达也显著下调，与浸润性乳腺癌的远处转移和致死率呈负相关。在体外和体内过表达CircNR3C2导致Hrd1通过海绵miR-513a-3p的抑制肿瘤作用。总之，我们阐明了一个真正的大约NR3C2/miR-513a-3p/Hrd1/Vimentin轴，它负向调节TNBC的转移，提示CircNR3C2和Hrd1可以作为潜在的预后生物标志物。我们的研究可能会促进针对CircNR3C2和Hrd1的侵袭性乳腺癌患者的治疗药物的开发。网上版载有补充材料，可在10.1186/s12943-021-01321-x查阅。
E3 ubiquitin ligase HRD1 (HMG-CoA reductase degradation protein 1, alias synoviolin with SYVN1 as the official gene symbol) was found downregulated and acting as a tumor suppressor in breast cancer, while the exact expression profile of HRD1 in different breast cancer subtypes remains unknown. Recent studies characterized circular RNAs (circRNAs) playing an regulatory role as miRNA sponge in tumor progression, presenting a new viewpoint for the post-transcriptional regulation of cancer-related genes. Examination of the expression of HRD1 protein and mRNA was implemented using public microarray/RNA-sequencing datasets and breast cancer tissues/cell lines. Based on public RNA-sequencing results, online databases and enrichment/clustering analyses were used to predict the specific combinations of circRNA/miRNA that potentially govern HRD1 expression. Gain-of-function and rescue experiments in vitro and in vivo were executed to evaluate the suppressive effects of circNR3C2 on breast cancer progression through HRD1-mediated proteasomal degradation of Vimentin, which was identified using immunoblotting, immunoprecipitation, and in vitro ubiquitination assays. HRD1 is significantly underexpressed in triple-negative breast cancer (TNBC) against other subtypes and has an inverse correlation with Vimentin, inhibiting the proliferation, migration, invasion and EMT (epithelial-mesenchymal transition) process of breast cancer cells via inducing polyubiquitination-mediated proteasomal degradation of Vimentin. CircNR3C2 (hsa_circ_0071127) is also remarkably downregulated in TNBC, negatively correlated with the distant metastasis and lethality of invasive breast carcinoma. Overexpressing circNR3C2 in vitro and in vivo leads to a crucial enhancement of the tumor-suppressive effects of HRD1 through sponging miR-513a-3p. Collectively, we elucidated a bona fide circNR3C2/miR-513a-3p/HRD1/Vimentin axis that negatively regulates the metastasis of TNBC, suggesting that circNR3C2 and HRD1 can act as potential prognostic biomarkers. Our study may facilitate the development of therapeutic agents targeting circNR3C2 and HRD1 for patients with aggressive breast cancer. The online version contains supplementary material available at 10.1186/s12943-021-01321-x.
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影响因子：
--
作者：
Kim J;Kong J;Chang H;Kim H;Kim A
通讯作者：
Kim A
影响因子：
6.6
作者：
Beaty, Brian T.;Condeelis, John
通讯作者：
Condeelis, John
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影响因子：
8
作者：
Liu L;Wong CC;Gong B;Yu J
通讯作者：
Yu J
影响因子：
--
作者：
Noh H;Yan J;Hong S;Kong LY;Gabrusiewicz K;Xia X;Heimberger AB;Li S
通讯作者：
Li S
影响因子：
4.1
作者：
Dudekulay, Dawood B.;Panda, Amaresh C.;Gorospe, Myriam
通讯作者：
Gorospe, Myriam