The feedback loop between miR-222-3p and ZEB1 harnesses metastasis in renal cell carcinoma.

IF 7 2区生物学 Q1 CELL BIOLOGY Cell Death Discovery Pub Date : 2025-03-12 DOI:10.1038/s41420-025-02385-0

Fan Wang, Liao Li, Xiangfu Sun, Xianfu Cai, Jianjun Wang, Huiwen Luo, Yaodong Wang, Dong Ni, Decai Wang

{"title":"The feedback loop between miR-222-3p and ZEB1 harnesses metastasis in renal cell carcinoma.","authors":"Fan Wang, Liao Li, Xiangfu Sun, Xianfu Cai, Jianjun Wang, Huiwen Luo, Yaodong Wang, Dong Ni, Decai Wang","doi":"10.1038/s41420-025-02385-0","DOIUrl":null,"url":null,"abstract":"<p><p>Renal cell carcinoma (RCC) is an aggressive malignancy originating from the renal parenchyma, often leading to high mortality due to local invasion and distant metastasis. MicroRNAs (miRNAs) play essential roles in RCC progression. Through miRNA sequencing, we identified significant upregulation of miR-222-3p in metastatic RCC tissues. Exosomes from highly metastatic RCC cells were found to transfer miR-222-3p to low-metastatic cells, enhancing their migration and invasion. Mechanistically, miR-222-3p directly targets the 3' untranslated region (3'UTR) of the tumor-suppressor TRPS1, reducing its expression. TRPS1 downregulation releases its inhibitory effect on ZEB1, a key regulator of epithelial-mesenchymal transition (EMT), thereby promoting EMT and metastatic traits. ZEB1 further transactivates miR-222-3p, establishing a positive feedback loop. Additionally, miR-222-3p promotes a pre-metastatic niche by inducing M2 macrophage polarization, facilitating distant metastasis. These findings highlight miR-222-3p as a critical driver of RCC metastasis and suggest its potential as a diagnostic marker and therapeutic target for RCC.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"97"},"PeriodicalIF":7.0000,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11903659/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Death Discovery","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41420-025-02385-0","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Renal cell carcinoma (RCC) is an aggressive malignancy originating from the renal parenchyma, often leading to high mortality due to local invasion and distant metastasis. MicroRNAs (miRNAs) play essential roles in RCC progression. Through miRNA sequencing, we identified significant upregulation of miR-222-3p in metastatic RCC tissues. Exosomes from highly metastatic RCC cells were found to transfer miR-222-3p to low-metastatic cells, enhancing their migration and invasion. Mechanistically, miR-222-3p directly targets the 3' untranslated region (3'UTR) of the tumor-suppressor TRPS1, reducing its expression. TRPS1 downregulation releases its inhibitory effect on ZEB1, a key regulator of epithelial-mesenchymal transition (EMT), thereby promoting EMT and metastatic traits. ZEB1 further transactivates miR-222-3p, establishing a positive feedback loop. Additionally, miR-222-3p promotes a pre-metastatic niche by inducing M2 macrophage polarization, facilitating distant metastasis. These findings highlight miR-222-3p as a critical driver of RCC metastasis and suggest its potential as a diagnostic marker and therapeutic target for RCC.

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

miR-222-3p和ZEB1之间的反馈回路控制了肾细胞癌的转移。

肾细胞癌（RCC）是一种起源于肾实质的侵袭性恶性肿瘤，由于局部侵袭和远处转移，往往导致高死亡率。MicroRNAs （miRNAs）在RCC的进展中起重要作用。通过miRNA测序，我们发现miR-222-3p在转移性RCC组织中显著上调。来自高转移性RCC细胞的外泌体被发现将miR-222-3p转移到低转移细胞，增强其迁移和侵袭。在机制上，miR-222-3p直接靶向肿瘤抑制因子TRPS1的3‘非翻译区（3’ utr），从而降低其表达。TRPS1下调释放其对上皮-间质转化（epithelial-mesenchymal transition， EMT）关键调控因子ZEB1的抑制作用，从而促进EMT和转移性状。ZEB1进一步激活miR-222-3p，建立正反馈回路。此外，miR-222-3p通过诱导M2巨噬细胞极化促进转移前生态位，促进远处转移。这些发现强调了miR-222-3p是RCC转移的关键驱动因素，并提示其作为RCC的诊断标记和治疗靶点的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.