Micropeptide MIAC inhibits the tumor progression by interacting with AQP2 and inhibiting EREG/EGFR signaling in renal cell carcinoma.
Micropeptide MIAC inhibits the tumor progression by interacting with AQP2 and inhibiting EREG/EGFR signaling in renal cell carcinoma.
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DOI：
10.1186/s12943-022-01654-1
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发表时间：
2022-09-19
期刊：
影响因子：
37.3
通讯作者：
Xu, Hanmei
中科院分区：
文献类型：
--
作者：
Li, Mengwei;Liu, Guangxiang;Jin, Xinrong;Guo, Hongqian;Setrerrahmane, Sarra;Xu, Xindi;Li, Tiantian;Lin, Yunfei;Xu, Hanmei
虽然非编码RNA编码的多肽在多种肿瘤发生发展过程中发挥重要作用，但在肾细胞癌（RCC）中的作用尚未见报道。本研究基于前期工作中发现并命名的微肽MIAC（micropeptide inhibiting actin cytoskeleton，微肽抑制肌动蛋白细胞骨架），筛选其肿瘤谱，探讨其在肾癌发生发展中的作用机制及潜在的诊疗价值。通过TCGA数据库中530例肾透明细胞癌（KIRC）患者的高通量RNA-seq数据，以及70例肾癌临床标本的检测，通过生物信息学分析探讨MIAC在RCC中的临床意义。体外和体内实验确定MIAC在肾癌细胞生长和转移中的作用;高通量转录组学、蛋白质印迹、免疫沉淀、分子对接、亲和实验和链霉亲和素下拉实验确定MIAC直接结合蛋白和关键调控通路。对600例不同来源的肾癌标本分析发现，MIAC的表达水平明显降低，且与肾癌患者的预后及肿瘤的临床分期相关。MIAC在肾癌细胞中的过表达可显著抑制肾癌细胞的增殖和迁移能力，促进肾癌细胞凋亡，并影响细胞在各个阶段的分布。在击倒MIAC之后，趋势发生了逆转。体内实验发现，MIAC过表达抑制RCC的生长和转移，而合成的MIAC肽在体内外均能显著抑制RCC的发生和发展。进一步的机制研究表明，MIAC直接与AQP 2蛋白结合，抑制EREG/EGFR表达，激活下游通路PI 3 K/AKT和MAPK，从而达到抗肿瘤作用。该研究首次揭示了lncRNA编码的微肽MIAC在RCC中的肿瘤抑制潜力，其通过直接结合AQP 2蛋白来抑制EREG/EGFR信号通路的激活，从而抑制肾癌进展和转移。提示微肽MIAC可为肾细胞癌的诊断和治疗提供新的策略。在线版本包含补充材料，可通过10.1186/s12943-022-01654-1获得。
Although, micropeptides encoded by non-coding RNA have been shown to have an important role in a variety of tumors processes, there have been no reports on micropeptide in renal cell carcinoma (RCC). Based on the micropeptide MIAC (micropeptide inhibiting actin cytoskeleton) discovered and named in the previous work, this study screened its tumor spectrum, and explored its mechanism of action and potential diagnosis and treatment value in the occurrence and development of renal carcinoma. The clinical significance of MIAC in RCC was explored by bioinformatics analysis through high-throughput RNA-seq data from 530 patients with kidney renal clear cell carcinoma (KIRC) in the TCGA database, and the detection of clinical samples of 70 cases of kidney cancer. In vitro and in vivo experiments to determine the role of MIAC in renal carcinoma cell growth and metastasis; High-throughput transcriptomics, western blotting, immunoprecipitation, molecular docking, affinity experiments, and Streptavidin pulldown experiments identify MIAC direct binding protein and key regulatory pathways. The analysis of 600 renal carcinoma samples from different sources revealed that the expression level of MIAC is significantly decreased, and corelated with the prognosis and clinical stage of tumors in patients with renal carcinoma. Overexpression of MIAC in renal carcinoma cells can significantly inhibit the proliferation and migration ability, promote apoptosis of renal carcinoma cells, and affect the distribution of cells at various stages. After knocking down MIAC, the trend is reversed. In vivo experiments have found that MIAC overexpression inhibit the growth and metastasis of RCC, while the synthetized MIAC peptides can significantly inhibit the occurrence and development of RCC in vitro and in vivo. Further mechanistic studies have demonstrated that MIAC directly bind to AQP2 protein, inhibit EREG/EGFR expression and activate downstream pathways PI3K/AKT and MAPK to achieve anti-tumor effects. This study revealed for the first time the tumor suppressor potential of the lncRNA-encoded micropeptide MIAC in RCC, which inhibits the activation of the EREG/EGFR signaling pathway by direct binding to AQP2 protein, thereby inhibiting renal carcinoma progression and metastasis. This result emphasizes that the micropeptide MIAC can provide a new strategy for the diagnosis and treatment of RCC. The online version contains supplementary material available at 10.1186/s12943-022-01654-1.
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影响因子：
14.8
作者：
Saghatelian A;Couso JP
通讯作者：
Couso JP
影响因子：
14.8
作者：
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64.8
作者：
Nakane T;Kotecha A;Sente A;McMullan G;Masiulis S;Brown PMGE;Grigoras IT;Malinauskaite L;Malinauskas T;Miehling J;Uchański T;Yu L;Karia D;Pechnikova EV;de Jong E;Keizer J;Bischoff M;McCormack J;Tiemeijer P;Hardwick SW;Chirgadze DY;Murshudov G;Aricescu AR;Scheres SHW
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Scheres SHW
影响因子：
56.9
作者：
Chen, Jin;Brunner, Andreas-David;Weissman, Jonathan S.
通讯作者：
Weissman, Jonathan S.
影响因子：
9.7
作者：
Setrerrahmane, Sarra;Li, Mengwei;Xu, Hanmei
通讯作者：
Xu, Hanmei