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SHARPIN 通过促进抑血管生成因子蛋白泛素化和降解来调控肾透明细胞癌的发展。

SHARPIN regulates the development of clear cell renal cell carcinoma by promoting von Hippel-Lindau protein ubiquitination and degradation.

机构信息

Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.

出版信息

Cancer Sci. 2021 Oct;112(10):4100-4111. doi: 10.1111/cas.15096. Epub 2021 Aug 22.

DOI:10.1111/cas.15096
PMID:34339558
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8486188/
Abstract

SHANK-associated RH domain interacting protein (SHARPIN) plays an important role in carcinogenesis, as well as inflammation and immunity. Our study explored the effects and underlying mechanisms of SHARPIN in clear cell renal cell carcinoma (ccRCC). By analyzing The Cancer Genome Atlas database, we found that upregulated SHARPIN in patients with ccRCC led to a poor prognosis. Semiquantitative immunohistochemical analysis of clinical samples was carried out and the results suggested the positive association between SHARPIN and hypoxia-induced factor-2α (HIF-2α). Von Hippel-Lindau protein (pVHL) is a tumor suppressor that contributes to degrading HIF-2α. Mechanically, SHARPIN promoted the ubiquitination and proteasomal degradation of pVHL, resulting in the sustained activation of HIF-2α. The α and β domains of pVHL and ubiquitin-like domain of SHARPIN are required for the interaction. The knockdown of SHARPIN effectively inhibited acquired sorafenib resistance in ccRCC cell lines and tumor growth in xenograft models. In conclusion, our work reveals a novel posttranslational regulation of SHARPIN on pVHL, indicating that SHARPIN could be a potential target for ccRCC treatment.

摘要

支架相关 RH 结构域相互作用蛋白 (SHARPIN) 在癌症发生以及炎症和免疫中发挥重要作用。我们的研究探讨了 SHARPIN 在透明细胞肾细胞癌 (ccRCC) 中的作用及其潜在机制。通过分析癌症基因组图谱数据库，我们发现 ccRCC 患者中上调的 SHARPIN 导致预后不良。对临床样本进行半定量免疫组织化学分析的结果表明 SHARPIN 与缺氧诱导因子-2α (HIF-2α) 呈正相关。von Hippel-Lindau 蛋白 (pVHL) 是一种肿瘤抑制因子，有助于降解 HIF-2α。在机制上，SHARPIN 促进了 pVHL 的泛素化和蛋白酶体降解，导致 HIF-2α 的持续激活。pVHL 的α和β结构域以及 SHARPIN 的泛素样结构域是相互作用所必需的。SHARPIN 的敲低有效地抑制了 ccRCC 细胞系中获得性索拉非尼耐药和异种移植模型中的肿瘤生长。总之，我们的工作揭示了 SHARPIN 对 pVHL 的一种新的翻译后调控，表明 SHARPIN 可能是 ccRCC 治疗的一个潜在靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b85e/8486188/0a684fbae2a3/CAS-112-4100-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b85e/8486188/6635ea6b4aa2/CAS-112-4100-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b85e/8486188/4a86cd6d07fb/CAS-112-4100-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b85e/8486188/92282be129a5/CAS-112-4100-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b85e/8486188/1953c798d1d3/CAS-112-4100-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b85e/8486188/01b835ac6718/CAS-112-4100-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b85e/8486188/0a684fbae2a3/CAS-112-4100-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b85e/8486188/6635ea6b4aa2/CAS-112-4100-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b85e/8486188/4a86cd6d07fb/CAS-112-4100-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b85e/8486188/92282be129a5/CAS-112-4100-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b85e/8486188/1953c798d1d3/CAS-112-4100-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b85e/8486188/01b835ac6718/CAS-112-4100-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b85e/8486188/0a684fbae2a3/CAS-112-4100-g006.jpg

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