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NEDD4L的泛癌分析及其在透明细胞肾细胞癌中的肿瘤抑制作用

Pan-cancer Analysis of NEDD4L and Its Tumor Suppressor Effects in Clear Cell Renal Cell Carcinoma.

作者信息

Dong Huiyue, Zhu Ling, Sun Jingjing, Zhang Yi, Cui Qiang, Wu Lin, Chen Shushang, Lu Jun

机构信息

Fujian Provincial Key Laboratory of Transplant Biology, Fuzong Clinical College, Fujian Medical University, Fuzhou 350025, China.

Laboratory of Basic Medicine, Dongfang Hospital (900 Hospital of the Joint Logistics Team), Xiamen University, Fuzhou 350025, China.

出版信息

J Cancer. 2021 Aug 28;12(20):6242-6253. doi: 10.7150/jca.58004. eCollection 2021.

DOI:10.7150/jca.58004
PMID:34539897
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8425189/
Abstract

The expression level of NEDD4L, an E3 ubiquitin ligase, has changed significantly in human cancers. In this study, we aimed to study the expression of NEDD4L in pan-carcinoma and its function in malignant tumors. We analyzed the gene expression level of NEDD4L in pan-cancer from The Cancer Genome Atlas (TCGA) microarray data set, the correlation between gene expression and overall survival, disease-specific survival, and tumor immune microenvironment changes. NEDD4L expression changes in half of the cancer types. Low expression of NEDD4L gene predicts poor overall survival and disease-specific survival (DSS) in renal clear cell carcinoma (KIRC) and renal chromophobe cell carcinoma (KIRP). NEDD4L is negatively related to interstitial cell infiltration and immune cell infiltration in most common cancers. Furthermore, the low expression of NEDD4L was verified in our clear cell renal cell carcinoma (ccRCC) clinical tissues. In ccRCC cells, NEDD4L overexpression significantly reduced cell proliferation and migration. In the functional analysis, we proved that NEDD4L could inhibit ERBB3 and MAPK signaling pathways. When cells are deficient in nutrition, NEDD4L promoted the degradation of the autophagy regulatory protein ULK1. Our study provides novel insights into the role of NEDD4L in pan-cancer. NEDD4L may play a tumor suppressor effect in ccRCC, through tumor immune regulation and ubiquitination of key intracellular kinases.

摘要

E3泛素连接酶NEDD4L的表达水平在人类癌症中发生了显著变化。在本研究中，我们旨在研究NEDD4L在泛癌中的表达及其在恶性肿瘤中的功能。我们分析了来自癌症基因组图谱（TCGA）微阵列数据集的泛癌中NEDD4L的基因表达水平、基因表达与总生存期、疾病特异性生存期以及肿瘤免疫微环境变化之间的相关性。NEDD4L的表达在一半的癌症类型中发生改变。NEDD4L基因的低表达预示着肾透明细胞癌（KIRC）和肾嫌色细胞癌（KIRP）的总生存期和疾病特异性生存期较差。在大多数常见癌症中，NEDD4L与间质细胞浸润和免疫细胞浸润呈负相关。此外，我们在肾透明细胞癌（ccRCC）临床组织中验证了NEDD4L的低表达。在ccRCC细胞中，NEDD4L的过表达显著降低了细胞增殖和迁移。在功能分析中，我们证明NEDD4L可以抑制ERBB3和MAPK信号通路。当细胞营养缺乏时，NEDD4L促进自噬调节蛋白ULK

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