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鉴定MX2作为透明细胞肾细胞癌中舒尼替尼耐药的新型预后生物标志物

Identification of MX2 as a Novel Prognostic Biomarker for Sunitinib Resistance in Clear Cell Renal Cell Carcinoma.

作者信息

Wei Yuang, Chen Xinglin, Ren Xiaohan, Wang Bao, Zhang Qian, Bu Hengtao, Qian Jian, Shao Pengfei

机构信息

Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

出版信息

Front Genet. 2021 Jul 9;12:680369. doi: 10.3389/fgene.2021.680369. eCollection 2021.

DOI:10.3389/fgene.2021.680369
PMID:34306023
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8299280/
Abstract

BACKGROUND: Antiangiogenic agents that specifically target vascular endothelial growth factor receptor (VEGFR), such as sunitinib, have been utilized as the standard therapy for metastatic clear cell renal cell carcinoma (ccRCC) patients. However, most patients eventually show no responses to the targeted drugs, and the mechanisms for the resistance remain unclear. This study is aimed to identify pivotal molecules and to uncover their potential functions involved in this adverse event in ccRCC treatment. METHODS: Two datasets, GSE64052 and GSE76068, were obtained from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified using the limma package in R software. The gene set enrichment analysis (GSEA) was conducted using clusterProfiler package. A protein-protein interaction (PPI) network was built using the STRING database and Cytoscape software. Kaplan-Meier survival curves were plotted using R software. qRT-PCR and Western blotting were used to detect the MX2 and pathway expression in RCC cell lines. Sunitinib-resistant cell lines were constructed, and loss-of-function experiments were conducted by knocking down MX2. All statistical analyses were performed using R version 3.6.1 and SPSS 23.0. RESULTS: A total of 760 DEGs were derived from two datasets in GEO database, and five hub genes were identified, among which high-level MX2 exhibited a pronounced correlation with poor overall survival (OS) in sunitinib-resistant ccRCC patients. Clinical correlation analysis and Gene Set Variation Analysis (GSVA) on MX2 showed that the upregulation of MX2 was significantly related to the malignant phenotype of ccRCC, and it was involved in several pathways and biological processes associated with anticancer drug resistance. qRT-PCR and Western blotting revealed that MX2 was distinctly upregulated in sunitinib-resistant RCC cell lines. Colony formation assay and Cell Counting Kit-8 (CCK8) assay showed that MX2 strongly promoted resistant capability to sunitinib of ccRCC cells. CONCLUSION: MX2 is a potent indicator for sunitinib resistance and a therapeutic target in ccRCC patients.

摘要

背景：特异性靶向血管内皮生长因子受体（VEGFR）的抗血管生成药物，如舒尼替尼，已被用作转移性透明细胞肾细胞癌（ccRCC）患者的标准治疗药物。然而，大多数患者最终对靶向药物无反应，耐药机制仍不清楚。本研究旨在鉴定关键分子，并揭示其在ccRCC治疗中参与这一不良事件的潜在功能。 方法：从基因表达综合数据库（GEO）中获取两个数据集GSE64052和GSE76068。使用R软件中的limma包鉴定差异表达基因（DEG）。使用clusterProfiler包进行基因集富集分析（GSEA）。使用STRING数据库和Cytoscape软件构建蛋白质-蛋白质相互作用（PPI）网络。使用R软件绘制Kaplan-Meier生存曲线。采用qRT-PCR和蛋白质印迹法检测RCC细胞系中MX2及相关通路的表达。构建舒尼替尼耐药细胞系，并通过敲低MX2进行功能丧失实验。所有统计分析均使用R 3.6.1版和SPSS 23.0进行。 结果：从GEO数据库的两个数据集中共获得760个DEG，鉴定出5个枢纽基因，其中高水平的MX2与舒尼替尼耐药的ccRCC患者的总生存期（OS）较差显著相关。对MX2的临床相关性分析和基因集变异分析（GSVA）表明，MX2的上调与ccRCC的恶性表型显著相关，并且它参与了与抗癌药物耐药相关的多个通路和生物学过程。qRT-PCR和蛋白质印迹显示MX2在舒尼替尼耐药的RCC细胞系中明显上调。集落形成实验和细胞计数试剂盒-8（CCK8）实验表明，MX2强烈促进ccRCC细胞对舒尼替尼的耐药能力。 结论：MX2是ccRCC患者舒尼替尼耐药的有力指标和治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bc1/8299280/1fb52518f976/fgene-12-680369-g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bc1/8299280/38a229136daa/fgene-12-680369-g005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bc1/8299280/bcb06822c02d/fgene-12-680369-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bc1/8299280/1fb52518f976/fgene-12-680369-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bc1/8299280/18c2258fa988/fgene-12-680369-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bc1/8299280/c4cd062bac5d/fgene-12-680369-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bc1/8299280/317bb9f57b62/fgene-12-680369-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bc1/8299280/925919bc3795/fgene-12-680369-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bc1/8299280/38a229136daa/fgene-12-680369-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bc1/8299280/bd7f121a8827/fgene-12-680369-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bc1/8299280/bcb06822c02d/fgene-12-680369-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bc1/8299280/1fb52518f976/fgene-12-680369-g008.jpg

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