Abstract
BackgroundAntiangiogenic 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.MethodsTwo 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.ResultsA 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.ConclusionMX2 is a potent indicator for sunitinib resistance and a therapeutic target in ccRCC patients.
Highlights
Kidney cancer is a lethal urological disease and one of the most malignant tumors in human beings
A total of 760 differentially expressed genes (DEG) were derived from two datasets in Gene Expression Omnibus (GEO) database, and five hub genes were identified, among which high-level Human myxovirus resistance protein 2 (MX2) exhibited a pronounced correlation with poor overall survival (OS) in sunitinib-resistant clear cell RCC (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 Renal cell carcinoma (RCC) cell lines
Summary
Kidney cancer is a lethal urological disease and one of the most malignant tumors in human beings. Renal cell carcinoma (RCC) is commonly divided into three main different histological subtypes, among which clear cell RCC (ccRCC) is the most frequent with a proportion of 75– 80% (Motzer et al, 1996). Localized carcinoma can be treated with active surveillance and partial/radical nephrectomy, while patients with metastatic ccRCC require systematic treatment to obtain a better survival (Curti, 2004). With in-depth knowledge of the pathophysiology of ccRCC, the advent of therapeutic agents targeting the vascular endothelial growth factor (VEGF) signaling axis has become a milestone in ccRCC therapy (Rini et al, 2009). Antiangiogenic agents that 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. This study is aimed to identify pivotal molecules and to uncover their potential functions involved in this adverse event in ccRCC treatment
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