Potential New Therapeutic Approaches for Renal Cell Carcinoma

Yang, David C.H.; Chen, Ching Hsien

doi:10.1016/j.semnephrol.2019.12.010

Cited by 35 publications

(27 citation statements)

References 78 publications

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“…Today, there are several Food and Drug Administration (FDA)-approved therapies of ccRCC for first-line and second-line standard treatments targeting a wide range of targets, including VEGF (bevacizumab), VEGFR/PDGFR (lenvatinib, cabozantinib, pazopanib, axitinib, sorafenib, and sunitinib), mTOR (everolimus and temsirolimus), PD-1 (nivolumab and pembrolizumab), and PD-L1 (avelumab and atezolizumab) (Yang and Chen, 2020). Despite the effectiveness of targeted therapy on metastatic ccRCC, many patients would eventually develop resistance to the antiangiogenic therapy with a median time of 6-15 months, followed by poor overall survival (OS) (Motzer et al, 2007;Bergers and Hanahan, 2008;Molina et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype (80% to 90%) ( 4 ). Although the molecular targeted therapy of ccRCC has made great progress, the therapeutic effect is not yet satisfactory ( 5 ). The molecular mechanism of ccRCC tumorigenesis and development helps to identify the novel therapeutic targets of ccRCC.…”

Section: Introductionmentioning

confidence: 99%

SDHB Suppresses the Tumorigenesis and Development of ccRCC by Inhibiting Glycolysis

et al. 2021

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Metabolic reprogramming is the prominent feature of clear cell renal cell carcinoma (ccRCC). Succinate dehydrogenase subunit B (SDHB) is one of subunits of mitochondrial respiratory chain complex II. The loss of SDHB function is closely related with metabolic changes in kidney cancer cells. However, the role and molecular mechanism of SDHB in ccRCC occurrence and progression are still unclear. In this study, the results of bioinformatics analyses on GEO, TCGA and oncomine databases and immunohistochemistry showed that the expression level of SDHB was downregulated in ccRCC tissues. SDHB level was gradually downregulated as ccRCC stage and grade progressed. The low level of SDHB was associated with poor prognosis of ccRCC patients, especially for advanced ccRCC patients. Increased methylation levels in SDHB gene promoter led to the downregulation of SDHB level in ccRCC tissues. SDHB was correlated with many metabolism related genes and its interacting proteins were enriched in metabolic pathways. SDHB overexpression suppressed the proliferation, colony formation and migration of ccRCC cells by inhibiting aerobic glycolysis. SDHB may be a potential prognostic marker and therapeutic target for ccRCC.

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“…The latest statistics show that the incidence of ccRCC is increasing at a rate of 2% per year (3). At present, early ccRCC patients mainly rely on surgical treatment, but most early patients have no specific symptoms, so about 1/3 of patients have already metastasized at the time of diagnosis (4). Patients with metastasis and recurrence not only lose the chance of radical surgery, but also easily tolerate traditional radiotherapy and chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

MCM2-7 in Clear Cell Renal Cell Carcinoma: MCM7 Promotes Tumor Cell Proliferation

Zhang¹,

Zhang²,

Wang³

et al. 2021

Front. Oncol.

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BackgroundClear cell renal cell carcinoma (ccRCC) accounts for 60-70% of renal cell carcinoma (RCC) cases. Finding more therapeutic targets for advanced ccRCC is an urgent mission. The minichromosome maintenance proteins 2-7 (MCM2-7) protein forms a stable heterohexamer and plays an important role in DNA replication in eukaryotic cells. In the study, we provide a comprehensive study of MCM2-7 genes expression and their potential roles in ccRCC.MethodsThe expression and prognosis of the MCM2-7 genes in ccRCC were analyzed using data from TCGA, GEO and ArrayExpress. MCM2-7 related genes were identified by weighted co-expression network analysis (WGCNA) and Metascape. CancerSEA and GSEA were used to analyze the function of MCM2–7 genes in ccRCC. The gene effect scores (CERES) of MCM2-7, which reflects carcinogenic or tumor suppressor, were obtained from DepMap. We used clinical and expression data of MCM2-7 from the TCGA dataset and the LASSO Cox regression analysis to develop a risk score to predict survival of patients with ccRCC. The correlations between risk score and other clinical indicators such as gender, age and stage were also analyzed. Further validation of this risk score was engaged in another cohort, E-MTAB-1980 from the ArrayExpress dataset.ResultsThe mRNA and protein expression of MCM2-7 were increased in ccRCC compared with normal tissues. High MCM2, MCM4, MCM6 and MCM7 expression were associated with a poor prognosis of ccRCC patients. Functional enrichment analysis revealed that MCM2-7 might influence the progress of ccRCC by regulating the cell cycle. Knockdown of MCM7 can inhibit the proliferation of ccRCC cells. A two-gene risk score including MCM4 and MCM6 can predict overall survival (OS) of ccRCC patients. The risk score was successfully verified by further using Arrayexpress cohort.ConclusionWe analyze MCM2-7 mRNA and protein levels in ccRCC. MCM7 is determined to promote tumor proliferation. Meanwhile, our study has determined a risk score model composed of MCM2-7 can predict the prognosis of ccRCC patients, which may help future treatment strategies.

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Potential New Therapeutic Approaches for Renal Cell Carcinoma

Cited by 35 publications

References 78 publications

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

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

SDHB Suppresses the Tumorigenesis and Development of ccRCC by Inhibiting Glycolysis

MCM2-7 in Clear Cell Renal Cell Carcinoma: MCM7 Promotes Tumor Cell Proliferation

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