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Nuclear localization of the CK2?-subunit correlates with poor prognosis in clear cell renal cell carcinoma.

ABSTRACT: Protein kinase CK2?, one of the two catalytic isoforms of the protein kinase CK2 has been shown to contribute to tumor development, tumor proliferation and suppression of apoptosis in various malignancies. We conducted this study to investigate CK2 expression in different subtypes of Renal Cell Carcinoma (RCC) and in the benign oncocytoma. qRT-PCR, immunohistochemistry and Western blot analyses revealed that CK2? expression was significantly increased at the mRNA and protein levels in clear cell RCC (ccRCC). Also the kinase activity of CK2 was significantly increased in ccRCC compared to normal renal cortex. Nuclear protein expression of CK2? correlated in univariate analysis with poor Progression Free Survival (HR = 8.11, p = 0.016). Functional analyses (cell proliferation assay) revealed an inhibitory effect of Caki-2 cell growth following CK2 inhibition with CX-4945. Our results suggest that CK2? promotes migration and invasion of ccRCC and therefore could serve as a novel prognostic biomarker and molecular therapeutic target in this type of cancer.

SUBMITTER: Rabjerg M

PROVIDER: S-EPMC5352082 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Nuclear localization of the CK2α-subunit correlates with poor prognosis in clear cell renal cell carcinoma.

Rabjerg Maj M Guerra Barbara B Oliván-Viguera Aida A Mikkelsen Minne Line Nedergaard ML Köhler Ralf R Issinger Olaf-Georg OG Marcussen Niels N

Oncotarget 20170101 1

Protein kinase CK2α, one of the two catalytic isoforms of the protein kinase CK2 has been shown to contribute to tumor development, tumor proliferation and suppression of apoptosis in various malignancies. We conducted this study to investigate CK2 expression in different subtypes of Renal Cell Carcinoma (RCC) and in the benign oncocytoma. qRT-PCR, immunohistochemistry and Western blot analyses revealed that CK2α expression was significantly increased at the mRNA and protein levels in clear cell ...[more]

PMID: 27906674

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Project description:Background and objectiveEmerging evidence has proven the robust role of tumor mutation burden (TMB) and immune cell infiltration (ICI) in cancer immunotherapy. However, the precise effect of TMB and ICI on clear cell renal cell carcinoma (ccRCC) remains elusive and merits further investigation. Therefore, we aim to identify the TMB-related genes in predicting prognosis and to explore the potential mechanisms of the identified Interleukin 20 receptor subunit beta (IL20RB) in ICI in ccRCC.MethodThe relative information of patients with ccRCC was obtained from The Cancer Genome Atlas database (TCGA). Immune-related genes were downloaded from the Immunology Database and Analysis Portal database. Cox regression analysis was used to identify prognosis-related immune genes for ccRCC. The relationship of IL20RB expression levels with clinicopathological parameters was analyzed using the "limma" and "survival" packages. Gene Expression Omnibus (GEO) and International Cancer Genome Consortium (ICGC) databases were used as external validation. Quantitative Real-time PCR (qRT-PCR) and western blots were used to validate the expression levels of IL20RB in tumor cells. Cell counting kit-8 (CCK-8) assay and colony formation assay were used to examine the effect of IL20RB on the viability of ccRCC cells. Gene set enrichment analysis (GSEA) was introduced for the analysis of IL20RB-related signaling pathways. Tumor Immune Estimation Resource (TIMER) and Tumor and Immune System Interaction Database (TISIDB) were utilized to determine the correlation of IL20RB expression levels with tumor-infiltrating immune cells (TIICs).ResultsIL20RB was significantly overexpressed in different ccRCC tissues and cells. High IL20RB expression in ccRCC patients was associated with short overall survival, high tumor grade, and advanced TNM stage. After knockdown of IL20RB with small interfering RNA (siRNA) technology, ccRCC cells' proliferation was significantly attenuated. Moreover, overexpression of IL20RB could increase the infiltration level of several immune cells, especially T follicular helper cells (Tfh), and overexpressed Tfh cells were correlated with poor prognosis in ccRCC.ConclusionsIL20RB may function as an immune-associated therapeutic target for it determines cancer progression and regulates immune cell infiltration in ccRCC.

Project description:BackgroundRunt-related transcription factor 1 (RUNX1) was previously reported to play a dual role in promoting or suppressing tumorigenesis in various malignancies. A public dataset from The Cancer Genome Atlas (TCGA) was used to evaluate the role of RUNX1 in clear cell renal cell carcinoma (ccRCC).MethodsThe Wilcoxon signed-rank test was used to compare the expression of RUNX1 in ccRCC tissues and normal tissues. The Wilcoxon signed-rank test and logistic regression were utilized to investigate the relationship between clinicopathological factors and RUNX1 expression. Additionally, we analysed the differences in prognosis between patients with high and low expression of RUNX1 via the Kaplan-Meier method and Cox regression. Gene set enrichment analysis (GSEA) was performed to explore the mechanisms of RUNX1 in ccRCC.ResultsThe expression of RUNX1 in ccRCC tissues was significantly higher than that in normal tissues. High expression of RUNX1 was significantly associated with gender (p = 0.003), clinical stage (p < 0.001), tissue infiltration (p < 0.001), lymph node metastasis (p = 0.037) and histological grade (p < 0.001). Logistic regression analysis showed that high RUNX1 expression was significantly correlated with gender (OR = 1.71 for male vs. female, p = 0.004), histological grade (OR = 11.61 for grade IV vs. I, p < 0.001), clinical stage (OR = 1.55 for stage III/IV vs. I/II, p = 0.014) and tissue infiltration (OR = 1.54 for positive vs. negative, p = 0.018). Kaplan-Meier survival curves revealed that the prognosis of patients with ccRCC with high RUNX1 expression was worse than that of patients with ccRCC with low RUNX1 expression (p < 0.001). Univariate Cox regression analysis showed that high RUNX1 expression was strongly correlated with poor prognosis (HR = 1.60, 95% CI [1.31-1.97], p < 0.001). In addition, high expression of RUNX1 was an independent prognostic factor for poor overall survival (OS), with an HR of 1.50 (95% CI [1.20-1.87], p < 0.001) in multivariate Cox analysis. GSEA showed that the apoptosis, B cell receptor signalling pathway, calcium signalling pathway, chemokine signalling pathway, JAK/STAT signalling pathway, MAPK signalling pathway, p53 signalling pathway, pathways in cancer, T cell receptor signalling pathway, Toll-like receptor signalling pathway, VEGF signalling pathway, and Wnt signalling pathway were significantly enriched in the RUNX1 high-expression phenotype. In conclusion, RUNX1 can be used as a novel prognostic factor and therapeutic target in ccRCC.

Project description:BackgroundPrevious reports have shown that short/branched chain acyl-CoA dehydrogenase (ACADSB) plays an important role in glioma, but its role in clear cell renal carcinoma (ccRCC) has not been reported.MethodsThe TIMER and UALCAN databases were used for pan-cancer analysis. RNA sequencing and microarray data of patients with ccRCC were downloaded from the Cancer Genome Atlas and Gene Expression Omnibus database. The differential expression of ACADSB in ccRCC and normal kidney tissues was tested. Correlations between ACADSB expression and clinicopathological parameters were assessed using the Wilcoxon test. The influences of ACADSB expression and clinicopathological parameters on overall survival were assessed using Cox proportional hazards models. Gene set enrichment analysis (GSEA) was performed to explore the associated gene sets enriched in different ACADSB expression phenotypes. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on genes with similar expression patterns to ACADSB. Correlations between ACADSB and ferroptosis-related genes were assessed using Spearman's correlation analysis.ResultsPan-cancer analysis revealed that ACADSB is down-regulated in multiple cancers, and decreased expression of ACADSB correlates with poor prognosis in certain types of cancer. Differential expression analyses revealed that ACADSB was down-regulated in ccRCC, indicating that ACADSB expression could be a single significant parameter to discriminate between normal and tumor tissues. Clinical association analysis indicated that decreased ACADSB expression was associated with high tumor stage and grade. The Cox regression model indicated that low ACADSB expression was an independent risk factor for the overall survival of patients with ccRCC. GSEA showed that 10 gene sets, including fatty acid (FA) metabolism, were differentially enriched in the ACADSB high expression phenotype. GO and KEGG pathway enrichment analysis revealed that ACADSB-related genes were significantly enriched in categories related to FA metabolism, branched-chain amino acid (BCAA) metabolism, and iron regulation. Spearman's correlation analysis suggested that the expression of ACADSB was positively correlated with the expression of ferroptosis driver genes.ConclusionsACADSB showed good diagnostic and prognostic abilities for ccRCC. The downregulation of ACADSB might promote tumorigenesis and tumor progression by inhibiting FA catabolism, BCAA catabolism, and ferroptosis in ccRCC.

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Nuclear localization of the CK2?-subunit correlates with poor prognosis in clear cell renal cell carcinoma.

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Nuclear localization of the CK2α-subunit correlates with poor prognosis in clear cell renal cell carcinoma.

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