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Downregulation of WDR20 due to loss of 14q is involved in the malignant transformation of clear cell renal cell carcinoma (WDR20 overexpression in RCC cell line)

ABSTRACT: Previously, we have reported that genomic loss of 14q occurs more frequently in high grade clear cell renal cell carcinomas (ccRCCs) than low grade ones and shows a significant impact on the expression levels of genes located on this region, suggesting that the genes located on the region and downregulated by the loss may be involved in the malignant transformation of ccRCCs. Here, among the genes located on the minimal common region of 14q loss, we found that 6 were significantly downregulated in high grade ccRCCs due to copy number loss. Using the data set from The Cancer Genome Atlas (TCGA) Research Network, downregulation of one out of the 6 genes, WDR20, was significantly associated with poorer prognosis for the patients with ccRCC, suggesting that downregulation of WDR20 may be involved in the malignant transformation of ccRCC. In this array study, we aimed to investigate the effect of WDR20 overexpression on the gene expression profile of an RCC cell line, 786_O. For this aim, we established 3 cell clones stably transfected with the WDR20 expressing vector (786O_WDR20cl1, 786O_WDR20cl2 and 786O_WDR20cl3) and one cell clone stably transfected with the corresponding empty vector (786O_vector) and performed expression microarray analysis using RNAs from these cell lines.

ORGANISM(S): Homo sapiens

PROVIDER: GSE76177 | GEO | 2016/12/07

SECONDARY ACCESSION(S): PRJNA306522

REPOSITORIES: GEO

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Downregulation of WDR20 due to loss of 14q is involved in the malignant transformation of clear cell renal cell carcinoma

Project description:Previously, we have reported that genomic loss of 14q occurs more frequently in high grade clear cell renal cell carcinomas (ccRCCs) than low grade ones and shows a significant impact on the expression levels of genes located on this region, suggesting that the genes located on the region and downregulated by the loss may be involved in the malignant transformation of ccRCCs. Here, among the genes located on the minimal common region of 14q loss, we found that 6 were significantly downregulated in high grade ccRCCs due to copy number loss. Using the data set from The Cancer Genome Atlas (TCGA) Research Network, downregulation of one out of the 6 genes, WDR20, was significantly associated with poorer prognosis for the patients with ccRCC, suggesting that downregulation of WDR20 may be involved in the malignant transformation of ccRCC. In functional assays, exogeneous WDR20 significantly inhibited growth and induced apoptosis in RCC cell lines. Interestingly, the phosphorylation levels of ERK and AKT, which reportedly contribute to the malignant phenotype of RCC cells, were clearly reduced by the exogeneous expression of WDR20. Thus, our data suggest that downregulation of WDR20 due to 14q loss may be involved in the malignant transformation of ccRCCs in part through the activation of ERK and AKT pathways. Downregulated expression levels of genes in minimal common region due to 14q loss. Expression levels of 6 genes were determined by microarray analysis and compared between normal kidney tissues (normal, n=16), low grade (low, n=16) and high grade (high, n=16) ccRCCs. The expression level (log2) normalized by the median expression level for the 16 normal samples.

2016-08-09 | E-GEOD-71963 | biostudies-arrayexpress

Downregulation of WDR20 due to loss of 14q is involved in the malignant transformation of clear cell renal cell carcinoma

2016-08-09 | GSE71963 | GEO

Genomic aberrations predicts survival in clear cell renal cell carcinoma

Project description:Detailed genetic profiling of clear cell Renal Cell Carcinoma (ccRCC) has shown that these tumors are characterized by large genetic heterogeneity with some genomic regions commonly affected by structural changes. Loss on chromosomes 3p and 14q, and gain on 5q and 7 are examples of alterations commonly reported in ccRCC. However, there is no consensus regarding the potential prognostic information carried by the identified alterations. We report on poorer outcome for patients with gain on 5q and 7, and loss on 9p, 9q and 14q. These aberrations were in addition found more frequently in metastasized tumors, suggesting that they are markers for advanced disease. Furthermore, the presence of M-bM-^IM-% 4 common aberrations was associated with decreased survival time. Shorter relative telomere length (RTL) has been associated with loss of chromosomal regions in ccRCC tumors, but we found no significant associations between tumor RTL and chromosomal deletions. However, significantly lower tumor-to-nontumor (T/N) RTL ratio was detected for patients with loss on 4q and 9p. Finally, we found a minimum region (MR) of genetic loss of 1.4 Mbp on chromosome 9p and this region contains only one gene, the tumor suppressor candidate 1 gene (TUSC1). TUSC1 has been implicated in lung carcinogenesis and our result further strengthens its role in tumorigenesis. Seventy-four ccRCC tumors and 22 paired normal kidney cortex and blood samples were genotyped on Illuminas HumanCytoSNP-12 bead chips.

2014-07-01 | E-GEOD-30460 | biostudies-arrayexpress

Genomic aberrations predicts survival in clear cell renal cell carcinoma

Project description:Detailed genetic profiling of clear cell Renal Cell Carcinoma (ccRCC) has shown that these tumors are characterized by large genetic heterogeneity with some genomic regions commonly affected by structural changes. Loss on chromosomes 3p and 14q, and gain on 5q and 7 are examples of alterations commonly reported in ccRCC. However, there is no consensus regarding the potential prognostic information carried by the identified alterations. We report on poorer outcome for patients with gain on 5q and 7, and loss on 9p, 9q and 14q. These aberrations were in addition found more frequently in metastasized tumors, suggesting that they are markers for advanced disease. Furthermore, the presence of ≥ 4 common aberrations was associated with decreased survival time. Shorter relative telomere length (RTL) has been associated with loss of chromosomal regions in ccRCC tumors, but we found no significant associations between tumor RTL and chromosomal deletions. However, significantly lower tumor-to-nontumor (T/N) RTL ratio was detected for patients with loss on 4q and 9p. Finally, we found a minimum region (MR) of genetic loss of 1.4 Mbp on chromosome 9p and this region contains only one gene, the tumor suppressor candidate 1 gene (TUSC1). TUSC1 has been implicated in lung carcinogenesis and our result further strengthens its role in tumorigenesis.

2014-07-01 | GSE30460 | GEO

Deregulated Expression of the 14q32 miRNA Cluster in Clear Cell Renal Cell Carcinomas

Project description:Clear cell renal cell carcinomas (ccRCC) are characterized by arm-wide chromosomal alterations. Loss at 14q is associated with disease aggressiveness in ccRCC, which responds poorly to chemotherapeutics. The 14q locus contains one of the largest miRNA clusters in the human genome; however, little is known about the contribution of these miRNAs to ccRCC pathogenesis. In this regard, we investigated the expression pattern of selected miRNAs at the 14q32 locus in TCGA kidney tumors and in ccRCC cell lines. We validated that the miRNA cluster is downregulated in ccRCC (and cell lines) as well as in papillary kidney tumors relative to normal kidney tissues and primary renal proximal tubule epithelial (RPTEC) cells. We demonstrated that agents modulating expression of DNMT1 (e.g., 5-Aza-deoxycytidine) could modulate miRNA expression in ccRCC cell lines. Lysophosphatidic acid (LPA, a Lysophospholipid mediator elevated in ccRCC) not only increased labile iron content but also modulated expression of 14q32 miRNAs. Through an overexpression approach targeting a subset of 14q32 miRNAs (specifically at subcluster A: miR-431, miR-432, miR-127, and miR-433) in 769-P cells, we uncovered changes in cellular viability and claudin-1, a tight junction marker. A global proteomic approach was implemented using these miRNA overexpressing cell lines which uncovered ATXN2 as a highly downregulated target, which has a role in chronic kidney disease pathogenesis. Collectively, these findings support a contribution of miRNAs at 14q32 in ccRCC pathogenesis.

2023-05-10 | PXD036428 | Pride

cis-regulatory landscape in ccRCC [tissue]

Project description:VHL loss is the most common genetic alteration event in ccRCC, but its effect on epigenetic landscape has not been elucidated previously. By performing histone modifications (H3K27ac, H3K4me1, H3K4me3) from ccRCC cell lines, we describe the genome-wide cis-regulatory landscapes of VHL-deficient ccRCC tumors. We show that ccRCCs exhibit a pervasive gain of enhancers around hypoxic and metabolic transcriptional targets.

2017-08-22 | GSE86091 | GEO

cis-regulatory landscape in ccRCC [cell lines]

2017-08-22 | GSE86087 | GEO

Genome-wide microRNA expression analysis of clear cell Renal Cell Carcinoma by next generation deep sequencing

Project description:MicroRNAs (miRNAs), non-coding RNAs regulating gene expression, are frequently aberrantly expressed in human cancers. Next-generation deep sequencing technology enables genome-wide expression profiling of known miRNAs and discovery of novel miRNAs at unprecedented quantitative and qualitative accuracy. Deep sequencing was performed on 22 fresh frozen clear cell renal cell carcinoma (ccRCC), 11 non-tumoral renal cortex (NRC) samples and 2 ccRCC cell lines (n=35). The 22 ccRCCs patients belonged to 3 prognostic sub-groups, i.e. Those without disease recurrence, with recurrence and with metastatic disease at diagnosis Deep sequencing was performed on 22 fresh frozen clear cell renal cell carcinoma (ccRCC), 11 non-tumoral renal cortex (NRC) samples and 2 ccRCC cell lines (n=35). The 22 ccRCCs patients belonged to 3 prognostic sub-groups, i.e. Those without disease recurrence, with recurrence and with metastatic disease at diagnosis.

2012-06-21 | E-GEOD-37616 | biostudies-arrayexpress

miRNA expression in primary renal carcinomas, subgrouped based on HIF1α expression

Project description:Clear cell renal cell carcinoma (ccRCC), the most common type of renal cancer is often associated with inactivation of the tumor suppressor gene von-Hippel Lindau (VHL), leading to stable expression of hypoxia inducible factors, HIF1α and HIF2α. Although HIF1α functions as a tumor suppressor gene, majority of ccRCCs constitutively express HIF1α, stratifying VHL-deficient ccRCCs into groups which express either both HIF1α and HIF2α (H1H2) or HIF2α exclusively (H2). MicroRNA (miRNA) profiling performed in these two ccRCC subtypes to identify novel molecular mechanisms. ccRCCs were classified into H1H2 and H2 subtypes by immunohostochemical staining of H1F1α and H1F2α expression. Five H1H2 tumor samples and eight H2 tumor samples were used for the study. Matched adjacent normal renal tissues were used as respective controls.

2013-09-30 | E-GEOD-47582 | biostudies-arrayexpress

miRNA expression in primary renal carcinomas, subgrouped based on HIF1α expression

2013-09-30 | GSE47582 | GEO

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