Genome-wide analysis of gene expression patterns in human kidney cancer [patients without metastasis]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE66270 | GEO | 2016/08/31
SECONDARY ACCESSION(S): PRJNA276295
REPOSITORIES: GEO
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Project description:To investigate the mechanisms of ccRCC progression and metastasis, we performed expression profiling of human kidney cancer and benign tissues. mRNA microarray expression analysis was performed by using 28 matched malignant and non-malignant kidney tissue samples from 14 ccRCC patients without diagnosed metastasis. This dataset is part of the TransQST collection.
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Project description:To investigate the mechanisms of kidney tumor progression and metastasis, we performed expression profiling of human kidney cancer and benign tissues.
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Project description:Most kidney cancers display metabolic dysfunction but how this relates to cancer progression in humans is unknown. We infused 13C-labeled nutrients during surgical tumour resection in over 80 patients with kidney cancer. Labeling from [U-13C]glucose varies across subtypes, indicating that the kidney environment alone cannot account for all metabolic reprogramming in these tumours. Compared to the adjacent kidney, clear cell renal cell carcinomas (ccRCC) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in organotypic cultures ex vivo, indicating that suppressed labeling is tissue intrinsic. Infusions of [1,2-13C]acetate and [U-13C]glutamine in patients, coupled with measurements of respiration in mitochondria isolated from kidneys and tumours, reveal electron transport chain (ETC) defects in ccRCC. However, ccRCC metastases unexpectedly have enhanced TCA cycle labeling compared to primary ccRCCs, indicating a divergent metabolic program during metastasis in patients. In mice, stimulating respiration or NADH recycling in kidney cancer cells is sufficient to promote metastasis, while inhibiting ETC complex I decreases metastasis. These findings indicate that metabolic properties and liabilities evolve during kidney cancer progression in humans, and that mitochondrial function is limiting for metastasis but not for growth at the original site.
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Project description:Piwi-interacting RNAs (piRNAs) are a distinct group of small non-coding RNAs (sncRNAs) that silence transposable genetic elements to protect genome integrity. Due to their limited expression in gonads and sequence diversity, piRNAs remain the most mysterious class of small RNAs. Studies have shown piRNAs are present in somatic cells and dysregulated in gastric, breast and liver cancers. By deep sequencing 24 frozen benign kidney and clear cell renal cell carcinoma (ccRCC) specimens and using the publically available piRNA database, we found 26,991 piRNAs present in human kidney tissue. Among 920 piRNAs that at least had two copies in one specimen, 19 were differentially expressed in benign kidney and ccRCC tissues, and 46 were associated with metastasis. Among the metastasis-related piRNAs, we found 3 piRNAs, piR- 32051, piR-39894 and piR-43607, to be derived from the same piRNA cluster at chromosome 17. We confirmed the 3 selected piRNAs not to be miRNAs or miRNA-like sncRNAs. We further validated the aberrant expression of the 3 piRNAs in a 68-case formalin-fixed and paraffin-embedded (FFPE) ccRCC tissue cohort and showed the upregulation of the 3 piRNAs to be highly associated with ccRCC metastasis, late clinical stage and cancer-specific survival.
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Project description:The 5-year survival rate of kidney cancer drops dramatically from 93% to 15% when it is metastatic. Metastasis constitutes for 30% of kidney cancer cases, in which clear cell renal cell carcinoma (ccRCC) is the most prominent subtype. By sequencing mRNA of ccRCC patient samples, we found that apolipoprotein L1 (APOL1) was highly expressed in tumors compared to their adjacent normal tissues. This gene has been previously identified in a large body of kidney disease research and was reported as a potential prognosis marker in many types of cancers. However, the molecular function of APOL1 in ccRCC, especially in metastasis, remained unknown. In this study, we modulated the expression of APOL1 in various renal cancer cell lines and analyzed their proliferative, migratory, and invasive properties. Strikingly, APOL1 overexpression suppressed ccRCC metastasis both in vitro and in vivo. We then explored the mechanism by which APOL1 alleviated ccRCC malignant progression by investigating its downstream pathways. APOL1 overexpression diminished the activity of focal adhesive molecules, Akt signaling pathways, and EMT processes. Furthermore, in the upstream, we discovered that miR-30a-3p could inhibit APOL1 expression. In conclusion, our study revealed that APOL1 play a role as a tumor suppressor in ccRCC and inhibit metastasis, which may provide novel potential therapeutic approaches for ccRCC patients.
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Project description:The 5-year survival rate of kidney cancer drops dramatically from 93% to 15% when it is metastatic. Metastasis constitutes for 30% of kidney cancer cases, in which clear cell renal cell carcinoma (ccRCC) is the most prominent subtype. By sequencing mRNA of ccRCC patient samples, we found that apolipoprotein L1 (APOL1) was highly expressed in tumors compared to their adjacent normal tissues. This gene has been previously identified in a large body of kidney disease research and was reported as a potential prognosis marker in many types of cancers. However, the molecular function of APOL1 in ccRCC, especially in metastasis, remained unknown. In this study, we modulated the expression of APOL1 in various renal cancer cell lines and analyzed their proliferative, migratory, and invasive properties. Strikingly, APOL1 overexpression suppressed ccRCC metastasis both in vitro and in vivo. We then explored the mechanism by which APOL1 alleviated ccRCC malignant progression by investigating its downstream pathways. APOL1 overexpression diminished the activity of focal adhesive molecules, Akt signaling pathways, and EMT processes. Furthermore, in the upstream, we discovered that miR-30a-3p could inhibit APOL1 expression. In conclusion, our study revealed that APOL1 play a role as a tumor suppressor in ccRCC and inhibit metastasis, which may provide novel potential therapeutic approaches for ccRCC patients.
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Project description:Clear cell renal cell carcinoma (ccRCC) is characterized by a loss of tumor suppressor Von Hippel Lindau (VHL) function, which leads to accumulation of hypoxia inducible factor (including HIF1 and HIF2). HIF2 was previously reported to be one of the major oncogenic drivers in ccRCC, however its therapeutic targeting remains challenging. Here we performed a deubiquitinase (DUB) cDNA library binding screen and discovered that USP37 is a DUB that binds HIF2 and promotes HIF2 deubiquitination. As a result, USP37 promotes HIF2 protein stability in an enzymatically dependent manner and depletion of USP37 leads to HIF2 downregulation in ccRCC. Functionally, USP37 depletion causes decreased cell proliferation measured by MTS, 2-D colony formation as well as 3-D anchorage independent growth. USP37 is also essential for maintaining kidney tumorigenesis in an orthotopic xenograft model and its depletion leads to decreased primary kidney tumorigenesis and spontaneous lung metastasis. Our results suggest that USP37 is a potential new therapeutic target in ccRCC.
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