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Apolipoprotein L1 is a tumor suppressor in clear cell renal cell carcinoma metastasis [miRNA-Seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE252629 | GEO | 2024/04/10

REPOSITORIES: GEO

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Apolipoprotein L1 is a tumor suppressor in clear cell renal cell carcinoma metastasis [RNA-Seq]

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.

2024-04-10 | GSE252600 | GEO

APOL1 renal-risk variants induce mitochondrial dysfunction (Affymetrix 2)

Project description:To assess differential gene expression by APOL1 renal-risk (2 risk alleles) vs. non-risk (G0G0) genotypes in primary proximal tubule cells (PTCs), global gene expression (mRNA) levels were examined on Affymetrix HTA 2.0 arrays in primary PTCs cultured from non-diseased kidney in African Americans without CKD who underwent nephrectomy for localized renal cell carcinoma. To detect differentially expressed gene profiles attributable to APOL1 renal-risk genotypes, African American primary proximal tubule cells with two APOL1 renal-risk alleles (N=5) and lacking renal-risk alleles (N=25) were included in comparisons of global gene expression.

2016-08-23 | E-GEOD-85920 | biostudies-arrayexpress

HAVCR/KIM-1 activates the IL-6/STAT-3 Pathway in ccRCC and Determines Tumor Progression and Patient Outcome

Project description:Renal cell carcinoma (RCC), the third most prevalent urological cancer, claims more than 100,000 lives/year worldwide. The clear cell (ccRCC) is the most common and aggressive subtype of renal cancer. Commonly asymptomatic, more than 30% of ccRCCs are diagnosed when they are already metastatic resulting in a 95% mortality rate and one-third of organ-confined cancers treated by nephrectomy develop metastasis during the follow-up. Diagnosis and monitoring requires expensive and frequent imaging examinations; thereby, finding of diagnostic and prognostic biomarkers to screen, diagnose and monitor renal cancers are clearly needed. Hepatitis A virus receptor/kidney injury molecule 1 (HAVCR1/KIM-1) gene has been claimed to be a susceptibility gene for ccRCC and HAVCR1/KIM-1 ectodomain shedding a predictive biomarker of tumor progression.

2020-09-27 | E-MTAB-2071 | biostudies-arrayexpress

Effect of everolimus on clear cell renal cell carcinoma (ccRCC) cell lines - parental and stem cells

Project description:The aim of this study was to compare effect of everolimus on growth of different renal cell carcinoma (RCC) populations and develop design for experiments to measure the early response of everolimus in clear cell RCC (ccRCC) cell lines including renal cancer stem cells. Gene expression profiling using microarray was performed to determine the early response to everolimus after 3 days of treatment with optimizied concentration of drug in two ccRCC cell lines 1) parental clear cell renal cell carcinoma ccRCC-PCSC (HKPCSC -human parental kidney cancer stem cells) and 2) ccRCC-CSC - clear cell renal cell carcinoma -cancer stem cells (HKCSC - human kidney cancer stem cells).

2018-05-31 | GSE106819 | GEO

Evaluation of APOL1 ASO in a novel model of APOL1-associated renal disease

Project description:African Americans develop end-stage renal disease at a higher rate compared to European Americans due to two polymorphisms (G1 and G2 risk variants) in the apolipoprotein L1 (APOL1) gene that are common in people of African ancestry. Not all homozygous risk allele carriers, however, develop renal disease suggesting that modifying factors (“second hits”) are required. Although the compelling genetic evidence provides an exciting opportunity for personalized medicine in chronic kidney disease (CKD), drug discovery efforts have been greatly hindered by the fact that APOL1 expression is limited to humans and select nonhuman primates. We describe a novel physiologically-relevant genomic mouse model of APOL1-associated renal disease that expresses human APOL1 from the endogenous human promoter, resulting in expression in similar tissues and at similar relative levels as humans. While naïve genomic APOL1 transgenic mice did not exhibit a renal disease phenotype, a single administration of IFNγ was sufficient to robustly induce proteinuria only in APOL1 G1 transgenic mice, despite inducing kidney APOL1 expression in both G0 and G1 mice, serving as a clinically-relevant “second hit.” We also report on the discovery of the first APOL1 inhibitor, IONIS-APOL1Rx, a Generation 2.5 antisense oligonucleotide (ASO) targeting APOL1 mRNA. Treatment of APOL1 G1 mice with IONIS-APOL1Rx prior to IFNγ challenge robustly and dose-dependently inhibited kidney and liver APOL1 expression and protected against IFNγ-induced proteinuria, indicating that the disease-relevant cell types are sensitive to ASO treatment. Collectively, these data suggest that IONIS-APOL1Rx may be an effective therapeutic for APOL1 nephropathies and warrants further development.

2018-10-16 | GSE121286 | GEO

Genome-wide analysis of gene expression patterns in human kidney cancer [patients without metastasis]

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.

2016-08-31 | E-GEOD-66270 | biostudies-arrayexpress

Integrative genomic analysis of sporadic clear cell Renal Cell Carcinoma

Project description:Human clear cell renal cell carcinoma (ccRCC) is a common cancer of the kidney. We applied an integrated approach to identify important factors that influence carcinogenesis in ccRCC.

2011-12-01 | GSE27852 | GEO

APOL1 variant expression in mouse podocytes cause kidney disease

Project description:Next-generation sequencing (NGS) has become an important tool in molecular charactarization of animal models. APOL1 variants are associated with end stage renal disease in African Americans. We developed a mouse model with podocyte specific over expression of APOL1. Differential molecular signatures were identified between the groups by RNA-Sequencing on kidney.

2017-02-15 | GSE81492 | GEO

PIWI-interacting RNAs are dysregulated in renal cell carcinoma and associated with tumor metastasis and cancer specific survival

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.

2015-07-31 | GSE69259 | GEO

APOL1 renal-risk variants induce mitochondrial dysfunction (Illumina)

Project description:To elucidate pathways whereby apolipoprotein L1 gene (APOL1) G1 and G2 variants facilitate kidney disease in African Americans, human embryonic kidney cells (HEK293) were used to establish doxycycline-inducible (Tet-on) cell lines stably expressing reference APOL1 G0 and its G1 and G2 renal-risk variants. Illumina human HT-12-v4 arrays and Affymetrix HTA 2.0 arrays were employed to generate global gene expression data with doxycycline induction. Significantly altered pathways identified through bioinformatics involved mitochondrial function; results were validated using immunoblotting, immunofluorescence and functional assays. Global gene expression profiles were performed on HEK293 Tet-on G0, G1, G2 and empty vector cells with and without Dox induction using Illumina human HT-12 v4 arrays. Another independent gene expression array system, Affymetrix HTA 2.0, was used to verify the results of Illumina arrays. Pair-wise and pattern-based analyses were applied to detect the mostly impacted pathways due to overexpression and by APOL1 genotypes.

2016-08-23 | E-GEOD-85918 | biostudies-arrayexpress

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