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Transcriptome changes of whole kidney from conditional Vhl gene knockout in sub-populations of mouse kidney tubule cells

ABSTRACT: We are studying a tumor suppressor gene, von Hippel-Lindau (VHL). In humans, VHL mutations cause renal cell carcinoma of the clear cell type (ccRCC). We have generated a knockout mouse strain in which mouse Vhl is conditionally deleted in the kidney epithelium (that is, a subset of tubules including collecting ducts and ascending loop of Henle). Instead of ccRCC, these mice developed severe inflammation and fibrosis, accompanied by hyperplasia and the appearance of transformed clear cells. These phenotypes therefore support the notion that inflammation is the tissue precondition of cancer. Our hypothesis is that VHL loss-of-function-induced inflammation contribute to the initiation of carcinogenesis, through a mechanism that we want to determine. The aim of the microarray is to identify genes involved in the overgrowth of the epithelium, as well as in inflammation and fibrosis that may be important for ccRCC initiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE116326 | GEO | 2018/06/28

REPOSITORIES: GEO

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Changes of transcriptome in endothelial cells from kidney with tubule-specific conditional Vhlh gene knockout (Hoxb7-Cre-GFP; VhlhloxP/loxP), compared with wild-type.

Project description:Clear-cell renal cell carcinoma (ccRCC) is the most prevalent histological subtype of RCC in which more than 80% of ccRCC cases are associated with early inactivation of von Hippel-Lindau (VHL) tumor suppressor gene. We have generated a knockout mouse strain in which mouse allele of VHL (Vhlh) is conditionally deleted in the kidney epithelium (cortical tubules, collecting ducts and ascending Loops of Henle). These knockout mice showed high penetrance of inflammation and fibrosis in the kidney in addition to hyperplasia and the appearance of transformed clear cells. These results support the concept of tumor-promoting inflammation. Surprisingly, we found that the expression of pJNK, a marker of inflammation, was expressed in endothelial cells (ECs) in Vhlh mutant tissue although the knockout was in epithelial cells not in endothelial cells. The result indicated the important role of ECs in the initiation tumor progression. Therefore, the aim of this study is to investigate the molecular changes of ECs in the VHL mutant microenvironment.

2021-06-18 | GSE159754 | GEO

RNAseq transcriptome analysis of THP-1 macrophages activated by VHL-deficient kidney tubule cells

Project description:Clear-cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma (up-to 70% of all RCC types). There is a very close causal correlation between ccRCC and inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) located on chromosome 3p25‐26. Up to 80% of sporadic ccRCC carry genomic mutations or epigenetic inactivation of VHL and nearly 100% familial ccRCC (in VHL disease) contain VHL deficiency. Accumulating evidence has indicated that ccRCC arises at the site of chronic inflammation and this solid tumor contains a substantial number of infiltrated immune cells. This indicates that ccRCC may be induced by the interaction between kidney tubule cells carrying inactivated VHL gene and the inflammatory microenvironment. In this study we characterized the interaction between VHL-deficient kidney tubule cells and macrophages with relevance to ccRCC formation, and found that human macrophages induced by VHL-deficient kidney tubule cells exhibit distinct gene expression program containing the signatures of tumor-associated macrophages that can promote ccRCC progression.

2022-03-12 | GSE183976 | GEO

VHL Substrate Transcription Factor ZHX2 As An Oncogenic Driver In Clear Cell Renal Cell Carcinoma

Project description:Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bound VHL only when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with VHL loss-of-function mutations usually had increased ZHX2 amount and nuclear localization. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated ChIP-Seq and microarray analysis showed that ZHX2 promoted NF-kB activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.

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Transcriptomics profiles of patient-matched normal kidney and ccRCC pairs

Project description:VHL loss is the most common genetic alteration event in ccRCC, but its effect on epigenetic landscape has not been elucidated previously. We describe the genome-wide cis-regulatory landscapes of VHL-deficient ccRCC tumors by comparing the epigenetic changes in terms of histone modifications (H3K27ac, H3K4me1, H3K4me3) with the transcriptomics profiles in 10 pairs of normal kidney and ccRCC tissues.

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Gene expression changes in response to VHL-reintroduction in metastatic 786-M1A cells.

Project description:Inactivation of the von Hippel-Lindau tumor suppressor gene, VHL, is an archetypical tumor-initiating event in clear cell renal carcinoma (ccRCC) that leads to the activation of hypoxia-inducible transcription factors (HIFs). However, VHL mutation status in ccRCC is not correlated with clinical outcome. Here we show that during ccRCC progression, cancer cells exploit diverse epigenetic alterations to empower a branch of the VHL-HIF pathway for metastasis, and the strength of this activation is associated with poor clinical outcome. By analyzing metastatic subpopulations of VHL-deficient ccRCC cells, we discovered an epigenetically altered VHL-HIF response that is specific to metastatic ccRCC. Focusing on the two most prominent pro-metastatic VHL-HIF target genes, we show that loss of polycomb repressive complex 2 (PRC2)-dependent histone H3 Lys27 trimethylation (H3K27me3) activates HIF-driven chemokine (C-X-C motif) receptor 4 (CXCR4) expression in support of chemotactic cell invasion, whereas loss of DNA methylation enables HIF-driven cytohesin 1 interacting protein (CYTIP) expression to protect cancer cells from death cytokine signals. Thus, metastasis in ccRCC is based on an epigenetically expanded output of the tumor-initiating pathway. Gene expression data from metastatic 786-M1A cells with and without reintroduced HA-VHL. The empty vector, pBabe-puro, was used as control.

2012-12-05 | E-GEOD-32297 | biostudies-arrayexpress

Next Generation Sequencing of 786-O-Ctrl and786-O-VHL Transcriptomes

Project description:Inactivation of the E3 ubiquitin ligase protein von Hippel-Lindau (VHL) is critical to clear cell renal cell carcinomas (ccRCC) and VHL syndrome. VHL loss leads to stabilization of hypoxia-inducible factor α (HIFα) and other substrate proteins, which may drive various tumor-promoting pathways. This process is likely reversible, because even in the highly aggressive human VHL-deficient ccRCC cell line 786-O, restoring VHL expression almost completely abolishes orthotopic tumor formation in immuno-deficient mice. This result highlights the potential of treating ccRCC by re-expressing VHL with gene therapy. However, there is inadequate understanding of the consequence of VHL restoration at the molecular level. Here, we reinstalled VHL expression in 786-O and performed transcriptome, proteome and ubiquitome profiling to assess the molecular impact.

2021-10-18 | GSE186013 | GEO

USP13 Promotes Deubiquitination of ZHX2 and Tumorigenesis in Kidney Cancer

Project description:Clear cell renal cell carcinoma (ccRCC) is characterized by loss of tumor suppressor Von Hippel Lindau (VHL) function. VHL is the component of E3 ligase complex that promotes the ubiquitination and degradation of hypoxia inducible factor alpha (including HIF1alpha and HIF2alpha) and Zinc Fingers And Homeoboxes 2 (ZHX2). Our recent research showed that ZHX2 contributed to ccRCC tumorigenesis in a HIF independent manner. However, it remains unknown whether ZHX2 can be regulated through deubiquitination. Here we performed a deubiquitinase (DUB) cDNA library binding screen and identified USP13 as a novel DUB that bound ZHX2 and promoted ZHX2 deubiquitination. As a result, USP13 promoted ZHX2 protein stability in an enzymatically dependent manner and depletion of USP13 led to ZHX2 downregulation in ccRCC. Functionally, USP13 depletion led to decreased cell proliferation measured by 2-D colony formation and 3-D anchorage independent growth. USP was a critical effector on maintaining kidney tumorigenesis in an orthotopic xenograft model and its depletion led to both decreased primary kidney tumorigenesis and spontaneous lung metastasis. Our results suggest that USP13 is a potential new therapeutic target in ccRCC.

2022-07-27 | GSE186717 | GEO

The OGT/HIF-2α axis promotes the progression of clear cell renal cell carcinoma and its targetable vulnerability to ferroptosis

Project description:O-GlcNAc transferase (OGT) has been reported to participate in the development of various cancers, but its role in clear cell renal cell carcinoma (ccRCC) remains unclear. In this study, we found that OGT was upregulated in ccRCC compared with paired nontumor renal tissues and was associated with worse survival. Moreover, OGT promoted the proliferation, clone formation, and invasive abilities of VHL-mutated ccRCC cells. Mechanistically, OGT promoted the expression of hypoxia-inducible factor-2α (HIF-2α) (the main driver of the clear cell phenotype) by repressing ubiquitin‒proteasome system-mediated degradation. Interestingly, the OGT/HIF-2α axis confers ccRCC sensitivity to ferroptosis, rendering it vulnerable. In conclusion, OGT promotes the progression of VHL-mutated ccRCC by inhibiting the degradation of HIF-2α. On the other hand, the OGT/HIF-2α axis renders ccRCC vulnerable to ferroptosis, suggesting that ferroptosis inducers are a promising therapy for patients with upregulated OGT and mutated VHL ccRCC.

2023-04-29 | GSE230386 | GEO

Gene expression changes in 786-O cells in response to 5DC treatment.

Project description:Inactivation of the von Hippel-Lindau tumor suppressor gene, VHL, is an archetypical tumor-initiating event in clear cell renal carcinoma (ccRCC) that leads to the activation of hypoxia-inducible transcription factors (HIFs). However, VHL mutation status in ccRCC is not correlated with clinical outcome. Here we show that during ccRCC progression, cancer cells exploit diverse epigenetic alterations to empower a branch of the VHL-HIF pathway for metastasis, and the strength of this activation is associated with poor clinical outcome. By analyzing metastatic subpopulations of VHL-deficient ccRCC cells, we discovered an epigenetically altered VHL-HIF response that is specific to metastatic ccRCC. Focusing on the two most prominent pro-metastatic VHL-HIF target genes, we show that loss of polycomb repressive complex 2 (PRC2)-dependent histone H3 Lys27 trimethylation (H3K27me3) activates HIF-driven chemokine (C-X-C motif) receptor 4 (CXCR4) expression in support of chemotactic cell invasion, whereas loss of DNA methylation enables HIF-driven cytohesin 1 interacting protein (CYTIP) expression to protect cancer cells from death cytokine signals. Thus, metastasis in ccRCC is based on an epigenetically expanded output of the tumor-initiating pathway. Gene expression data from 786-O cells after 3-day treatment with 100uM 5’-aza-deoxycytidine (5DC) or vehicle (DMSO).

2012-12-05 | E-GEOD-32298 | biostudies-arrayexpress

Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer

Project description:Inactivation of the von Hippel-Lindau tumor suppressor gene, VHL, is an archetypical tumor-initiating event in clear cell renal carcinoma (ccRCC) that leads to the activation of hypoxia-inducible transcription factors (HIFs). However, VHL mutation status in ccRCC is not correlated with clinical outcome. Here we show that during ccRCC progression, cancer cells exploit diverse epigenetic alterations to empower a branch of the VHL-HIF pathway for metastasis, and the strength of this activation is associated with poor clinical outcome. By analyzing metastatic subpopulations of VHL-deficient ccRCC cells, we discovered an epigenetically altered VHL-HIF response that is specific to metastatic ccRCC. Focusing on the two most prominent pro-metastatic VHL-HIF target genes, we show that loss of polycomb repressive complex 2 (PRC2)-dependent histone H3 Lys27 trimethylation (H3K27me3) activates HIF-driven chemokine (C-X-C motif) receptor 4 (CXCR4) expression in support of chemotactic cell invasion, whereas loss of DNA methylation enables HIF-driven cytohesin 1 interacting protein (CYTIP) expression to protect cancer cells from death cytokine signals. Thus, metastasis in ccRCC is based on an epigenetically expanded output of the tumor-initiating pathway. This SuperSeries is composed of the SubSeries listed below. Refer to individual Series.

2012-12-05 | E-GEOD-32299 | biostudies-arrayexpress

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