Transcriptome analysis reveals manifold mechanisms of cyst development in ADPKD

Almeida, Rita Maria Cunha de; Clendenon, Sherry G.; Richards, William G.; Boedigheimer, Michael; Damore, Michael A.; Rossetti, Sandro; Harris, Peter C.; Herbert, Brittney Shea; Xu, Wei; Wandinger‐Ness, Angela; Ward, Heather H.; Glazier, James A.; Bacallao, Robert L.

doi:10.1186/s40246-016-0095-x

Cited by 30 publications

(28 citation statements)

References 109 publications

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“…Hierarchical clustering analysis showed the differential RNA expression levels between CRC and paracancerous tissues (Figure C). A volcano plot (Figure D) was constructed using fold change (FC) and false discovery rate (FDR) values to visualize the relationship between FC and statistical significance …”

Section: Resultsmentioning

confidence: 99%

Expression profiles of circular RNAs in human colorectal cancer based on RNA deep sequencing

Jin

et al. 2019

Clinical Laboratory Analysis

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BackgroundCircular RNAs (circRNAs) are a novel group of RNAs and play essential roles in cancers. However, the expression profiles of circRNAs in human colorectal cancer (CRC) are largely unclear.MethodsThe differentially expressed circRNAs, mRNAs, and microRNAs (miRNAs) between CRC tissues and paired adjacent normal tissues were first screened. Then, gene ontology and pathway analyses were performed to predict the possible functions. In addition, we identified the differentially expressed circRNAs in CRC correlated with Krüppel‐like factor 4 (KLF4) and validated their expression levels in CRC tissues. Finally, the correlations between hsa_circ_0142527 expression levels and clinicopathological features of patients with CRC were also analyzed.ResultsAfter filtered 4735 circRNAs by RNA deep sequencing, 67 differentially expressed circRNAs (fold change >2.0, P < 0.05) were selected. The top two pathways were cell cycle and other glycan degradation. Hsa_circ_0142527 and KLF4 mRNA were significantly lower expressed in CRC tissues in both training and confirm groups and have high positive correlation (r = 0.754). We further found that the expression levels of hsa_circ_0142527 were significantly associated with age (P = 0.004), differentiation (P = 0.008), invasion (P = 0.029), distal metastasis (P = 0.004), TNM stage (P = 0.005), and carcinoembryonic antigen (CEA; P = 0.037).ConclusionsThe circRNA expression profile of CRC provided new clues for understanding the occurrence of CRC. Hsa_circ_0142527 may be served as a potential biomarker for the diagnosis of CRC.

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Section: Resultsmentioning

confidence: 99%

Expression profiles of circular RNAs in human colorectal cancer based on RNA deep sequencing

Jin

et al. 2019

Clinical Laboratory Analysis

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“…It expands on the previous transcriptomics efforts performed by others in the field. In this study we used deep RNA-sequencing of ADPKD transcriptomics across multiple disease stages, rather than microarrays [15,29,57,58]. The aforementioned studies differ in several elements, most notably their source of studied samples.…”

Section: Gene Categorymentioning

confidence: 99%

Prioritization of novel ADPKD drug candidates from disease-stage specific gene expression profiles

Malas

Leonhard

Bange³

et al. 2020

EBioMedicine

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Background: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most common causes of end-stage renal failure, caused by mutations in PKD1 or PKD2 genes. Tolvaptan, the only drug approved for ADPKD treatment, results in serious side-effects, warranting the need for novel drugs. Methods: In this study, we applied RNA-sequencing of Pkd1cko mice at different disease stages, and with/ without drug treatment to identify genes involved in ADPKD progression that were further used to identify novel drug candidates for ADPKD. We followed an integrative computational approach using a combination of gene expression profiling, bioinformatics and cheminformatics data. Findings: We identified 1162 genes that had a normalized expression after treating the mice with drugs proven effective in preclinical models. Intersecting these genes with target affinity profiles for clinicallyapproved drugs in ChEMBL, resulted in the identification of 116 drugs targeting 29 proteins, of which several are previously linked to Polycystic Kidney Disease such as Rosiglitazone. Further testing the efficacy of six candidate drugs for inhibition of cyst swelling using a human 3D-cyst assay, revealed that three of the six had cyst-growth reducing effects with limited toxicity. Interpretation: Our data further establishes drug repurposing as a robust drug discovery method, with three promising drug candidates identified for ADPKD treatment (Meclofenamic Acid, Gamolenic Acid and Birinapant). Our strategy that combines multiple-omics data, can be extended for ADPKD and other diseases in the future.

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“…It is generally known that centrosome dysfunction is linked to aneuploidy and chromosomal instability[ 20 ]. Many studies have shown increased incidence of chromosome imbalances and abnormal chromosome segregation in ADPKD tissues[ 21 , 22 ]. Loss of function of the PCM1 gene may therefore be a key factor in these processes.…”

Section: Discussionmentioning

confidence: 99%

Genetic defects in ciliary genes in autosomal dominant polycystic kidney disease

Skalická¹,

Hrčková²,

Vaska³

et al. 2018

WJN

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AIMTo evaluate the genetic defects of ciliary genes causing the loss of primary cilium in autosomal dominant polycystic kidney disease (ADPKD).METHODSWe analyzed 191 structural and functional genes of the primary cilium using next-generation sequencing analysis. We analyzed the kidney samples, which were obtained from 7 patients with ADPKD who underwent nephrectomy. Each sample contained polycystic kidney tissue and matched normal kidney tissue.RESULTSIn our study, we identified genetic defects in the 5 to 15 genes in each ADPKD sample. The most frequently identified defects were found in genes encoding centrosomal proteins (PCM1, ODF2, HTT and CEP89) and kinesin family member 19 (KIF19), which are important for ciliogenesis. In addition, pathogenic mutations in the PCM1 and KIF19 genes were found in all ADPKD samples. Interestingly, mutations in the genes encoding the intraflagellar transport proteins, which are the basis of animal models of ADPKD, were only rarely detected.CONCLUSIONThe results of our study revealed the actual state of structural ciliary genes in human ADPKD tissues and provided valuable indications for further research.

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Transcriptome analysis reveals manifold mechanisms of cyst development in ADPKD

Cited by 30 publications

References 109 publications

Expression profiles of circular RNAs in human colorectal cancer based on RNA deep sequencing

Expression profiles of circular RNAs in human colorectal cancer based on RNA deep sequencing

Prioritization of novel ADPKD drug candidates from disease-stage specific gene expression profiles

Genetic defects in ciliary genes in autosomal dominant polycystic kidney disease

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