Genetic and epigenetic mechanisms deregulate the CRL2pVHL complex in hepatocellular carcinoma
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ABSTRACT:
PROVIDER: PRJNA798918 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17676911.fastq.gz | Fastqsanger.gz | |||
| SRR17676912.fastq.gz | Fastqsanger.gz | |||
| SRR17676913.fastq.gz | Fastqsanger.gz | |||
| SRR17676914.fastq.gz | Fastqsanger.gz | |||
| SRR17676915.fastq.gz | Fastqsanger.gz |
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Project description:Dysregulation of ubiquitin-proteasome pathway genes through copy number alteration, promoter hypomethylation, and miRNA deregulation is involved in cancer development and progression. Further characterizing alterations in these genes may uncover novel drug targets across a range of diseases in which druggable alterations are uncommon, including hepatocellular carcinoma (HCC). We analyzed 377 HCC and 59 adjacent non-malignant liver tissue samples, focusing on alterations to component genes of the widely studied CRL2pVHL complex. Patient outcome was significantly worse when complex components VHL, CUL2, ELOC, or RBX1 were overexpressed in tumours. DNA hypomethylation and copy number increase were correlated with this overexpression, but many tumours had mRNA upregulation that was not explained by either mechanism. To assess the potential role of miRNA downregulation in component gene upregulation, we first acquired a wide-ranging view of the liver miRNA transcriptome by finding all miRNAs that were expressed in fetal liver, HCC, or adjacent non-malignant samples. Interestingly, we found 66 miRNAs, including 39 previously unannotated miRNAs, that were downregulated in HCC and predicted to target one or more CRL2pVHL components. Several miRNAs, including hsa-miR-101-3p and hsa-miR-139-5p, were negatively correlated with multiple component genes, suggesting that miRNA deregulation may contribute to CRL2pVHL overexpression. Combining miRNA and mRNA expression, DNA copy number, and methylation status into one multidimensional survival analysis, we found a significant association between greater numbers of alterations and poorer overall survival for multiple component genes. While the intricacies of CRL2pVHL complex gene regulation require additional research, it is evident that multiple causes for the deregulation of these genes must be considered in HCC, including non-traditional mechanisms. A better understanding of the CRL2pVHL components and further elucidation of their regulation could expand our understanding of HCC oncogenesis and aid in the development of novel inhibitors.
2022-06-21 | GSE194052 | GEO
Project description:Dysregulation of ubiquitin-proteasome pathway genes through copy number alteration, promoter hypomethylation, and miRNA deregulation is involved in cancer development and progression. Further characterizing alterations in these genes may uncover novel drug targets across a range of diseases in which druggable alterations are uncommon, including hepatocellular carcinoma (HCC). We analyzed 377 HCC and 59 adjacent non-malignant liver tissue samples, focusing on alterations to component genes of the widely studied CRL2pVHL E3 ubiquitin ligase complex. mRNA upregulation of the component genes was common, and was correlated with DNA hypomethylation and copy number increase, but many tumours displayed overexpression that was not explained by either mechanism. Interestingly, we found 66 miRNAs, including 39 previously unannotated miRNAs, that were downregulated in HCC and predicted to target one or more CRL2pVHL components. Several miRNAs, including hsa-miR-101-3p and hsa-miR-139-5p, were negatively correlated with multiple component genes, suggesting that miRNA deregulation may contribute to CRL2pVHL overexpression. Combining miRNA and mRNA expression, DNA copy number, and methylation status into one multidimensional survival analysis, we found a significant association between greater numbers of alterations and poorer overall survival for multiple component genes. While the intricacies of CRL2pVHL complex gene regulation require additional research, it is evident that multiple causes for the deregulation of these genes must be considered in HCC, including non-traditional mechanisms.
| S-EPMC9159809 | biostudies-literature
Project description:Multiple carcinogenesis is one of the major characteristics of human hepatocellular carcinoma (HCC). The history of multiple tumors, i.e., whether they are derived from a common precancerous or cancerous ancestor or individually from hepatocytes, is a major issue. Multiple HCC is clinically classified into intratumor metastasis (IM) and multicentric carcinogenesis (MC). Molecular markers differentiating IM and MC are of interest to clinical practitioners because clinical diagnosis of IM and MC often leads to different therapies. We analyzed multiple HCCs for somatic mutations of cancer-related genes, chromosomal aberrations, and promoter methylation of tumor suppressor genes, using techniques such as high-resolution melting, array-comparative genomic hybridization (CGH), and quantitative methylation-specific PCR. Comparative genomic hybridizaion experiments. A total of 20 tumor samples: ten pairs of HCC (from ten patients).
2010-09-08 | E-GEOD-22635 | biostudies-arrayexpress
Project description:Multiple carcinogenesis is one of the major characteristics of human hepatocellular carcinoma (HCC). The history of multiple tumors, i.e., whether they are derived from a common precancerous or cancerous ancestor or individually from hepatocytes, is a major issue. Multiple HCC is clinically classified into intratumor metastasis (IM) and multicentric carcinogenesis (MC). Molecular markers differentiating IM and MC are of interest to clinical practitioners because clinical diagnosis of IM and MC often leads to different therapies. We analyzed multiple HCCs for somatic mutations of cancer-related genes, chromosomal aberrations, and promoter methylation of tumor suppressor genes, using techniques such as high-resolution melting, array-comparative genomic hybridization (CGH), and quantitative methylation-specific PCR.
2010-09-09 | GSE22635 | GEO
Project description: Not available
| S-DIXA-D-1065 | biostudies-other
Project description:MicroRNA-224 (miR-224) is one of the most commonly up-regulated microRNAs in hepatocellular carcinoma (HCC), which affects crucial cellular processes such as apoptosis and cell proliferation. In this study, we aim to elucidate the molecular mechanism that leads to the overexpression of miR-224 in HCC. We examined the transcript expression of miR-224 and neighboring miR-452 and genes on chromosome Xq28 in tumor and paired adjacent nontumorous tissues from 100 patients with HCC and found that miR-224 is coordinately up-regulated with its neighboring microRNA (miRNA) and genes. This coordinated up-regulation of miRNAs and genes at the Xq28 locus can be mimicked in nontransformed immortalized human liver cells by the introduction of histone deacetylase (HDAC) inhibitors, which resulted in a corresponding increase in histone H3 acetylation in this region. This miR-224-residing locus in Xq28 is reciprocally regulated by HDAC1, HDAC3, and histone acetylase protein, E1A binding protein p300 (EP300). Notably, in HCC tumors that significantly overexpress microRNA-224, EP300 is also overexpressed and displays increased binding to the Xq28 locus. In transformed HCC cells, high miR-224 expression can be attenuated through the inhibition of EP300, using either siRNA or the specific drug C646. In summary, overexpression of EP300 may account, in part, for the up-regulation of miR-224 expression in patients with HCC.
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Project description:Single cell genome, DNA methylome, and transcriptome sequencing has been achieved separately. However, to analyze the regulation of RNA expression by genetic and epigenetic factors within an individual cell, it is necessary to analyze these omics simultaneously from the same single cell. Here we developed a single cell triple omics sequencing technique- scTrio-seq, to analyze the genome, DNA methylome, and transcriptome concurrently of a mammalian cell. 6 single human HepG2 cell line cells were sequenced using the newly developed scTrio-seq, other 2 HepG2 cells were sequenced using scRNA-seq and other 2 HepG2 cells were sequenced using scRRBS as technique control. 6 single mouse embryonic stem cells (mESCs) were sequenced using the newly developted scTrio-seq. Meanwhile, two scRNA-seq and two scRRBS were also completed using two mESCs separately. 26 single cells from hepatocellular carcinoma were sequenced using scTrio-seq to analyze the regulation relations between three omics of cancer cells.
2016-03-01 | E-GEOD-65364 | biostudies-arrayexpress
Project description:BackgroundMultiple carcinogenesis is one of the major characteristics of human hepatocellular carcinoma (HCC). The history of multiple tumors, that is, whether they derive from a common precancerous or cancerous ancestor or individually from hepatocytes, is a major clinical issue. Multiple HCC is clinically classified as either intratumor metastasis (IM) or multicentric carcinogenesis (MC). Molecular markers that differentiate IM and MC are of interest to clinical practitioners because the clinical diagnoses of IM and MC often lead to different therapies.MethodsWe analyzed 30 multiple tumors from 15 patients for somatic mutations of cancer-related genes, chromosomal aberrations, and promoter methylation of tumor suppressor genes using techniques such as high-resolution melting, array-comparative genomic hybridization (CGH), and quantitative methylation-specific PCR.ResultsSomatic mutations were found in TP53 and CTNNB1 but not in CDKN2A or KRAS. Tumors from the same patient did not share the same mutations. Array-CGH analysis revealed variations in the number of chromosomal aberrations, and the detection of common aberrations in tumors from the same patient was found to depend on the total number of chromosomal aberrations. A promoter methylation analysis of genes revealed dense methylation in HCC but not in the adjacent non-tumor tissue. The correlation coefficients (r) of methylation patterns between tumors from the same patient were more similar than those between tumors from different patients. In total, 47% of tumor samples from the same patients had an r ≥ 0.8, whereas, in contrast, only 18% of tumor samples from different patients had an r ≥ 0.8 (p = 0.01). All IM cases were highly similar; that is, r ≥ 0.8 (p = 0.025).ConclusionsThe overall scarcity of common somatic mutations and chromosomal aberrations suggests that biological IM is likely to be rare. Tumors from the same patient had a methylation pattern that was more similar than those from different patients. As all clinical IM cases exhibited high similarity, the methylation pattern may be applicable to support the clinical diagnosis of IM and MC.
| S-EPMC2978203 | biostudies-literature
Project description:Spatial transcriptome on human hepatocellular carcinoma
| PRJEB62485 | ENA
Project description:Hepatocellular carcinoma (HCC) constitutes most primary liver cancers and is one of the most lethal and life-threatening malignancies globally. Unfortunately, a substantial proportion of HCC patients are identified at an advanced stage that is unavailable for curative surgery. Thus, palliative therapies represented by multi-tyrosine kinase inhibitors (TKIs) sorafenib remained the front-line treatment over the past decades. Recently, the application of immune checkpoint inhibitors (ICIs), especially targeting the PD-1/PD-L1/CTLA-4 axis, has achieved an inspiring clinical breakthrough for treating unresectable solid tumors. However, many HCC patients with poor responses lead to limited benefits in clinical applications, which has quickly drawn researchers' attention to the regulatory mechanisms of immune checkpoints in HCC immune evasion. Evasion of immune surveillance by cancer is attributed to intricate reprogramming modulation in the tumor microenvironment. Currently, more and more studies have found that epigenetic modifications, such as chromatin structure remodeling, DNA methylation, histone post-translational modifications, and non-coding RNA levels, may contribute significantly to remodeling the tumor microenvironment to avoid immune clearance, affecting the efficacy of immunotherapy for HCC. This review summarizes the rapidly emerging progress of epigenetic-related changes during HCC resistance to ICIs and discusses the mechanisms of underlying epigenetic therapies available for surmounting immune resistance. Finally, we summarize the clinical advances in combining epigenetic therapies with immunotherapy, aiming to promote the formation of immune combination therapy strategies.
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