Integration of chronological omics data reveals mitochondrial regulatory mechanisms during the development of hepatocellular carcinoma.
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ABSTRACT:
SUBMITTER: Garcia-Chavez JN
PROVIDER: S-EPMC8360386 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundGenetic aberrations in hepatocellular carcinoma (HCC) are well known, but the functional consequences of such aberrations remain poorly understood.ResultsHere, we explored the effect of defined genetic changes on the transcriptome, proteome and phosphoproteome in twelve tumors from an mTOR-driven hepatocellular carcinoma mouse model. Using Network-based Integration of multi-omiCS data (NetICS), we detected 74 'mediators' that relay via molecular interactions the effects of genetic and miRNA expression changes. The detected mediators account for the effects of oncogenic mTOR signaling on the transcriptome, proteome and phosphoproteome. We confirmed the dysregulation of the mediators YAP1, GRB2, SIRT1, HDAC4 and LIS1 in human HCC.ConclusionsThis study suggests that targeting pathways such as YAP1 or GRB2 signaling and pathways regulating global histone acetylation could be beneficial in treating HCC with hyperactive mTOR signaling.
| S-EPMC8340535 | biostudies-literature
Project description:BackgroundHCC is one of the most common malignancies with an increasing incidence worldwide, especially in Asian countries. However, even though targeted cancer therapy drugs such as sorafenib and regorafenib are available, the overall outcome of HCC remains unsatisfactory. Thus, it is urgent to investigate the molecular mechanisms of HCC progression, so as to provide accurate diagnostic criteria and therapeutic targets.MethodsRNA-seq data was used to identify and quantify circular RNAs (circRNAs). DESeq2 was used to identify the differentially expressed circRNAs. miRNA binding sites within circRNAs were identified by miRanda. Gene set enrichment analysis (GSEA) was conducted to predict the biological function of circRNAs.ResultsThe differential expression analysis identified 107 upregulated and 95 downregulated circRNAs in HCC tissues. We observed that a differentially expressed circRNA (DE-circRNA), hsa_circ_0141900 was highly negatively correlated with its parental gene RAB1A (PCC < -0.6), which was also closely associated with mTOR signaling pathway. Moreover, we also constructed competing endogenous RNA (ceRNA) network to identify key circRNAs involved in HCC. Notably, hsa_circ_0002130 and hsa_circ_0008774 were highly correlated with the genes involved in gluconeogenesis and HNF3A pathway via the target genes, GOT2 and AR, suggesting that the two circRNAs might regulate these pathways, respectively. Survival analysis revealed that GOT2 was associated with favorable prognosis. Furthermore, high expression of hsa_circ_0002130 was found to inhibit tumor cell growth and promotes GOT2 expression.ConclusionIn summary, the circRNAs highlighted by the integrative analysis greatly improved our understanding of the underlying mechanism of circRNAs in HCC.
| S-EPMC8170000 | biostudies-literature
Project description:Triple negative breast cancer (TNBC) is an aggressive type of breast cancer with very little treatment options. TNBC is very heterogeneous with large alterations in the genomic, transcriptomic, and proteomic landscapes leading to various subtypes with differing responses to therapeutic treatments. We applied a multi-omics data integration method to evaluate the correlation of important regulatory features in TNBC BRCA1 wild-type MDA-MB-231 and TNBC BRCA1 5382insC mutated HCC1937 cells compared with non-tumorigenic epithelial breast MCF10A cells. The data includes DNA methylation, RNAseq, protein, phosphoproteomics, and histone post-translational modification. Data integration methods identified regulatory features from each omics method that had greater than 80% positive correlation within each TNBC subtype. Key regulatory features at each omics level were identified distinguishing the three cell lines and were involved in important cancer related pathways such as TGFβ signaling, PI3K/AKT/mTOR, and Wnt/beta-catenin signaling. We observed overexpression of PTEN, which antagonizes the PI3K/AKT/mTOR pathway, and MYC, which downregulates the same pathway in the HCC1937 cells relative to the MDA-MB-231 cells. The PI3K/AKT/mTOR and Wnt/beta-catenin pathways are both downregulated in HCC1937 cells relative to MDA-MB-231 cells, which likely explains the divergent sensitivities of these cell lines to inhibitors of downstream signaling pathways. The DNA methylation and RNAseq data is freely available via GEO GSE171958 and the proteomics data is available via the ProteomeXchange PXD025238.
| S-EPMC8504614 | biostudies-literature
Project description:BackgroundGlycosylation plays an essential role in driving the progression and treatment resistance of hepatocellular carcinoma (HCC). However, its function in regulating the acquisition and maintenance of the cancer stemness-like phenotype in HCC remains largely unknown. There is also very little known about how CAD and other potential glycosylation regulators may influence stemness. This study explores the relationship between glycosylation and stemness in HCC.MethodsGene set variance analysis (GSVA) was used to assess the TCGA pan-cancer enrichment in glycosylation-related pathways. Univariate, LASSO, and multivariate COX regression were then used to identify prognostic genes in the TCGA-LIHC and construct a prognostic signature. HCC patients were classified into high- and low-risk subgroups based on the signature. The relationship between gene expression profiles and stemness was confirmed using bulk and single-cell RNA-sequencing data. The role of CAD and other genes in regulating the stemness of HCC was also validated by RT-qPCR, CCK-8, and colony formation assay. Copy number variation (CNV), immune infiltration, and clinical features were further analyzed in different subgroups and subsequent gene expression profiles. Sensitive drugs were also screened.ResultsIn the pan-cancer analysis, HCC was shown to have specific glycosylation alterations. Five genes, CAD, SLC51B, LGALS3, B3GAT3, and MT3, identified from 572 glycosylation-related genes, were used to construct a gene signature and predict HCC patient survival in the TCGA cohort. The results demonstrated a significant positive correlation between patients in the high-risk group and both elevated gene expression and HCC dedifferentiation status. A significant reduction in the stemness-related markers, CD24, CD44, CD20, FOXM1, and EpCAM, was found after the knockdown of CAD and other genes in HepG2 and Huh7 cells. Frequent mutations increased CNVs, immune-suppressive responses, and poor prognosis were also associated with the high-risk profile. The ICGC-LIRI-JP cohort confirmed a similar relationship between glycosylation-related subtypes and stemness. Finally, 84 sensitive drugs were screened for abnormal glycosylation of HCC, and carfilzomib was most highly correlated with CAD.ConclusionsGlycosylation-related molecular subtypes are associated with HCC stemness and disease prognosis. These results provide new directions for further research on the relationship between glycosylation and stemness phenotypes.
| S-EPMC9259879 | biostudies-literature
Project description:Although disruption of mitochondrial function has been associated with energetic deregulation in cancer, the chronological changes in mitochondria during cancer development remain unclear. With the aim to assess the role of mitochondria throughout cancer development, we analyzed samples chronologically obtained from induced hepatocellular carcinoma (HCC) in rats. In our analyses, we integrated mitochondrial proteomic data, mitochondrial metabolomic data and nuclear genome transcriptomic data. We used pathway over-representation and weighted gene co-expression network analysis (WGCNA) to integrate expression profiles of genes, miRNAs, proteins and metabolite levels throughout HCC development. Our results show that mitochondria are dynamic organelles presenting specific modifications in different stages of HCC development. For carcinogenesis, a modified resistant hepatocyte model was used. Rats were initiated with diethylnitrosamine (DEN) (200 mg/kg of body weight) at day 0. Then, 2-acetylaminofluorene (AAF) was administered (20 mg/kg per dose) at days 7, 8 and 9, followed by 3/5 partial hepatectomy (PH) at day 10. Three control groups of non-treated animals were sacrificed by exsanguination on the first day and at 9 and 18 months after the beginning of the experiment. Treated animals were sacrificed at 1, 7, 11 and 16 days and at 1, 9 and 18 months. Their livers were excised, washed in physiological saline solution, frozen with liquid nitrogen in 2-methyl butane and stored at -80°C. Once selected and separately collected nodular, tumoral and its adjacent tissues, total RNA was isolated using TriPureIsolation Reagent (Roche) according to the manufacturer’s protocol. The microarray analysis was performed using GeneChip Rat Exon 1.0 ST Arrays. Four replicas for each condition and controls were analyzed. This created 11 pairwise contrasts for the differential expression analysis. We grouped all evaluated conditions in three categories: i) early stages, including samples obtained since day one until one month after treatment, these were compared against rats without treatment sacrificed the first day; ii) tumor, nodular and its adjacent tissues obtained from nine months rats were compared against rats without treatment of the same age; and iii) tumor and its adjacent tissues obtained from eighteen months rats were compared against rats without treatment of the same age.
2021-09-09 | PXD023388 | Pride
Project description:Splicing factors (SFs) have been increasingly documented to perturb the genome of cancers. However, little is known about the alterations of SFs in hepatocellular carcinoma (HCC). This study comprehensively delineated the genomic and epigenomic characteristics of 404 SFs in HCC based on the multi-omics data from the Cancer Genome Atlas database. The analysis revealed several clinically relevant SFs that could be effective biomarkers for monitoring the onset and prognosis of HCC (such as, HSPB1, DDX39A, and NELFE, which were the three most significant clinically relevant SFs). Functional enrichment analysis of these indicators showed the enrichment of pathways related to splicing and mRNA processes. Furthermore, the study found that SF copy number variation is common in HCC and could be a typical characteristic of hepato-carcinogenesis; the complex expression regulation of SFs was significantly affected by copy number variant and methylation. Several SFs with significant mutation patterns were identified (such as, RNF213, SF3B1, SPEN, NOVA1, and EEF1A1), and the potential regulatory network of SFs was constructed to identify their potential mechanisms for regulating clinically relevant alternative splicing events. Therefore, this study established a foundation to uncover the broad molecular spectrum of SFs for future functional and therapeutic studies of HCC.
| S-EPMC8806902 | biostudies-literature
Project description:Hepatocellular carcinoma is one of the most heterogeneous cancers, as reflected by its multiple grades and difficulty to subtype. In this study, we integrated copy number variation, DNA methylation, mRNA, and miRNA data with the developed "cluster of cluster" method and classified 256 HCC samples from TCGA (The Cancer Genome Atlas) into five major subgroups (S1-S5). We observed that this classification was associated with specific mutations and protein expression, and we detected that each subgroup had distinct molecular signatures. The subclasses were associated not only with survival but also with clinical observations. S1 was characterized by bulk amplification on 8q24, TP53 mutation, low lipid metabolism, highly expressed onco-proteins, attenuated tumor suppressor proteins and a worse survival rate. S2 and S3 were characterized by telomere hypomethylation and a low expression of TERT and DNMT1/3B. Compared to S2, S3 was associated with less copy number variation and some good prognosis biomarkers, including CRP and CYP2E1. In contrast, the mutation rate of CTNNB1 was higher in S3. S4 was associated with bulk amplification and various molecular characteristics at different biological levels. In summary, we classified the HCC samples into five subgroups using multiple "-omics" data. Each subgroup had a distinct survival rate and molecular signature, which may provide information about the pathogenesis of subtypes in HCC.
| S-EPMC5091875 | biostudies-literature
Project description:Although apatinib is a promising drug for the treatment of liver cancer, the underlying drug resistance mechanism is still unclear. Here, we constructed apatinib-resistant HepG2 cells. We then characterized the epigenomic, transcriptomic, and proteomic landscapes both in apatinib-resistant and non-resistant HepG2 cells. Differential expression, ATAC-seq, and proteomic data analyses were performed. We found that the cell cycle related protein RB1 may play an essential role in the process of apatinib resistant to hepatocarcinoma. Moreover, there were extensive variations at the transcriptome, epigenetic, and proteomic level. Finally, quantitative PCR (qPCR) and western blot analysis showed that expression level of RB1 in apatinib-resistant cell as well as the samples of patients in progressive disease were significantly lower than that in controls. Those results also showed that the RB1 pathway inhibitors CDK2-IN-73 and Palbociclib could relieve the resistance of apatinib resistant cells. Our results further enhance our understanding of the anti-tumorigenic and anti-angiogenic efficacy of apatinib in liver cancer and provide a novel perspective regarding apatinib resistance. Furthermore, we proved that CDKN2B inhibition of RB1 signaling promoted apatinib resistance in hepatocellular carcinoma. Those findings have greatly important biological significance for the resistance of apatinib and the treatment of liver cancer.
| S-EPMC10535702 | biostudies-literature
Project description:BackgroundThe genetic mechanisms that underlie phenotypic differentiation in breeding animals have important implications in evolutionary biology and agriculture. However, the contribution of cis-regulatory variants to pig phenotypes is poorly understood. Therefore, our aim was to elucidate the molecular mechanisms by which non-coding variants cause phenotypic differences in pigs by combining evolutionary biology analyses and functional genomics.ResultsWe obtained a high-resolution phased chromosome-scale reference genome with a contig N50 of 18.03 Mb for the Luchuan pig breed (a representative eastern breed) and profiled potential selective sweeps in eastern and western pigs by resequencing the genomes of 234 pigs. Multi-tissue transcriptome and chromatin accessibility analyses of these regions suggest that tissue-specific selection pressure is mediated by promoters and distal cis-regulatory elements. Promoter variants that are associated with increased expression of the lysozyme (LYZ) gene in the small intestine might enhance the immunity of the gastrointestinal tract and roughage tolerance in pigs. In skeletal muscle, an enhancer-modulating single-nucleotide polymorphism that is associated with up-regulation of the expression of the troponin C1, slow skeletal and cardiac type (TNNC1) gene might increase the proportion of slow muscle fibers and affect meat quality.ConclusionsOur work sheds light on the molecular mechanisms by which non-coding variants shape phenotypic differences in pigs and provides valuable resources and novel perspectives to dissect the role of gene regulatory evolution in animal domestication and breeding.
| S-EPMC9476355 | biostudies-literature
Project description:The immune environment in primary tumor has a profound impact on immunotherapy. However, the clinical relevance of immune environment in hepatocellular carcinoma (HCC) is largely unknown. Here, the immune profile and its clinical response in HCC were investigated. The gene expression profiles of 569 HCCs from three cohorts (The Cancer Genome Atlas, TCGA, n = 257; Gene Expression Omnibus, GEO, n = 170; International Cancer Genome Consortium, ICGC, n = 142) were used in the current study. Five gene expression subtypes (C1-C5) responsible for global immune genes were identified in HCCs at stage I/II. It was found that subtype C4 was associated with upregulation and subtype C5 was associated with downregulation of immune profiles in most metagenes. Immune-correlation analysis of the five subtypes demonstrated that C3 and C4 had higher immune score and better prognostic outcome, as compared with other subtypes. Moreover, the mutation frequencies of TP53, CTNNB1, and AXIN1 had significant difference in the five subgroups. Further, the expression of PDCD1, CD274, PDCD1LG2, CTLA4, CD86, and CD80 was higher in subtype C4 in comparison with the other subtypes. The WGCNA of immune-related genes in the five subtypes revealed that blue and turquoise modules were positively correlated with subtype C4 and were associated with 12 common pathways in the KEGG database. These results were validated in external cohorts from the NCI (National Cancer Institute) cohort (GSE14520) and the ICGC (International Cancer Genome Consortium) cohort. In summary, one immune-enhanced subtype and one immune-decreased subtype having different immune and clinical characteristics may provide guidance for developing novel treatment strategies for immune system malfunction-related cancer.
| S-EPMC6803502 | biostudies-literature