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Analysis of the Cancer Genome Atlas Data Reveals Novel Putative ncRNAs Targets in Hepatocellular Carcinoma.

ABSTRACT: Hepatocellular carcinoma (HCC) is the prevalent type of primary liver malignancy. Different noncoding RNAs (ncRNAs) that negatively regulate gene expression, such as the microRNAs and the long ncRNAs (lncRNAs), have been associated with cell invasiveness and cell dissemination, tumor recurrence, and metastasis in HCC. To evaluate which regulatory ncRNAs might be good candidates to disrupt HCC proliferation pathways, we performed both unsupervised and supervised analyses of HCC expression data, comparing samples of solid tumor tissue (TP) and adjacent tissue (NT) of a set of patients, focusing on ncRNAs and searching for common mechanisms that may shed light in future therapeutic options. All analyses were performed using the R software. Differential expression (total RNA and miRNA) and enrichment analyses (Gene Ontology + Pathways) were performed using the package TCGABiolinks. As a result, we improved the set of lncRNAs that could be the target of future studies in HCC, highlighting the potential of FAM170B-AS1 and TTN-AS1.

SUBMITTER: Falcon T

PROVIDER: S-EPMC6038674 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Analysis of the Cancer Genome Atlas Data Reveals Novel Putative ncRNAs Targets in Hepatocellular Carcinoma.

Falcon Tiago T Freitas Martiela M Mello Ana Carolina AC Coutinho Laura L Alvares-da-Silva Mario R MR Matte Ursula U

BioMed research international 20180626

Hepatocellular carcinoma (HCC) is the prevalent type of primary liver malignancy. Different noncoding RNAs (ncRNAs) that negatively regulate gene expression, such as the microRNAs and the long ncRNAs (lncRNAs), have been associated with cell invasiveness and cell dissemination, tumor recurrence, and metastasis in HCC. To evaluate which regulatory ncRNAs might be good candidates to disrupt HCC proliferation pathways, we performed both unsupervised and supervised analyses of HCC expression data, c ...[more]

PMID: 30046591

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Project description:BackgroundSingle-cell RNA sequencing, also known as scRNA-seq, is a method profiling cell populations on an individual cell basis. It is particularly useful for more deeply understanding cell behavior in a complicated tumor microenvironment. Although several previous studies have examined scRNA-seq for hepatocellular carcinoma (HCC) tissues, no one has tested and analyzed HCC with different stages.MethodsIn this investigation, immune cells isolated from surrounding normal tissues and cancer tissues from 3 II-stage and 4 III-stage HCC cases were subjected to deep scRNA-seq. The analysis included 15 samples. We distinguished developmentally relevant trajectories, unique immune cell subtypes, and enriched pathways regarding differential genes. Western blot and co-immunoprecipitation were performed to demonstrate the interaction between fatty acid binding protein 1 (FABP1) and peroxisome proliferator-activated receptor gamma(PPARG). In vivo experiments were performed in a C57BL/6 mouse model of HCC established via subcutaneous injection.ResultsFABP1 was discovered to be overexpressed in tumor-associated macrophages (TAMs) with III-stage HCC tissues compared with II-stage HCC tissues. This finding was fully supported by immunofluorescence detection in significant amounts of HCC human samples. FABP1 deficiency in TAMs inhibited HCC progression in vitro. Mechanistically, FABP1 interacted with PPARG/CD36 in TAMs to increase fatty acid oxidation in HCC. When compared with C57BL/6 mice of the wild type, tumors in FABP1-/- mice consistently showed attenuation. The FABP1-/- group's relative proportion of regulatory T cells and natural killer cells showed a downward trend, while dendritic cells, M1 macrophages, and B cells showed an upward trend, according to the results of mass cytometry. In further clinical translation, we found that orlistat significantly inhibited FABP1 activity, while the combination of anti-programmed cell death 1(PD-1) could synergistically treat HCC progression. Liposomes loaded with orlistat and connected with IR780 probe could further enhance the therapeutic effect of orlistat and visualize drug metabolism in vivo.ConclusionsScRNA-seq atlas revealed an FABP1-dependent immunosuppressive environment in HCC. Orlistat significantly inhibited FABP1 activity, while the combination of anti-PD-1 could synergistically treat HCC progression. This study identified new treatment targets and strategies for HCC progression, contributing to patients with advanced HCC from new perspectives.

Project description:IntroductionHepatocellular carcinoma (HCC) is an aggressive malignancy with steadily increasing incidence rates worldwide and poor therapeutic outcomes. Studies show that metabolic reprogramming plays a key role in tumor genesis and progression. In this study, we analyzed the metabolic heterogeneity of epithelial cells in the HCC and screened for potential biomarkers.MethodsThe hepatic single-cell RNA sequencing (scRNA-seq) datasets of HCC patients and healthy controls were obtained from the Gene Expression Omnibus (GEO) database. Based on data intergration and measurement of differences among groups, the metabolic epithelial cell subpopulations were identified. The single-cell metabolic pathway was analyzed and the myeloid subpopulations were identified. Cell-cell interaction analysis and single-cell proliferation analysis were performed. The gene expression profiles of HCC patients were obtained from the GSE14520 dataset of GEO and TCGA-LIHC cohort of the UCSC Xena website. Immune analysis was performed. The differentially expressed genes (DEGs) were identified and functionally annotated. Tumor tissues from HCC patients were probed with anti-ALDOA, anti-CD68, anti-CD163, anti-CD4 and anti-FOXP3 antibodies. Results We analyzed the scRNA-seq data from 48 HCC patients and 14 healthy controls. The epithelial cells were significantly enriched in HCC patients compared to the controls (p = 0.011). The epithelial cells from HCC patients were classified into two metabolism-related subpopulations (MRSs) - pertaining to amino acid metabolism (MRS1) and glycolysis (MRS2). Depending on the abundance of these metabolic subpopulations, the HCC patients were also classified into the MRS1 and MRS2 subtype distinct prognoses and immune infiltration. The MRS2 group had significantly worse clinical outcomes and more inflamed tumor microenvironment (TME), as well as a stronger crosstalk between MRS2 cells and immune subpopulations that resulted in an immunosuppressive TME. We also detected high expression levels of ALDOA in the MRS2 cells and HCC tissues. In the clinical cohort, HCC patients with higher ALDOA expression showed greater enrichment of immunosuppressive cells including M2 macrophages and T regulatory cells.DiscussionThe glycolytic subtype of HCC cells with high ALDOA expression is associated with an immunosuppressive TME and predicts worse clinical outcomes, providing new insights into the metabolism and prognosis of HCC.

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Analysis of the Cancer Genome Atlas Data Reveals Novel Putative ncRNAs Targets in Hepatocellular Carcinoma.

Publications

Analysis of the Cancer Genome Atlas Data Reveals Novel Putative ncRNAs Targets in Hepatocellular Carcinoma.

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