Single-nucleus RNA sequencing (snRNA-seq) is a method used to analyze gene expression in cells for which isolation is complex, such as those in hepatocellular carcinoma (HCC) tissues. It constitutes an alternative to single-cell RNA sequencing (scRNA-seq) by analyzing the nucleus rather than the whole cell; however, whether it can completely replace scRNA-seq in HCC remains to be clarified. In the present study, scRNA-seq was compared with snRNA-seq in tumor tissue obtained from patients with HCC, using the 10X Genomics Chromium platform. Seurat was also used to process the data and compare the differences between the two sequencing methods in identifying different cell types. In the present study, the transcriptomes of 14,349 single nuclei and 9,504 single cells were obtained from the aforementioned HCC tissue. A total of 21 discrete cell clusters, including hepatocytes, endothelial cells, fibroblasts, B cells, T cells, natural killer cells and macrophages were identified. Notably, a high number of hepatocytes were detected using snRNA-seq, while an increased number of immunocytes were identified in the tumor microenvironment using scRNA-seq. Results of the present study provided a comprehensive image of human HCC at a single-cell resolution. Moreover, results of the present study further demonstrated that snRNA-seq may be adequate in replacing scRNA-seq in certain cases, and snRNA-seq performs at an improved level in hepatocyte sequencing. Combined use of the two sequencing methods may contribute to the study of intercellular interactions.

/pdf/comparison-of-single-nucleus-and-single-cell-transcriptomes-15zk1ufu.pdf

Comparison of single-nucleus and single-cell transcriptomes in hepatocellular carcinoma tissue

WNT/β-catenin signaling in hepatocellular carcinoma: The aberrant activation, pathogenic roles, and therapeutic opportunities

Non-alcoholic fatty liver disease (NAFLD) contributes to the global epidemic of metabolic syndrome and is considered a prelude to end-stage liver diseases such as cirrhosis and hepatocellular carcinoma. During NAFLD pathogenesis, hepatic parenchymal cells (hepatocytes) undergo both morphological and functional changes owing to a rewired transcriptome. The underlying mechanism is not entirely clear. In the present study, we investigated the involvement of early growth response 1 (Egr1) in NAFLD.Quantitative PCR, Western blotting, and histochemical staining were used to assess gene expression levels. Chromatin immunoprecipitation was used to evaluate protein binding to DNA. NAFLD was evaluated in leptin receptor-deficient (db/db) mice.We report here that Egr1 was upregulated by pro-NAFLD stimuli in vitro and in vivo. Further analysis revealed that serum response factor (SRF) was recruited to the Egr1 promoter and mediated Egr1 transactivation. Importantly, Egr1 depletion markedly mitigated NAFLD in db/db mice. RNA sequencing revealed that Egr1 knockdown in hepatocytes, on the one hand, boosted fatty acid oxidation (FAO) and, on the other hand, suppressed the synthesis of chemoattractants. Mechanistically, Egr1 interacted with peroxisome proliferator-activated receptor α (PPARα) to repress PPARα-dependent transcription of FAO genes by recruiting its co-repressor NGFI-A binding protein 1 (Nab1), which potentially led to promoter deacetylation of FAO genes.Our data identify Egr1 as a novel modulator of NAFLD and a potential target for NAFLD intervention.Non-alcoholic fatty liver disease (NAFLD) precedes cirrhosis and hepatocellular carcinoma. In this paper, we describe a novel mechanism whereby early growth response 1 (Egr1), a transcription factor, contributes to NAFLD pathogenesis by regulating fatty acid oxidation. Our data provide novel insights and translational potential for NAFLD intervention. 

Zinc finger transcription factor Egf1 promotes non-alcoholic fatty liver disease

/pdf/transcription-factors-tead2-and-e2a-globally-repress-acetyl-2ow37xpb.pdf

Transcription factors TEAD2 and E2A globally repress acetyl-CoA synthesis to promote tumorigenesis.

Recent technological advancements in mass spectrometry (MS)-based proteomics technologies have accelerated its application to study greater and greater numbers of human tumor specimens. Over the last several years, the Clinical Proteomic Tumor Analysis Consortium, the International Cancer Proteogenome Consortium, and others have generated MS-based proteomic profiling data combined with corresponding multiomics data on thousands of human tumors to date. Proteomic data sets in the public domain can be re-examined by other researchers with different questions in mind from what the original studies explored. In this review, we examine the increasing role of proteomics in studying cancer, along with the potential for previous studies and their associated data sets to contribute to improving the diagnosis and treatment of cancer in the clinical setting. We also explore publicly available proteomics and multi-omics data from cancer cell line models to show how such data may aid in identifying therapeutic strategies for cancer subsets.

Clinical proteomics towards multiomics in cancer.

Abstract Proteogenomic analyses of hepatocellular carcinomas (HCC) have focused on early-stage, HBV-associated HCCs. Here we present an integrated proteogenomic analysis of HCCs across clinical stages and etiologies. Pathways related to cell cycle, transcriptional and translational control, signaling transduction, and metabolism are dysregulated and differentially regulated on the genomic, transcriptomic, proteomic and phosphoproteomic levels. We describe candidate copy number-driven driver genes involved in epithelial-to-mesenchymal transition, the Wnt-β-catenin, AKT/mTOR and Notch pathways, cell cycle and DNA damage regulation. The targetable aurora kinase A and CDKs are upregulated. CTNNB1 and TP53 mutations are associated with altered protein phosphorylation related to actin filament organization and lipid metabolism, respectively. Integrative proteogenomic clusters show that HCC constitutes heterogeneous subgroups with distinct regulation of biological processes, metabolic reprogramming and kinase activation. Our study provides a comprehensive overview of the proteomic and phophoproteomic landscapes of HCCs, revealing the major pathways altered in the (phospho)proteome. 

/pdf/integrative-proteogenomic-characterization-of-hepatocellular-26228k05.pdf

Integrative proteogenomic characterization of hepatocellular carcinoma across etiologies and stages

Abstract Non-alcoholic fatty liver disease is a continuum of disorders among which non-alcoholic steatohepatitis (NASH) is particularly associated with a negative prognosis. Hepatocyte lipotoxicity is one of the main pathogenic factors of liver fibrosis and NASH. However, the molecular mechanisms regulating this process are poorly understood. The main aim of this study was to dissect transcriptional mechanisms regulated by lipotoxicity in hepatocytes. We achieved this aim by combining transcriptomic, proteomic and chromatin accessibility analyses from human liver and mouse hepatocytes. This integrative approach revealed several transcription factor networks deregulated by NASH and lipotoxicity. To validate these predictions, genetic deletion of the transcription factors MAFK and TCF4 was performed, resulting in hepatocytes that were better protected against saturated fatty acid oversupply. MAFK- and TCF4-regulated gene expression profiles suggest a mitigating effect against cell stress, while promoting cell survival and growth. Moreover, in the context of lipotoxicity, some MAFK and TCF4 target genes were to the corresponding differentially regulated transcripts in human liver fibrosis. Collectively, our findings comprehensively profile the transcriptional response to lipotoxicity in hepatocytes, revealing new molecular insights and providing a valuable resource for future endeavours to tackle the molecular mechanisms of NASH. 

/pdf/characterization-of-regulatory-transcriptional-mechanisms-in-1g4hu191.pdf

Characterization of regulatory transcriptional mechanisms in hepatocyte lipotoxicity

Glycosphingolipids are mediators of cancer plasticity through independent signaling pathways.

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Integrative proteogenomic characterization of hepatocellular carcinoma across etiologies and stages

Characterization of regulatory transcriptional mechanisms in hepatocyte lipotoxicity

Glycosphingolipids are mediators of cancer plasticity through independent signaling pathways.