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

/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.

Efforts to precisely assess tumor-specific T-cell immune responses still face major challenges, and the potential molecular mechanisms mediating hepatocellular carcinoma (HCC) microenvironment imbalance after incomplete radiofrequency ablation (iRFA) are unclear. This study aimed to provide further insight into the integrated transcriptomic and proteogenomic landscape and identify a new target involved in HCC progression following iRFA.Peripheral blood and matched tissue samples were collected from 10 RFA-treated HCC patients. Multiplex immunostaining and flow cytometry were used to assess local and systemic immune responses. Differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) were explored via transcriptomic and proteogenomic analyses. Proteinase-3 (PRTN3) was identified in these analyses. And then, the ability of PRTN3 to predict overall survival (OS) was assessed in 70 HCC patients with early recurrence after RFA. In vitro CCK-8, wound healing and transwell assays were conducted to observe interactions between Kupffer cells (KCs) and HCC cells induced by PRTN3. The protein levels of multiple oncogenic factors and signaling pathway components were detected by western blotting. A xenograft mouse model was built to observe the tumorigenic effect of PRTN3 overexpression on HCC.Multiplex immunostaining revealed no immediate significant change in local immune cell counts in periablational tumor tissues after 30 min of iRFA. Flow cytometry showed significantly increased levels of CD4+ T cells, CD4+CD8+ T cells, and CD4+CD25+CD127- Tregs and significantly decreased the levels of CD16+CD56+ natural killer cells on day 5 after cRFA (p < 0.05). Transcriptomics and proteomics revealed 389 DEGs and 20 DEPs. Pathway analysis showed that the DEP-DEGs were mainly enriched in the immunoinflammatory response, cancer progression and metabolic processes. Among the DEP-DEGs, PRTN3 was persistently upregulated and closely associated with the OS of patients with early recurrent HCC following RFA. PRTN3 expressed in KCs may affect the migration and invasion of heat stress-treated HCC cells. PRTN3 promotes tumor growth via multiple oncogenic factors and the PI3K/AKT and P38/ERK signaling pathways.This study provides a comprehensive overview of the immune response and transcriptomic and proteogenomic landscapes of the HCC milieu induced by iRFA, revealing that PRTN3 promotes HCC progression after iRFA.ChiCTR2200055606, http://www.chictr.org.cn/showproj.aspx?proj=32588 . 

/pdf/integrated-proteogenomic-characterization-reveals-an-2jj3v2cv.pdf

Integrated proteogenomic characterization reveals an imbalanced hepatocellular carcinoma microenvironment after incomplete radiofrequency ablation

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

Neural stem cells (NSCs) are multipotent and correct fate determination is crucial to guarantee brain formation and homeostasis. How NSCs are instructed to generate neuronal or glial progeny is not well understood. Here we addressed how murine adult hippocampal NSC fate is regulated and describe how Scaffold Attachment Factor B (SAFB) blocks oligodendrocyte production to enable neuron generation. We found that SAFB prevents NSC expression of the transcription factor Nuclear Factor I/B (NFIB) by binding to sequences in the Nfib mRNA and enhancing Drosha-dependent cleavage of the transcripts. We show that increasing SAFB expression prevents oligodendrocyte production by multipotent adult NSCs, and conditional deletion of Safb increases NFIB expression and oligodendrocyte formation in the adult hippocampus. Our results provide novel insights into a mechanism that controls Drosha functions for selective regulation of NSC fate by modulating the post-transcriptional destabilization of Nfib mRNA in a lineage-specific manner.

SAFB regulates hippocampal stem cell fate by targeting Drosha to destabilize Nfib mRNA.

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Integrative proteogenomic characterization of hepatocellular carcinoma across etiologies and stages

SAFB regulates hippocampal stem cell fate by targeting Drosha to destabilize Nfib mRNA.