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      Mining TCGA Database for Tumor Microenvironment-Related Genes of Prognostic Value in Hepatocellular Carcinoma

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          Abstract

          Hepatocellular carcinoma (HCC) is one of the most common and lethal malignancies. Recent studies reveal that tumor microenvironment (TME) components significantly affect HCC growth and progression, particularly the infiltrating stromal and immune cells. Thus, mining of TME-related biomarkers is crucial to improve the survival of patients with HCC. Public access of The Cancer Genome Atlas (TCGA) database allows convenient performance of gene expression-based analysis of big data, which contributes to the exploration of potential association between genes and prognosis of a variety of malignancies, including HCC. The “Estimation of STromal and Immune cells in MAlignant Tumors using Expression data” algorithm renders the quantification of the stromal and immune components in TME possible by calculating the stromal and immune scores. Differentially expressed genes (DEGs) were screened by dividing the HCC cohort of TCGA database into high- and low-score groups according to stromal and immune scores. Further analyses of functional enrichment and protein-protein interaction networks show that the DEGs are mainly involved in immune response, cell adhesion, and extracellular matrix. Finally, seven DEGs have significant association with HCC poor outcomes. These genes contain FABP3, GALNT5, GPR84, ITGB6, MYEOV, PLEKHS1, and STRA6 and may be candidate biomarkers for HCC prognosis.

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          Most cited references36

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          Immunological hallmarks of stromal cells in the tumour microenvironment.

          A dynamic and mutualistic interaction between tumour cells and the surrounding stroma promotes the initiation, progression, metastasis and chemoresistance of solid tumours. Far less understood is the relationship between the stroma and tumour-infiltrating leukocytes; however, emerging evidence suggests that the stromal compartment can shape antitumour immunity and responsiveness to immunotherapy. Thus, there is growing interest in elucidating the immunomodulatory roles of the stroma that evolve within the tumour microenvironment. In this Review, we discuss the evidence that stromal determinants interact with leukocytes and influence antitumour immunity, with emphasis on the immunological attributes of stromal cells that may foster their protumorigenic function.
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            Genome-wide analysis of non-coding regulatory mutations in cancer

            Cancer primarily develops due to somatic alterations in the genome. Advances in sequencing have enabled large-scale sequencing studies across many tumor types, emphasizing discovery of alterations in protein-coding genes. However, the protein-coding exome comprises less than 2% of the human genome. Here, we analyze complete genome sequences of 863 human tumors from The Cancer Genome Atlas and other sources to systematically identify non-coding regions that are recurrently mutated in cancer. We utilize novel frequency and sequence-based approaches to comprehensively scan the genome for non-coding mutations with potential regulatory impact. We identified recurrent mutations in regulatory elements upstream of PLEKHS1, WDR74, and SDHD, as well as previously identified mutations in the TERT promoter. SDHD promoter mutations are frequent in melanoma and associated with reduced gene expression and poor patient prognosis. The non-protein-coding cancer genome remains widely unexplored and our findings represent a step towards targeting the entire genome for clinical purposes.
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              The tumor microenvironment in hepatocellular carcinoma: current status and therapeutic targets.

              A growing body of literature highlights the cross-talk between tumor cells and the surrounding peri-tumoral stroma as a key modulator of the processes of hepatocarcinogenesis, epithelial mesenchymal transition (EMT), tumor invasion and metastasis. The tumor microenvironment can be broadly classified into cellular and non-cellular components. The major cellular components include hepatic stellate cells, fibroblasts, immune, and endothelial cells. These cell types produce the non-cellular components of the tumor stroma, including extracellular matrix (ECM) proteins, proteolytic enzymes, growth factors and inflammatory cytokines. The non-cellular component of the tumor stroma modulates hepatocellular carcinoma (HCC) biology by effects on cancer signaling pathways in tumor cells and on tumor invasion and metastasis. Global gene expression profiling of HCC has revealed that the tumor microenvironment is an important component in the biologic and prognostic classification of HCC. There are substantial efforts underway to develop novel drugs targeting tumor-stromal interactions. In this review, we discuss the current knowledge about the role of the tumor microenvironment in pathogenesis of HCC, the role of the tumor microenvironment in the classification of HCC and efforts to develop treatments targeting the tumor microenvironment. Copyright © 2010 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Biomed Res Int
                Biomed Res Int
                BMRI
                BioMed Research International
                Hindawi
                2314-6133
                2314-6141
                2019
                19 November 2019
                : 2019
                : 2408348
                Affiliations
                1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
                2Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
                Author notes

                Academic Editor: Paul Harrison

                Author information
                https://orcid.org/0000-0001-5226-9392
                https://orcid.org/0000-0001-7626-7199
                https://orcid.org/0000-0001-7270-3504
                https://orcid.org/0000-0002-4267-8069
                https://orcid.org/0000-0002-4783-9925
                https://orcid.org/0000-0002-0523-5736
                https://orcid.org/0000-0001-9040-9739
                https://orcid.org/0000-0003-0393-7045
                https://orcid.org/0000-0003-4268-540X
                Article
                10.1155/2019/2408348
                6885833
                31828095
                d8a541c6-3321-4305-a110-7a97d50a77a1
                Copyright © 2019 Zhenfeng Deng et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 5 August 2019
                : 29 September 2019
                : 9 October 2019
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 81560387
                Funded by: Natural Science Foundation of Guangxi Province
                Award ID: 2018GXNSFBA050030
                Funded by: Guangxi Medical University
                Award ID: 180327
                Categories
                Research Article

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