Epigenetic and Immune-Cell Infiltration Changes in the Tumor Microenvironment in Hepatocellular Carcinoma

BackgroundEpigenetics regulate gene expression without altering the DNA sequence. Epigenetics targeted chemotherapeutic approach can be used to overcome treatment resistance and low response rate in HCC. However, a comprehensive review of genomic data was carried out to determine the role of epigene...

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Autores principales:	Zeng-Hong Wu, Dong-Liang Yang, Liang Wang, Jia Liu
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	hepatocellular carcinoma epigenetic inflammatory response CRISPR TCGA Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/d7d3451611ad4bd2a0cb78a7fe90a363
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spelling	oai:doaj.org-article:d7d3451611ad4bd2a0cb78a7fe90a3632021-12-02T10:29:10ZEpigenetic and Immune-Cell Infiltration Changes in the Tumor Microenvironment in Hepatocellular Carcinoma1664-322410.3389/fimmu.2021.793343https://doaj.org/article/d7d3451611ad4bd2a0cb78a7fe90a3632021-12-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.793343/fullhttps://doaj.org/toc/1664-3224BackgroundEpigenetics regulate gene expression without altering the DNA sequence. Epigenetics targeted chemotherapeutic approach can be used to overcome treatment resistance and low response rate in HCC. However, a comprehensive review of genomic data was carried out to determine the role of epigenesis in the tumor microenvironment (TME), immune cell-infiltration characteristics in HCC is still insufficient.MethodsThe association between epigenetic-related genes (ERGs), inflammatory response-related genes (IRRGs) and CRISPR genes was determined by merging genomic and CRISPR data. Further, characteristics of immune-cell infiltration in the tumor microenvironment was evaluated.ResultsNine differentially expressed genes (ANP32B, ASF1A, BCORL1, BMI1, BUB1, CBX2, CBX3, CDK1, and CDK5) were shown to be independent prognostic factors based on lasso regression in the TCGA-LIHC and ICGC databases. In addition, the results showed significant differences in expression of PDCD-1 (PD-1) and CTLA4 between the high- and low-epigenetic score groups. The CTRP and PRISM-derived drug response data yielded four CTRP-derived compounds (SB-743921, GSK461364, gemcitabine, and paclitaxel) and two PRISM-derived compounds (dolastatin-10 and LY2606368). Patients with high ERGs benefited more from immune checkpoint inhibitor (ICI) therapy than patients with low ERGs. In addition, the high ERGs subgroup had a higher T cell exclusion score, while the low ERGs subgroup had a higher T cell dysfunction. However, there was no difference in microsatellite instability (MSI) score among the two subgroups. Further, genome-wide CRISPR-based loss-of function screening derived from DepMap was conducted to determine key genes leading to HCC development and progression. In total, 640 genes were identified to be essential for survival in HCC cell lines. The protein-protein interaction (PPI) network demonstrated that IRRGs PSEN1 was linked to most ERGs and CRISPR genes such as CDK1, TOP2A, CBX2 and CBX3.ConclusionEpigenetic alterations of cancer-related genes in the tumor microenvironment play a major role in carcinogenesis. This study showed that epigenetic-related novel biomarkers could be useful in predicting prognosis, clinical diagnosis, and management in HCC.Zeng-Hong WuDong-Liang YangLiang WangJia LiuFrontiers Media S.A.articlehepatocellular carcinomaepigeneticinflammatory responseCRISPRTCGAImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	hepatocellular carcinoma epigenetic inflammatory response CRISPR TCGA Immunologic diseases. Allergy RC581-607
spellingShingle	hepatocellular carcinoma epigenetic inflammatory response CRISPR TCGA Immunologic diseases. Allergy RC581-607 Zeng-Hong Wu Dong-Liang Yang Liang Wang Jia Liu Epigenetic and Immune-Cell Infiltration Changes in the Tumor Microenvironment in Hepatocellular Carcinoma
description	BackgroundEpigenetics regulate gene expression without altering the DNA sequence. Epigenetics targeted chemotherapeutic approach can be used to overcome treatment resistance and low response rate in HCC. However, a comprehensive review of genomic data was carried out to determine the role of epigenesis in the tumor microenvironment (TME), immune cell-infiltration characteristics in HCC is still insufficient.MethodsThe association between epigenetic-related genes (ERGs), inflammatory response-related genes (IRRGs) and CRISPR genes was determined by merging genomic and CRISPR data. Further, characteristics of immune-cell infiltration in the tumor microenvironment was evaluated.ResultsNine differentially expressed genes (ANP32B, ASF1A, BCORL1, BMI1, BUB1, CBX2, CBX3, CDK1, and CDK5) were shown to be independent prognostic factors based on lasso regression in the TCGA-LIHC and ICGC databases. In addition, the results showed significant differences in expression of PDCD-1 (PD-1) and CTLA4 between the high- and low-epigenetic score groups. The CTRP and PRISM-derived drug response data yielded four CTRP-derived compounds (SB-743921, GSK461364, gemcitabine, and paclitaxel) and two PRISM-derived compounds (dolastatin-10 and LY2606368). Patients with high ERGs benefited more from immune checkpoint inhibitor (ICI) therapy than patients with low ERGs. In addition, the high ERGs subgroup had a higher T cell exclusion score, while the low ERGs subgroup had a higher T cell dysfunction. However, there was no difference in microsatellite instability (MSI) score among the two subgroups. Further, genome-wide CRISPR-based loss-of function screening derived from DepMap was conducted to determine key genes leading to HCC development and progression. In total, 640 genes were identified to be essential for survival in HCC cell lines. The protein-protein interaction (PPI) network demonstrated that IRRGs PSEN1 was linked to most ERGs and CRISPR genes such as CDK1, TOP2A, CBX2 and CBX3.ConclusionEpigenetic alterations of cancer-related genes in the tumor microenvironment play a major role in carcinogenesis. This study showed that epigenetic-related novel biomarkers could be useful in predicting prognosis, clinical diagnosis, and management in HCC.
format	article
author	Zeng-Hong Wu Dong-Liang Yang Liang Wang Jia Liu
author_facet	Zeng-Hong Wu Dong-Liang Yang Liang Wang Jia Liu
author_sort	Zeng-Hong Wu
title	Epigenetic and Immune-Cell Infiltration Changes in the Tumor Microenvironment in Hepatocellular Carcinoma
title_short	Epigenetic and Immune-Cell Infiltration Changes in the Tumor Microenvironment in Hepatocellular Carcinoma
title_full	Epigenetic and Immune-Cell Infiltration Changes in the Tumor Microenvironment in Hepatocellular Carcinoma
title_fullStr	Epigenetic and Immune-Cell Infiltration Changes in the Tumor Microenvironment in Hepatocellular Carcinoma
title_full_unstemmed	Epigenetic and Immune-Cell Infiltration Changes in the Tumor Microenvironment in Hepatocellular Carcinoma
title_sort	epigenetic and immune-cell infiltration changes in the tumor microenvironment in hepatocellular carcinoma
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/d7d3451611ad4bd2a0cb78a7fe90a363
work_keys_str_mv	AT zenghongwu epigeneticandimmunecellinfiltrationchangesinthetumormicroenvironmentinhepatocellularcarcinoma AT dongliangyang epigeneticandimmunecellinfiltrationchangesinthetumormicroenvironmentinhepatocellularcarcinoma AT liangwang epigeneticandimmunecellinfiltrationchangesinthetumormicroenvironmentinhepatocellularcarcinoma AT jialiu epigeneticandimmunecellinfiltrationchangesinthetumormicroenvironmentinhepatocellularcarcinoma
_version_	1718397206458793984

Epigenetic and Immune-Cell Infiltration Changes in the Tumor Microenvironment in Hepatocellular Carcinoma

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