DUSP12 regulates the tumorigenesis and prognosis of hepatocellular carcinoma

Background Dual specificity protein phosphatase (DUSP)12 is an atypical member of the protein tyrosine phosphatase family, which are overexpressed in multiple types of malignant tumors. This protein family protect cells from apoptosis and promotes the proliferation and motility of cells. However, the pathological role of DUSP12 in hepatocellular carcinoma (HCC) is incompletely understood. Methods We analyzed mRNA expression of DUSP12 between HCC and normal liver tissues using multiple online databases, and explored the status of DUSP12 mutants using the cBioPortal database. The correlation between DUSP12 expression and tumor-infiltrating immune cells was demonstrated using the Tumor Immune Estimation Resource database and the Tumor and Immune System Interaction Database. Loss of function assay was utilized to evaluate the role of DUSP12 in HCC progression. Results DUSP12 had higher expression along with mRNA amplification in HCC tissues compared with those in normal liver tissues, which suggested that higher DUSP12 expression predicted shorter overall survival. Analyses of functional enrichment of differentially expressed genes suggested that DUSP12 regulated HCC tumorigenesis, and that knockdown of DUSP12 expression by short hairpin (sh)RNA decreased the proliferation and migration of HCC cells. Besides, DUSP12 expression was positively associated with the infiltration of cluster of differentiation (CD)4+ T cells (especially CD4+ regulatory T cells), macrophages, neutrophils and dendritic cells. DUSP12 expression was positively associated with immune-checkpoint moieties, and was downregulated in a C3 immune-subgroup of HCC (which had the longest survival). Conclusion These data suggest that DUSP12 may have a critical role in the tumorigenesis, infiltration of immune cells, and prognosis of HCC.

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

BioMed Research International ◽

10.1155/2019/2408348 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 7

Author(s):

Zhenfeng Deng ◽

Jilong Wang ◽

Banghao Xu ◽

Zongrui Jin ◽

Guolin Wu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Microenvironment ◽

Immune Cells ◽

Malignant Tumors ◽

Public Access ◽

The Cancer Genome Atlas ◽

Functional Enrichment ◽

Protein Protein Interaction ◽

Potential Association ◽

Poor Outcomes

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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LNCAROD enhances hepatocellular carcinoma malignancy by activating glycolysis through induction of pyruvate kinase isoform PKM2

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-02090-7 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Guizhi Jia ◽

Yan Wang ◽

Chengjie Lin ◽

Shihui Lai ◽

Hongliang Dai ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Pyruvate Kinase ◽

Cancer Cell ◽

Malignant Tumors ◽

Aerobic Glycolysis ◽

Cell Counting ◽

Loss Of Function ◽

Rna Immunoprecipitation

Abstract Background Mounting evidence has suggested the essential role of long non-coding RNAs (lncRNAs) in a plethora of malignant tumors, including hepatocellular carcinoma. However, the underlyling mechanisms of lncRNAs remain unidentified in HCC. The present work was aimed to explore the regulatory functions and mechanisms of LncRNA LNCAROD in HCC progression and chemotherapeutic response. Methods The expression of LNCAROD in HCC tissues and cell lines were detected by quantitative reverse transcription PCR (qPCR). Cancer cell proliferation, migration, invasion, and chemoresistance were evaluated by cell counting kit 8 (CCK8), colony formation, transwell, and chemosensitivity assays. Methylated RNA immunoprecipitation qRCR (MeRIP-qPCR) was used to determine N6-methyladenosine (m6A) modification level. RNA immunoprecipitation (RIP) and RNA pull down were applied to identify the molecular sponge role of LNCAROD for modulation of miR-145-5p via the competing endogenous RNA (ceRNA) mechanism, as well as the interaction between LNCAROD and serine-and arginine-rich splicing factor 3 (SRSF3). The interaction between insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) and LNCAROD was also identified by RIP assay. Gain- or-loss-of-function assays were used to identify the function and underlying mechanisms of LNCAROD in HCC. Results We found that LNCAROD was significantly upregulated and predicted a poorer prognosis in HCC patients. LNCAROD upregulation was maintained by increased m6A methylation-mediated RNA stability. LNCAROD significantly promoted HCC cell proliferation, migration, invasion, and chemoresistance both in vitro and in vivo. Furthermore, mechanistic studies revealed that pyruvate kinase isoform M2 (PKM2)-mediated glycolysis enhancement is critical for the role of LNACROD in HCC. According to bioinformatics prediction and our experimental data, LNCAROD directly binds to SRSF3 to induce PKM switching towards PKM2 and maintains PKM2 levels in HCC by acting as a ceRNA against miR-145-5p. The oncogenic effects of LNCAROD in HCC were more prominent under hypoxia than normoxia due to the upregulation of hypoxia-triggered hypoxia-inducible factor 1α. Conclusions In summary, our present study suggests that LNCAROD induces PKM2 upregulation via simultaneously enhancing SRSF3-mediated PKM switching to PKM2 and sponging miR-145-5p to increase PKM2 level, eventually increasing cancer cell aerobic glycolysis to participate in tumor malignancy and chemoresistance, especially under hypoxic microenvironment. This study provides a promising diagnostic marker and therapeutic target for HCC patients.

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Role of Immune Cells in Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms22158011 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8011

Author(s):

Hyo-Jung Cho ◽

Jae-Youn Cheong

Keyword(s):

Hepatocellular Carcinoma ◽

T Cells ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Chronic Inflammation ◽

Cd8 T Cells ◽

Immune Cells ◽

Adaptive Immune ◽

B Virus

Hepatocellular carcinoma (HCC) develops almost entirely in the presence of chronic inflammation. Chronic hepatitis B virus (HBV) infection with recurrent immune-mediated liver damage ultimately leads to cirrhosis and HCC. It is widely accepted that HBV infection induces the dysfunction of the innate and adaptive immune responses that engage various immune cells. Natural killer (NK) cells are associated with early antiviral and antitumor properties. On the other hand, inflammatory cells release various cytokines and chemokines that may promote HCC tumorigenesis. Moreover, immunosuppressive cells such as regulatory T cells (Treg) and myeloid-derived suppressive cells play a critical role in hepatocarcinogenesis. HBV-specific CD8+ T cells have been identified as pivotal players in antiviral responses, whilst extremely activated CD8+ T cells induce enormous inflammatory responses, and chronic inflammation can facilitate hepatocarcinogenesis. Controlling and maintaining the balance in the immune system is an important aspect in the management of HBV-related HCC. We conducted a review of the current knowledge on the immunopathogenesis of HBV-induced inflammation and the role of such immune activation in the tumorigenesis of HCC based on the recent studies on innate and adaptive immune cell dysfunction in HBV-related HCC.

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Immune Cells in Cancer Therapy and Drug Delivery

Mediators of Inflammation ◽

10.1155/2016/5230219 ◽

2016 ◽

Vol 2016 ◽

pp. 1-13 ◽

Cited By ~ 18

Author(s):

Ceren Eyileten ◽

Kinga Majchrzak ◽

Zofia Pilch ◽

Katarzyna Tonecka ◽

Joanna Mucha ◽

...

Keyword(s):

Drug Delivery ◽

Cell Proliferation ◽

T Cells ◽

Dendritic Cells ◽

Immune Cells ◽

Critical Role ◽

Tumour Microenvironment ◽

Cytokines And Chemokines

Recent studies indicate the critical role of tumour associated macrophages, tumour associated neutrophils, dendritic cells, T lymphocytes, and natural killer cells in tumourigenesis. These cells can have a significant impact on the tumour microenvironment via their production of cytokines and chemokines. Additionally, products secreted from all these cells have defined specific roles in regulating tumour cell proliferation, angiogenesis, and metastasis. They act in a protumour capacityin vivoas evidenced by the recent studies indicating that macrophages, T cells, and neutrophils may be manipulated to exhibit cytotoxic activity against tumours. Therefore therapy targeting these cells may be promising, or they may constitute drug or anticancer particles delivery systems to the tumours. Herein, we discussed all these possibilities that may be used in cancer treatment.

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Integrated Bioinformatics Analysis Identifies Heat Shock Factor 2 as a Prognostic Biomarker Associated With Immune Cell Infiltration in Hepatocellular Carcinoma

Frontiers in Genetics ◽

10.3389/fgene.2021.668516 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yumei Fan ◽

Jiajie Hou ◽

Xiaopeng Liu ◽

Bihui Han ◽

Yanxiu Meng ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Heat Shock ◽

Immune Cells ◽

Immune Cell ◽

Cox Regression ◽

Critical Role ◽

Enrichment Analysis ◽

Normal Liver ◽

Heat Shock Factor ◽

Gene Set Enrichment Analysis

Hepatocellular carcinoma (HCC) is one of the most common malignancies and ranks as the second leading cause of cancer-related mortality worldwide. Heat shock factor 2 (HSF2) is a transcription factor that plays a critical role in development, particularly corticogenesis and spermatogenesis. However, studies examining the expression and prognostic value of HSF2 and its association with tumor-infiltrating immune cells in HCC are still rare. In the present study, we found that HSF2 expression was significantly upregulated in HCC tissues compared with normal liver tissues using the TCGA, ICGC, GEO, UALCAN, HCCDB and HPA databases. High HSF2 expression was associated with shorter survival of patients with HCC. Cox regression analyses and nomogram were used to evaluate the association of HSF2 expression with the prognosis of patients with HCC. Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and gene set enrichment analysis (GSEA) revealed that HSF2 was associated with various signaling pathways, including the immune response. Notably, HSF2 expression was significantly correlated with the infiltration levels of different immune cells using the TIMER database and CIBERSORT algorithm. HSF2 expression also displayed a significant correlation with multiple immune marker sets in HCC tissues. Knockdown of HSF2 significantly inhibited the proliferation, migration, invasion and colony formation ability of HCC cells. In summary, we explored the clinical significance of HSF2 and provided a therapeutic basis for the early diagnosis, prognostic judgment, and immunotherapy of HCC.

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157 A critical role of CD40 and CD70 signaling in cDC1s in expansion and antitumor efficacy of adoptively transferred tumor-specific T cells

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0157 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A171-A171

Author(s):

Takaaki Oba ◽

Toshifumi Hoki ◽

Takayoshi Yamauchi ◽

Tibor Keler ◽

Henry Marsh ◽

...

Keyword(s):

T Cells ◽

Adoptive Cell Therapy ◽

Critical Role ◽

Flow Cytometric Analysis ◽

Antitumor Efficacy ◽

Tumor Control ◽

Type I ◽

Loss Of Function

BackgroundAdoptive cell therapy (ACT) with antigen-specific CD8+ T cells is a promising approach for treating patients with various solid malignancies including melanoma. In vivo expansion of adoptively transferred T cells is one of the major determinants of successful ACT. On the other hand, a frequently overlooked consideration is that the host antigen-presenting cells affect the antitumor efficacy of ACT. Accumulating evidence suggests that tumor-residing Batf3-dependent conventional type I dendritic cells (cDC1s) play an important role in trafficking of adoptively transferred T cells into the tumor by producing chemokines such as CXCL10, and improve antitumor efficacy of ACT. However, a role of cDC1s in expansion of adoptively transferred T cells remains unclear.MethodsWe utilized Pmel-1 T cell receptor transgenic T cells in the B16 melanoma model to investigate the role of cDC1s in expansion of adoptively transferred tumor-specific T cells.ResultsWhile adoptive transfer of in vitro-activated Pmel-1 T cells with vaccination of cognate antigen, hgp100, agonistic anti-CD40 monoclonal antibody (mAb), and Toll-like receptor 7 (TLR7) agonist delayed the tumor growth and survival in wild type C57BL/6 mice (WT), antitumor efficacy of ACT was completely abrogated in Batf3-/- mice. Flow cytometric analysis of peripheral blood showed expansion of adoptively transferred Pmel-1 T cells was significantly compromised in WT mice but not in in Batf3-/- mice. Mechanistically, loss-of-function studies using mixed bone marrow chimera reconstituted with Batf3-/- and CD40-/- (Batf3-/-/CD40-/-), Batf3-/- and CD70-/- (Batf3-/-/CD70-/-), or Batf3-/- and CD80/86-/- (Batf3-/-/CD80/86-/-) revealed CD40-CD70 axis but not CD80/86 signaling in host cDC1s plays an important role in expansion of adoptively transferred T cells. Accordingly, overall survival of Batf3-/-/CD70-/- mixed chimeric was significantly shorter than that of Batf3-/-/WT mice, while survival of Batf3-/-/CD80/86-/- mice was similar to that of Batf3-/-/WT mice. Furthermore, induction of cDC1s by administration of Fms-like tyrosine kinase 3 receptor ligand (gain-of-function) demonstrated significantly enhanced in vivo expansion of adoptively transferred Pmel-1 T cells associated with improved tumor control and survival.ConclusionsThese findings elucidate a role of host cDC1s in expansion of adoptively transferred in vivo restimulated tumor-specific T cells, and identify CD40 and CD70 as key molecules.

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Identification of Prognostic Stromal-Immune Score–Based Genes in Hepatocellular Carcinoma Microenvironment

Frontiers in Genetics ◽

10.3389/fgene.2021.625236 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shanshan Liu ◽

Guangchuang Yu ◽

Li Liu ◽

Xuejing Zou ◽

Lang Zhou ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Cancer ◽

Immune Cells ◽

Malignant Tumors ◽

Clinical Importance ◽

Enrichment Analysis ◽

Functional Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Functional Enrichment ◽

Immune Score

A growing amount of evidence has suggested the clinical importance of stromal and immune cells in the liver cancer microenvironment. However, reliable prognostic signatures based on assessments of stromal and immune components have not been well-established. This study aimed to identify stromal-immune score–based potential prognostic biomarkers for hepatocellular carcinoma. Stromal and immune scores were estimated from transcriptomic profiles of a liver cancer cohort from The Cancer Genome Atlas using the ESTIMATE (Estimation of STromal and Immune cells in MAlignant Tumors using Expression data) algorithm. Least absolute shrinkage and selection operator (LASSO) algorithm was applied to select prognostic genes. Favorable overall survivals and progression-free interval were found in patients with high stromal score and immune score, and 828 differentially expressed genes were identified. Functional enrichment analysis and protein–protein interaction networks further showed that these genes mainly participated in immune response, extracellular matrix, and cell adhesion. MMP9 (matrix metallopeptidase 9) was identified as a prognostic tumor microenvironment–associated gene by using LASSO and TIMER (Tumor IMmune Estimation Resource) algorithms and was found to be positively correlated with immunosuppressive molecules and drug response.

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Differential Immune Landscape of Hepatocellular Carcinoma Suggests Potential role of Macrophages in Hepatocarcinogenesis

Pakistan Journal of Medical Sciences ◽

10.12669/pjms.37.3.2973 ◽

2021 ◽

Vol 37 (3) ◽

Author(s):

Yusra Shafique ◽

Muhammad Asif Qureshi ◽

Saeed Khan ◽

Talat Mirza

Keyword(s):

Hepatocellular Carcinoma ◽

T Cells ◽

B Cells ◽

Cd8 T Cells ◽

Immune Cells ◽

Cd4 T Cells ◽

Potential Role ◽

Immune Cell ◽

P Value

Objectives: To investigate immune cell densities in tumor microenvironment of hepatocellular carcinoma. Methods: This cross-sectional study was conducted during 2017-2019 at the Dow University of Health Sciences Karachi. A total of 42 subsequent patients undergoing liver biopsy/resection and diagnosed with hepatocellular carcinoma were included in the study. Moreover, a total of 10 control tissues were also included. In order to investigate immune cells densities in hepatocellular carcinoma, immunohistochemistry was performed using antibodies including α-MPO(neutrophils), α-CD-68(macrophages), α-CD-3(T-cells), α-CD-20(B-cells), α-CD-4(CD4+ T-cells) and α-CD-8(CD8+ T-cells). Quantification of immune cells/mm2 was performed as per the College of American Pathologists’ guidelines. Data were analyzed using SPSS version 21. A p-value of 0.05 was considered significant at all times. Results: We report significantly increased infiltration of macrophages (mean macrophages= 306.57/mm2, p-value<0.05), moderately significant infiltration of neutrophils (p-value=0.06) and B-cells (p-value=0.07) while no significant infiltration of CD4+T-cells (p- value=0.31), and CD8+T-cells (p-value=0.39) in tumour microenvironment of patients with hepatocellular carcinoma. Conclusion: We provide evidence for increased macrophage infiltration in liver cancer microenvironment suggesting a potential role of these cells in hepatocarcinogenesis. doi: https://doi.org/10.12669/pjms.37.3.2973 How to cite this:Shafique Y, Qureshi MA, Khan S, Mirza T. Differential Immune Landscape of Hepatocellular Carcinoma Suggests Potential role of Macrophages in Hepatocarcinogenesis. Pak J Med Sci. 2021;37(3):---------. doi: https://doi.org/10.12669/pjms.37.3.2973 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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The Role of Distinct Subsets of Macrophages in the Pathogenesis of MS and the Impact of Different Therapeutic Agents on These Populations

Frontiers in Immunology ◽

10.3389/fimmu.2021.667705 ◽

2021 ◽

Vol 12 ◽

Author(s):

Maedeh Radandish ◽

Parvin Khalilian ◽

Nafiseh Esmaeil

Keyword(s):

T Cells ◽

Immune Cells ◽

Inflammatory Responses ◽

Critical Role ◽

Myeloid Cell ◽

Therapeutic Agents ◽

Vital Role ◽

Inflammatory Disorder ◽

The Impact

Multiple sclerosis (MS) is a demyelinating inflammatory disorder of the central nervous system (CNS). Besides the vital role of T cells, other immune cells, including B cells, innate immune cells, and macrophages (MФs), also play a critical role in MS pathogenesis. Tissue-resident MФs in the brain’s parenchyma, known as microglia and monocyte-derived MФs, enter into the CNS following alterations in CNS homeostasis that induce inflammatory responses in MS. Although the neuroprotective and anti-inflammatory actions of monocyte-derived MФs and resident MФs are required to maintain CNS tolerance, they can release inflammatory cytokines and reactivate primed T cells during neuroinflammation. In the CNS of MS patients, elevated myeloid cells and activated MФs have been found and associated with demyelination and axonal loss. Thus, according to the role of MФs in neuroinflammation, they have attracted attention as a therapeutic target. Also, due to their different origin, location, and turnover, other strategies may require to target the various myeloid cell populations. Here we review the role of distinct subsets of MФs in the pathogenesis of MS and different therapeutic agents that target these cells.

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AGTRAP Is a Prognostic Biomarker Correlated With Immune Infiltration in Hepatocellular Carcinoma

Frontiers in Oncology ◽

10.3389/fonc.2021.713017 ◽

2021 ◽

Vol 11 ◽

Author(s):

Shanshan Liu ◽

Wei Zhao ◽

Xuemei Li ◽

La Zhang ◽

Yu Gao ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

T Cells ◽

T Cell ◽

Normal Liver ◽

Mrna Levels ◽

T Cell Exhaustion ◽

Cell Exhaustion ◽

Immune Infiltration ◽

Protein Levels ◽

Liver Tissues

BackgroundRecently, it has been reported that angiotensin II receptor-associated protein (AGTRAP) plays a substantial role in tumor progression. Nevertheless, the possible role of AGTRAP in hepatocellular carcinoma (HCC) remains unrecognized.MethodsThe metabolic gene rapid visualizer, Cancer Cell Line Encyclopedia, Human Protein Atlas, and Hepatocellular Carcinoma Database were used to analyze the expression of AGTRAP in HCC tissues and normal liver tissues or adjacent tissues. Kaplan-Meier plotter and UALCAN analysis were used to assess the prognostic and diagnostic value of AGTRAP. LinkedOmics and cBioPortal were used to explore the genes co-expressed with AGTRAP in HCC. To further understand the potential mechanism of AGTRAP in HCC, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment pathway analyses were performed using R software, the protein-protein interaction (PPI) network was established using the STRING database, and the immune infiltration and T-cell exhaustion related to AGTRAP were explored via Timer and GEPIA. In addition, immunohistochemistry was used to detect the expression of AGTRAP protein in HCC tissues and paired adjacent tissues from clinical specimens.ResultsThis study found that the mRNA and protein levels of AGTRAP in HCC tissues were higher than those in normal liver tissues and adjacent tissues, and higher mRNA levels of AGTRAP were associated with higher histological grade and a poor overall survival in HCC patients. The area under the receiver operating characteristic curve (AUC) of AGTRAP was 0.856, suggesting that it could be a diagnostic marker for HCC. Moreover, the alteration rate of AGTRAP in HCC was 8%, and AGTRAP was involved in HCC probably through the NF-κB and MAPK signaling pathways. Furthermore, AGTRAP was positively correlated with the infiltration of CD8+ T cells, CD4+ T cells, B cells, macrophages, dendritic cells, and neutrophils, and the levels of AGTRAP were significantly correlated with T-cell exhaustion biomarkers. The immunohistochemistry results confirmed that the protein levels of AGTRAP were consistently higher in HCC tissues than in paired adjacent tissues.ConclusionThe clinical value of AGTRAP and its correlation with immune infiltration in HCC was effectively identified in clinical data from multiple recognized databases. These findings indicate that AGTRAP could serve as a potential biomarker in the treatment of HCC, thereby informing its prognosis, diagnosis, and even immunotherapy.

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