Common Transcriptional Signature of Tumor-Infiltrating Mononuclear Inflammatory Cells and Peripheral Blood Mononuclear Cells in Hepatocellular Carcinoma Patients

Abstract

Hepatocellular carcinoma (HCC) is frequently associated with infiltrating mononuclear inflammatory cells. We performed laser capture microdissection of HCC-infiltrating and noncancerous liver-infiltrating mononuclear inflammatory cells in patients with chronic hepatitis C (CH-C) and examined gene expression profiles. HCC-infiltrating mononuclear inflammatory cells had an expression profile distinct from noncancerous liver-infiltrating mononuclear inflammatory cells; they differed with regard to genes involved in biological processes, such as antigen presentation, ubiquitin-proteasomal proteolysis, and responses to hypoxia and oxidative stress. Immunohistochemical analysis and gene expression databases suggested that the up-regulated genes involved macrophages and Th1 and Th2 CD4 cells. We next examined the gene expression profile of peripheral blood mononuclear cells (PBMC) obtained from CH-C patients with or without HCC. The expression profiles of PBMCs from patients with HCC differed significantly from those of patients without HCC (P < 0.0005). Many of the up-regulated genes in HCCinfiltrating mononuclear inflammatory cells were also differentially expressed by PBMCs of HCC patients. Analysis of the commonly up-regulated or down-regulated genes in HCCinfiltrating mononuclear inflammatory cells and PBMCs of HCC patients showed networks of nucleophosmin, SMAD3, and proliferating cell nuclear antigen that are involved with redox status, the cell cycle, and the proteasome system, along with immunologic genes, suggesting regulation of anticancer immunity. Thus, exploring the gene expression profile of PBMCs may be a surrogate approach for the assessment of local HCC-infiltrating mononuclear inflammatory cells.

Association of Interleukin-28B Genotype and Hepatocellular Carcinoma Recurrence in Patients with Chronic Hepatitis C

“…Immunohistochemical analysis showed intratumoral infiltration of CD4 þ and CD8 þ lymphoid cells and slight infiltration of monocytes/macrophages in HCC of the IL-28B TG/GG genotype, compared with little infiltration of lymphocytes or monocytes/macrophages in HCC of the IL-28B TT genotype. Furthermore, the gene set differentially expressed in HCC-infiltrating mononuclear inflammatory cells from our previous study (24) was upregulated in HCC of the IL-28B TG/GG genotype (Z score, À9.879; P < 0.001). One-way hierarchical clustering was carried out of 122 genes involved in the gene set differentially expressed in HCC-infiltrating Fig.…”

“…We also investigated the gene set differentially expressed HCC-infiltrating mononuclear inflammatory cells studied previously (24). Z scores and P values of all gene sets were calculated using the PGSEA package and an estimate was made as to whether certain gene sets, and therefore functional gene categories, were differentially regulated in HCC tissue from patients with the IL-28B TT genotype and the IL-28B TG/GG genotype.…”

Separate enrichment analysis of pathways for up- and downregulated genes

“…Notably, many researchers often refer to the KEGG pathways that are enriched for up-or downregulated genes as activating or inhibiting pathways [19,43]. However, considering a KEGG pathway as an activating or inhibiting pathway based only on its enrichment for up-or downregulated genes may be inappropriate [44].…”

Macrophage Polarization at the Crossroad Between HIV-1 Infection and Cancer Development

“…72,81,82 In particular, TAM represent variants of a general M2-polarization phenotype based on the expression of a series of markers, such as CD163, the R for Fc fragment of IgG, C-type lectin domain proteins, and heat shock proteins characteristically expressed by alternatively activated macrophages. [83][84][85] In addition, the tumor microenvironment is characterized by the presence of several anti-inflammatory cytokines, such as IL-4, IL-10, IL-13, and transforming growth factor-β, that lead resident or recently migrated macrophages to adopt an M2-phenotype. 86 In addition to growth factors, cytokines, and chemokines, TAM (M2) express molecules, which affect tumor cell proliferation, angiogenesis, and dissolution of connective tissues, such as matrix metallo-proteinases, thus contributing to matrix degradation needed for promoting angiogenesis and release of growth factors, 87 plasmin, and urokinasetype plasminogen activator and its receptors urokinase-type plasminogen activator receptor.…”