Inflammatory microenvironment and expression of chemokines in hepatocellular carcinoma

Han, Ke-Qi; He, Xue-Qun; Ma, Mengyu; Guo, Xiaodong; Zhang, Xuemin; Chen, Jie; Han, Hui; Zhang, Weiwei; Zhu, Quangang; Ni, Hua; Ma, Lijun

doi:10.3748/wjg.v21.i16.4864

Cited by 26 publications

(22 citation statements)

References 40 publications

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“…Furthermore, it is worth pointing out that CCL2, a chemokine considered to be a central coordinator of hepatocyte-mediated inflammation, 38 showed decreased expression in DEGFR tumors. Finally, CXCL1, considered a critical player in both inflammation and tumor growth in HCC, 39 presented significantly decreased mRNA levels in DEGFR tumoral and nontumoral areas. Regardless of the mechanism and considering together our results and others in the literature, there is no doubt that one of the most essential functions of the EGFR pathway during hepatocarcinogesis should be regulation of inflammation addressed by parenchymal and/or nonparenchymal cells.…”

Section: Discussionmentioning

confidence: 97%

Dissecting the role of epidermal growth factor receptor catalytic activity during liver regeneration and hepatocarcinogenesis

et al. 2015

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Different data support a role for the epidermal growth factor receptor (EGFR) pathway during liver regeneration and hepatocarcinogenesis. However, important issues, such as the precise mechanisms mediating its actions and the unique versus redundant functions, have not been fully defined. Here, we present a novel transgenic mouse model expressing a hepatocyte-specific truncated form of human EGFR, which acts as negative dominant mutant (DEGFR) and allows definition of its tyrosine kinase-dependent functions. Results indicate a critical role for EGFR catalytic activity during the early stages of liver regeneration. Thus, after two-thirds partial hepatectomy, DEGFR livers displayed lower and delayed proliferation and lower activation of proliferative signals, which correlated with overactivation of the transforming growth factor-b pathway. Altered regenerative response was associated with amplification of cytostatic effects of transforming growth factor-b through induction of cell cycle negative regulators. Interestingly, lipid synthesis was severely inhibited in DEGFR livers after partial hepatectomy, revealing a new function for EGFR kinase activity as a lipid metabolism regulator in regenerating hepatocytes. In spite of these profound alterations, DEGFR livers were able to recover liver mass by overactivating compensatory signals, such as c-Met. Our results also indicate that EGFR catalytic activity is critical in the early preneoplastic stages of the liver because DEGFR mice showed a delay in the appearance of diethyl-nitrosamine-induced tumors, which correlated with decreased proliferation and delay in the diethyl-nitrosamine-induced inflammatory process. Conclusion: These studies demonstrate that EGFR catalytic activity is critical during the initial phases of both liver regeneration and carcinogenesis and provide key mechanistic insights into how this kinase acts to regulate liver pathophysiology. (HEPATOLOGY 2016;63:604-619) See Editorial on Page 371 T he liver is a unique organ in displaying reparative response and regenerative capacity. However, prolonged liver regeneration as a consequence of Abbreviations: DEN, diethyl-nitrosamine; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; HCC, hepatocellular carcinoma; HGF, hepatocyte growth factor; mRNA, messenger RNA; NADPH, reduced nicotinamide adenine dinucleotide phosphate; PH, partial hepatectomy; qRT-PCR, quantitative reverse-transcriptase polymerase chain reaction; TGF-a/-b, transforming growth factor (a/b); TNF-a, tumor necrosis factor-a; uPA, urokinase-type plasminogen activator; WT, wild type.From the

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Section: Discussionmentioning

confidence: 97%

Dissecting the role of epidermal growth factor receptor catalytic activity during liver regeneration and hepatocarcinogenesis

et al. 2015

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“…the carcinogenesis and progression of HCC (8,19,20). IL-32 is known as a pro-inflammatory cytokine since it enhances the production of IL-1β and TNFα (11,21).…”

Section: Discussionmentioning

confidence: 99%

“…A progressive increase in HCC-related mortality has been observed in the US and Western Europe (5)(6)(7). Accumulating evidence has revealed that inflammatory-related cytokines participate in the carcinogenesis and progression of HCC (8). Research has revealed that higher expression of interleukin-32 (IL-32), a novel pro-inflammatory cytokine, is detected in HCC (9).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of interleukin-32α promotes invasion by modulating VEGF in hepatocellular carcinoma

Zhao

Wang²,

Yang

et al. 2017

Oncol Rep

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Interleukin-32α (IL-32α) was reported to exhibit pluripotent pro-inflammatory properties. Recent studies indicate that it promotes the migration and invasion of cancers. We detected the expression of IL-32 in hepatocellular carcinoma (HCC) tissues and investigated its role in tumor angiogenesis and invasion. IL-32α expression in HCC was evaluated by real-time PCR, western blot analysis and immunohistochemical (IHC) staining. Secreted serum IL-32α and VEGF concentrations were detected using a custom-made sandwich ELISA. Furthermore, IL-32α was knocked down in HCC cell lines using siRNA and the cell migration and invasion abilities were assessed. IHC staining showed that IL32α-positive particles were mainly located in the cytoplasm of cancer cells, and it was significantly upregulated in the tumor tissues compared with that in peritumoral tissues. Notably, IL-32α was strongly expressed in perivascular areas. The mean serum concentration of IL-32α in HCC patients was significantly higher than that in the control group (571.45±102.28 vs. 144.60±51.172 pg/ml; P<0.01). Real-time RT-PCR showed that IL-32α mRNA was significantly overexpressed in HCC tumor tissues (IL-32/β-actin, 15.59±7.8 vs. 3.37±0.47; P<0.01). The in vitro results indicated that IL-32α knockdown inhibited the activation of VEGF-STAT3 signaling in HCC tumor cell lines. IL-32α expression was correlated with clinical relevance in HCC tumor tissues. It is strongly suggested that IL-32α may be a potential predictor of anti-angiogenesis therapy and prognosis of HCC.

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“…Meanwhile, we also found perforin deficiency increased IFN-g secretion in CD8 T cells, which may also contribute to the polarization of monocytes to the M1 phenotype. Moreover, compared with hepatic CD8 T cells from the WT group fed the MCD diet, CD8 T cells from the steatotic livers of Prf1 null mice express genes associated with the recruitment of monocytes such as CXCL3 at high levels; CXCL3 was reported to be involved in monocyte recruitment in the inflammatory microenvironment (25,26). Thus, perforin regulated monocyte accumulation and inhibited the monocyte-induced inflammation in the liver mainly through CD8 T cells during NASH development.…”

Section: Discussionmentioning

confidence: 99%

The immunoregulatory effects of CD8 T‐cell–derived perforin on diet‐induced nonalcoholic steatohepatitis

et al. 2019

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The liver is a central immunologic organ with a high density of myeloid and lymphoid immune cells that play important roles in the development and progression of nonalcoholic steatohepatitis (NASH). However, the immune‐cell–mediated regulation of NASH and its underlying mechanisms remain obscure. In this study, Prf1null mice showed significantly higher plasma alanine transaminase levels, with increased liver fat accumulation, lobular inflammation, and focal necrosis compared with wild‐type (WT) mice after 4 wk of feeding on a methionine‐ and choline‐deficient diet (MCD) or 16 wk of feeding on a high‐fat diet. Perforin deficiency promoted the M1 polarization of infiltrated monocytes. Moreover, MCD‐fed Prf1null mice exhibited increased accumulation, survival, activation, and proinflammatory cytokine production of CD8 T cells but not NK cells or CD4 T cells. Adoptive transfer of CD8 T cells or NK cells from WT or Prf1null mice, together with non‐CD8 cells or non‐NK cells from WT mice, indicated that CD8 T‐cell–derived perforin participates in the mechanism regulating liver inflammation and thus plays a protective role in the development of NASH. Perforin‐deficient CD8 T cells exhibited decreased cytotoxicity toward bone marrow‐derived M1 monocytes and macrophages. According to the RNA sequencing data, the perforin deficiency inhibited cell apoptosis and enhanced the activation, migration, and proinflammatory cytokine production of CD8 T cells in mice with NASH. Furthermore, we found higher plasma soluble perforin levels and hepatic perforin expression in NASH patients, suggesting clinical relevance of the findings. We have elucidated an important role for the cytotoxic immune effector molecule perforin from CD8 T cells in restricting hepatic inflammation in mice with NASH and suggest that therapies designed to maximize the function of endogenous perforin in CD8 T cells might have potential benefits as NASH treatments.—Wang, T., Sun, G., Wang, Y., Li, S., Zhao, X., Zhang, C., Jin, H., Tian, D., Liu, K., Shi, W., Tian, Y., Zhang, D. The immunoregulatory effects of CD8 T‐cell–derived perforin on diet‐induced nonalcoholic steatohepatitis. FASEB J. 33, 8490–8503 (2019). http://www.fasebj.org

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Inflammatory microenvironment and expression of chemokines in hepatocellular carcinoma

Abstract: These findings suggest that CXCL1 plays a critical role in tumor growth and may serve as a potential molecular target for use in HCC therapy.

Cited by 26 publications

References 40 publications

Dissecting the role of epidermal growth factor receptor catalytic activity during liver regeneration and hepatocarcinogenesis

Dissecting the role of epidermal growth factor receptor catalytic activity during liver regeneration and hepatocarcinogenesis

Overexpression of interleukin-32α promotes invasion by modulating VEGF in hepatocellular carcinoma

The immunoregulatory effects of CD8 T‐cell–derived perforin on diet‐induced nonalcoholic steatohepatitis

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