Membrane IL1α Inhibits the Development of Hepatocellular Carcinoma via Promoting T- and NK-cell Activation

Lin, Dandan; Lei, Lei; Liu, Yonghao; Zhang, Yinsheng; Hu, Bo; Bao, Guolian; Song, Yuan; Jin, Ziqi; Liu, Chunliang; Yu, Man; Sandikin, Dedy; Wu, Yan; Zhao, Lixiang; Yu, Xiao; Liu, Haiyan

doi:10.1158/0008-5472.can-15-2658

Cited by 28 publications

(30 citation statements)

References 40 publications

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“…β3GnT8 gene was cloned from peripheral blood mononuclear cells (PBMCs) and then inserted into lentiviral vectors expressing yellow fluorescence protein (YFP) [ 38 ]. The β3GnT8-expressing-lentiviral vectors were packaged into 293T cells and used to transduce SK-Hep-1 and SMMC7721 cells.…”

Section: Methodsmentioning

confidence: 99%

c-Jun-dependent β3GnT8 promotes tumorigenesis and metastasis of hepatocellular carcinoma by inducing CD147 glycosylation and altering N-glycan patterns

et al. 2018

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β3GnT8, a key polylactosamine synthase, plays a vital role in progression of various types of human cancer. The role of β3GnT8 in hepatocellular carcinoma (HCC) and the underlying mechanisms, however, remain largely unknown. In this study, we found that β3GnT8 and polylactosamine were highly expressed in HCC tissues compared with those in adjacent paracancer tissues. Overexpression of β3GnT8 promoted while knockdown of β3GnT8 inhibited HCC cell invasion and migration in vitro. Importantly, enhanced tumorigenesis was observed in nude mice inoculated with β3GnT8-overexpressing HCC cells, suggesting that β3GnT8 is important for HCC development in vitro and in vivo. Mechanistically, β3GnT8 modulated the N-glycosylation patterns of CD147 and altered the polylactosamine structures in HCC cells by physically interacting with CD147. In addition, our data showed the c-Jun could directly bind to the promoter of β3GnT8 gene and regulate β3GnT8 expression. β3GnT8 regulated HCC cell invasion and migration in a C-Jun-dependent manner. Collectively, our study identified β3GnT8 as a novel regulator for HCC invasion and tumorigenesis. Targeting β3GnT8 may be a potential therapeutic strategy against HCC.

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Section: Methodsmentioning

confidence: 99%

c-Jun-dependent β3GnT8 promotes tumorigenesis and metastasis of hepatocellular carcinoma by inducing CD147 glycosylation and altering N-glycan patterns

et al. 2018

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“…To assess the effect of RBPJ deficiency on hepatic type 1 ILC function, we chose a model of hepatocellular carcinoma by injection a Hepa1–6 mouse liver cancer cell line. It was shown that cNK and T cells are important in the control of the tumors via IFNg and lytic granules ( 20 ). Three weeks after subcutaneous injection of Hepa1–6 cells, the area of the tumor was significantly increased in RBPJ-deficient mice compared with control mice (Figure 6 A).…”

Section: Resultsmentioning

confidence: 99%

The Notch Signaling Pathway Is Balancing Type 1 Innate Lymphoid Cell Immune Functions

et al. 2018

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The Notch pathway is one of the canonical signaling pathways implicated in the development of various solid tumors. During carcinogenesis, the Notch pathway dysregulation induces tumor expression of Notch receptor ligands participating to escape the immune surveillance. The Notch pathway conditions both the development and the functional regulation of lymphoid subsets. Its importance on T cell subset polarization has been documented contrary to its action on innate lymphoid cells (ILC). We aim to analyze the effect of the Notch pathway on type 1 ILC polarization and functions after disruption of the RBPJk-dependent Notch signaling cascade. Indeed, type 1 ILC comprises conventional NK (cNK) cells and type 1 helper innate lymphoid cells (ILC1) that share Notch-related functional characteristics such as the IFNg secretion downstream of T-bet expression. cNK cells have strong antitumor properties. However, data are controversial concerning ILC1 functions during carcinogenesis with models showing antitumoral capacities and others reporting ILC1 inability to control tumor growth. Using various mouse models of Notch signaling pathway depletion, we analyze the effects of its absence on type 1 ILC differentiation and cytotoxic functions. We also provide clues into its role in the maintenance of immune homeostasis in tissues. We show that modulating the Notch pathway is not only acting on tumor-specific T cell activity but also on ILC immune subset functions. Hence, our study uncovers the intrinsic Notch signaling pathway in ILC1/cNK populations and their response in case of abnormal Notch ligand expression. This study help evaluating the possible side effects mediated by immune cells different from T cells, in case of multivalent forms of the Notch receptor ligand delta 1 treatments. In definitive, it should help determining the best novel combination of therapeutic strategies in case of solid tumors.

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“…26 , 27 Studies have suggested that membrane IL1α is immunostimulatory and can promote antitumor immune responses including HCC through activation of T- and natural killer cells. 28 …”

Section: Introductionmentioning

confidence: 99%

IL-1α correlates with severity of hepatitis C virus-related liver diseases

Tawfik¹,

Amin²,

Yousef³

et al. 2018

JIR

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Background and aimsImmunoregulatory cytokines influence the persistence of hepatitis C virus (HCV) chronic infection and the extent of liver damage. Interleukin-1 (IL-1) plays an important role in the inflammatory process. Some studies have demonstrated that IL-1α production was impaired in patients with chronic infections of HCV, implying that IL-1α may play a role in viral clearance. The aim of this study was to evaluate the serum level of proinflammatory cytokine IL-1α in patients with chronic hepatitis C (CHC).MethodsThis study was performed on 20 CHC patients with cirrhosis in (Group I), 20 CHC patients without cirrhosis in (Group II), 20 hepatocellular carcinoma (HCC) patients with positive anti-HCV in (Group III), and 10 healthy subjects as a control group. Serum levels of IL-1α were measured by enzyme-linked immunoassay technique.ResultsIL-1α had the highest mean concentration in the HCC group and then in the group of CHC with cirrhosis compared to the group of CHC without cirrhosis. Also, it was higher in all studied groups than in the control group (P<0.001). Statistical analysis showed that IL-1α was positively correlated with bilirubin (P≤0.001), alanine aminotransferase (P=0.006), aspartate aminotransferase (P=0.001), and viral load (P=0.001) but it was negatively correlated with albumin (P≤0.001) and Hb (P≤0.001), and was not significantly correlated with other parameters (age, international normalized ratio, urea, creatinine, white blood cells, and platelet count).ConclusionSerum level of IL-1α was elevated in patients with CHC and its related liver diseases (liver cirrhosis and HCC) and can be used as an important parameter of inflammatory activity and for fibrosis evaluation in patients with chronic liver disease.

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Membrane IL1α Inhibits the Development of Hepatocellular Carcinoma via Promoting T- and NK-cell Activation

Cited by 28 publications

References 40 publications

c-Jun-dependent β3GnT8 promotes tumorigenesis and metastasis of hepatocellular carcinoma by inducing CD147 glycosylation and altering N-glycan patterns

c-Jun-dependent β3GnT8 promotes tumorigenesis and metastasis of hepatocellular carcinoma by inducing CD147 glycosylation and altering N-glycan patterns

The Notch Signaling Pathway Is Balancing Type 1 Innate Lymphoid Cell Immune Functions

IL-1α correlates with severity of hepatitis C virus-related liver diseases

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Membrane IL1α Inhibits the Development of Hepatocellular Carcinoma via Promoting T- and NK-cell Activation

Cited by 28 publications

References 40 publications

c-Jun-dependent β3GnT8 promotes tumorigenesis and metastasis of hepatocellular carcinoma by inducing CD147 glycosylation and altering N-glycan patterns

c-Jun-dependent β3GnT8 promotes tumorigenesis and metastasis of hepatocellular carcinoma by inducing CD147 glycosylation and altering N-glycan patterns

The Notch Signaling Pathway Is Balancing Type 1 Innate Lymphoid Cell Immune Functions

IL-1&alpha; correlates with severity of hepatitis C virus-related liver diseases

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IL-1α correlates with severity of hepatitis C virus-related liver diseases