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Innate immune sensor laboratory of genetics and physiology 2 suppresses tumor cell growth and functions as a prognostic marker in neuroblastoma.

ABSTRACT: The innate immune receptors, such as toll-like receptor 3 (TLR3), melanoma differentiation-associated 5 (MDA5) and retinoic acid-inducible gene-I (RIG-I), have been shown to be differentially expressed in neuroblastoma (NB) and promote dsRNA poly (I:C)-induced NB suppression in vitro and in vivo. However, the role of another important innate immune cytosolic sensor, laboratory of genetics and physiology 2 (LGP2), in the cancer behavior of NB remains unclear. Here, we demonstrated that the expression levels of LGP2 were either low or undetectable in all NB cell lines tested with or without MYCN amplification. LGP2 expression levels were significantly increased only in NB cells without MYCN amplification, including SK-N-AS and SK-N-FI after poly (I:C) treatment in vitro and in mouse xenograft models. Ectopic expression of LGP2 in NB cells significantly enhanced poly (I:C)-induced NB cell death associated with downregulation of MDA5, RIG-I, MAVS and Bcl-2, as well as upregulation of Noxa and tBid. By immunofluorescence analyses, LGP2 localized mainly in the cytoplasm of NB cells after poly (I:C) treatment. In human NB tissue samples, cytoplasmic LGP2 expression was positively correlated with histological differentiation and inversely correlated with MYCN amplification. Positive cytoplasmic LGP2 expression in tumor tissues could predict a favorable outcome in NB patients independent of other prognostic factors. In short, LGP2 was effective in promoting poly (I:C)-induced NB suppression and cytoplasmic LGP2 can serve as an independent favorable prognostic factor in NB patients.

SUBMITTER: Lin LL

PROVIDER: S-EPMC6215871 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Innate immune sensor laboratory of genetics and physiology 2 suppresses tumor cell growth and functions as a prognostic marker in neuroblastoma.

Lin Li-Ling LL Huang Chao-Cheng CC Wu Min-Tsui MT Hsu Wen-Ming WM Chuang Jiin-Haur JH

Cancer science 20181004 11

The innate immune receptors, such as toll-like receptor 3 (TLR3), melanoma differentiation-associated 5 (MDA5) and retinoic acid-inducible gene-I (RIG-I), have been shown to be differentially expressed in neuroblastoma (NB) and promote dsRNA poly (I:C)-induced NB suppression in vitro and in vivo. However, the role of another important innate immune cytosolic sensor, laboratory of genetics and physiology 2 (LGP2), in the cancer behavior of NB remains unclear. Here, we demonstrated that the expres ...[more]

PMID: 30179292

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Project description:BackgroundNeuroblastoma (NB) is the most common solid tumor in children. NB treatment has made significant progress; however, given the high degree of heterogeneity, basic research findings and their clinical application to NB still face challenges. Herein, we identify novel prognostic models for NB.MethodsWe obtained RNA expression data of NB and normal nervous tissue from TARGET and GTEx databases and determined the differential expression patterns of RNA binding protein (RBP) genes between normal and cancerous tissues. Lasso regression and Cox regression analyses identified the five most important differentially expressed genes and were used to construct a new prognostic model. The function and prognostic value of these RBPs were systematically studied and the predictive accuracy verified in an independent dataset.ResultsIn total, 348 differentially expressed RBPs were identified. Of these, 166 were up-regulated and 182 down-regulated RBPs. Two hubs RBPs (CPEB3 and CTU1) were identified as prognostic-related genes and were chosen to build the prognostic risk score models. Multivariate Cox analysis was performed on genes from univariate Cox regression and Lasso regression analysis using proportional hazards regression model. A five gene prognostic model: Risk score = (-0.60901*expCPEB3)+(0.851637*expCTU1) was built. Based on this model, the overall survival of patients in the high-risk subgroup was lower (P = 2.152e-04). The area under the curve (AUC) of the receiver-operator characteristic curve of the prognostic model was 0.720 in the TARGET cohort. There were significant differences in the survival rate of patients in the high and low-risk subgroups in the validation data set GSE85047 (P = 0.1237e-08), with the AUC 0.730. The risk model was also regarded as an independent predictor of prognosis (HR = 1.535, 95% CI = 1.368-1.722, P = 2.69E-13).ConclusionsThis study identified a potential risk model for prognosis in NB using Cox regression analysis. RNA binding proteins (CPEB3 and CTU1) can be used as molecular markers of NB.

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Innate immune sensor laboratory of genetics and physiology 2 suppresses tumor cell growth and functions as a prognostic marker in neuroblastoma.

Publications

Innate immune sensor laboratory of genetics and physiology 2 suppresses tumor cell growth and functions as a prognostic marker in neuroblastoma.

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