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Survival Association and Cell Cycle Effects of B7H3 in Neuroblastoma.

ABSTRACT: OBJECTIVE:The function of B7H3, a member of the B7 family of proteins, in neuroblastoma (NB) remains poorly characterized. Here we examine the expression pattern of B7H3 in clinical NB specimens and characterize the phenotype of B7H3 knock-down in NB cell line. METHODS:Immunohistochemical (IHC) staining was carried out to assess the expression of B7H3 in clinical NB specimens. Survival association was analyzed using five Gene Expression Omnibus (GEO) datasets (GSE85047, GSE45480, GSE62564, GSE16476, GSE49710). Clonogenic survival and flow cytometry were performed after B7H3 knockdown to assess the cellular proliferation and cell survival in vitro. Impact of B7H3 silencing on NB growth was examined in vivo using the SH-SY5Y xenograft model. RESULTS:On IHC staining, B7H3 was widely expressed in clinical NB specimens. Analysis of the transcriptional profiles of five GEO datasets clinically annotated NB specimens revealed that decreased B7H3 expression was associated with improved overall survival. B7H3 knockdown suppressed the proliferation of the SH-SY5Y NB model in vitro and in vivo. Cell cycle analysis revealed that B7H3 silencing induced G1/S arrest. This arrest was associated with the suppression of E2F1 expression and induction of Rb expression. CONCLUSION:Our results demonstrate that B7H3 expression correlate with clinical survival in NB patients. Preliminary studies suggest that B7H3 may mediate the G1/S transition.

SUBMITTER: Zhang H

PROVIDER: S-EPMC7671786 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Survival Association and Cell Cycle Effects of B7H3 in Neuroblastoma.

Zhang Haibo H Zhang Jinsen J Li Chunjie C Xu Hao H Dong Rui R Chen Clark C CC Hua Wei W

Journal of Korean Neurosurgical Society 20200624 6

<h4>Objective</h4>The function of B7H3, a member of the B7 family of proteins, in neuroblastoma (NB) remains poorly characterized. Here we examine the expression pattern of B7H3 in clinical NB specimens and characterize the phenotype of B7H3 knock-down in NB cell line.<h4>Methods</h4>Immunohistochemical (IHC) staining was carried out to assess the expression of B7H3 in clinical NB specimens. Survival association was analyzed using five Gene Expression Omnibus (GEO) datasets (GSE85047, GSE45480, ...[more]

PMID: 32580265

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Project description:Abstract BACKGROUND: While immunotherapy has revolutionized the treatment for several solid tumors, pseudoprogression, radiographically defined as the initial increase in tumor volume followed by tumor shrinkage, is less clearly defined. This is particularly noteworthy for patients with central nervous system metastases, commonly seen in patients with advanced melanoma or non-small cell lung cancer treated with PD-1 or CTLA-4 inhibitors. B7-H3 (CD276) is a transmembrane protein belonging to the B7 family of costimulatory molecules. 1 Several solid tumors overexpress B7-H3, and expression appears to be closely associated with immune escape, tumor cell invasion and metastases. The incidence of pseudoprogression after B7-H3 therapy is unknown. METHOD: A 4 year old girl with central nervous system metastases of neuroblastoma underwent resection of 2 left parietal lobe lesions, the largest 1.4 cm with edema, enhancement and restricted diffusion, followed by craniospinal radiation therapy, irinotecan, temozolomide, inducing a second remission with expected MR appearance in the operative cavity. She was then registered to clinicaltrials.gov (NCT00089245) with intraventricular 131-I-anti B7-H3. One month after therapy, routine MR revealed increased nodular enhancement around both operative cavities with adjacent leptomeningeal enhancement, concerning for progressive neuroblastoma. The patient remained asymptomatic. RESULTS: A repeat brain performed 2 weeks later showed interval resolution of both the operative cavity and leptomeningeal enhancement and edema. Repeat brain and spine MR performed 6 months later shows continued remission with complete resolution of all enhancement and edema. RESULTS: Anti- B7-H3 therapy caused an immediate inflammatory reaction with spontaneous radiographic resolution and return to baseline 2 weeks later, all in the absence of concurrent steroid administration. CONCLUSION: Though the precise frequency and timeline is unclear, B7-H3 directed therapy may be added to the list of immunotherapeutic agents recognized to cause pseudoprogression. Key efforts are now being made to correlate the appearance of CNS neuroblastoma pseudoprogression with overall survival.

Project description:BackgroundNBPF1 (Neuroblastoma Breakpoint Family, member 1) was originally identified in a neuroblastoma patient on the basis of its disruption by a chromosomal translocation t(1;17)(p36.2;q11.2). Considering this genetic defect and the frequent genomic alterations of the NBPF1 locus in several cancer types, we hypothesized that NBPF1 is a tumor suppressor. Decreased expression of NBPF1 in neuroblastoma cell lines with loss of 1p36 heterozygosity and the marked decrease of anchorage-independent clonal growth of DLD1 colorectal carcinoma cells with induced NBPF1 expression further suggest that NBPF1 functions as tumor suppressor. However, little is known about the mechanisms involved.MethodsExpression of NBPF was analyzed in human skin and human cervix by immunohistochemistry. The effects of NBPF1 on the cell cycle were evaluated by flow cytometry. We investigated by real-time quantitative RT-PCR the expression profile of a panel of genes important in cell cycle regulation. Protein levels of CDKN1A-encoded p21(CIP1/WAF1) were determined by western blotting and the importance of p53 was shown by immunofluorescence and by a loss-of-function approach. LC-MS/MS analysis was used to investigate the proteome of DLD1 colon cancer cells with induced NBPF1 expression. Possible biological interactions between the differentially regulated proteins were investigated with the Ingenuity Pathway Analysis tool.ResultsWe show that NBPF is expressed in the non-proliferative suprabasal layers of squamous stratified epithelia of human skin and cervix. Forced expression of NBPF1 in HEK293T cells resulted in a G1 cell cycle arrest that was accompanied by upregulation of the cyclin-dependent kinase inhibitor p21(CIP1/WAF1) in a p53-dependent manner. Additionally, forced expression of NBPF1 in two p53-mutant neuroblastoma cell lines also resulted in a G1 cell cycle arrest and CDKN1A upregulation. However, CDKN1A upregulation by NBPF1 was not observed in the DLD1 cells, which demonstrates that NBPF1 exerts cell-specific effects. In addition, proteome analysis of NBPF1-overexpressing DLD1 cells identified 32 differentially expressed proteins, of which several are implicated in carcinogenesis.ConclusionsWe demonstrated that NBPF1 exerts different tumor suppressive effects, depending on the cell line analyzed, and provide new clues into the molecular mechanism of the enigmatic NBPF proteins.

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Survival Association and Cell Cycle Effects of B7H3 in Neuroblastoma.

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Survival Association and Cell Cycle Effects of B7H3 in Neuroblastoma.

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