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Dysregulated co-stimulatory molecule expression in a Sjogren's syndrome mouse model with potential implications by microRNA-146a.

ABSTRACT: Sjögren's syndrome (SjS) is an autoimmune condition that primarily affects salivary and lacrimal glands, causing loss of secretion. We have previously shown that microRNA-146a (miR-146a) is over-expressed in the salivary glands and peripheral blood mononuclear cells (PBMC) of SjS-prone mice (C57BL/6.NOD-Aec1Aec2, B6DC) and in PBMC of SjS patients. The purpose of this research was to identify a target molecule of miR-146a and identify subpopulations of cells affected by altered miR-146a in the salivary glands of SjS-prone mice. In silico analyses identified costimulatory molecule CD80 as a potential target of miR-146a. Luciferase assay of the human CD80 3'untranslated region demonstrated miR-146a directly inhibited CD80 protein expression as indicated by reduced luciferase reporter expression and an examination of B6DC salivary glands revealed a reduction in CD80 protein. More interestingly, the specific reduction in CD80 protein was detected from the salivary gland epithelial cell population and in interstitial dendritic cells in the glands as well. The reduction in CD80 protein levels in salivary gland epithelial cells were negatively associated with elevated miR-146a expression. Therefore, this study provides the first indication that salivary gland epithelial cells may be critically involved in SjS progression by altering CD86:CD80 protein ratio in response to miR-146a upregulation.

SUBMITTER: Gauna AE

PROVIDER: S-EPMC4679674 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Dysregulated co-stimulatory molecule expression in a Sjögren's syndrome mouse model with potential implications by microRNA-146a.

Gauna Adrienne E AE Park Yun-Jong YJ Nayar Gautam G Onate Marelys M Jin Jun-o JO Stewart Carol M CM Yu Qing Q Cha Seunghee S

Molecular immunology 20151023 2 Pt C

Sjögren's syndrome (SjS) is an autoimmune condition that primarily affects salivary and lacrimal glands, causing loss of secretion. We have previously shown that microRNA-146a (miR-146a) is over-expressed in the salivary glands and peripheral blood mononuclear cells (PBMC) of SjS-prone mice (C57BL/6.NOD-Aec1Aec2, B6DC) and in PBMC of SjS patients. The purpose of this research was to identify a target molecule of miR-146a and identify subpopulations of cells affected by altered miR-146a in the sa ...[more]

PMID: 26505653

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Project description:Background: B7-H3, also known as CD276, an important immune checkpoint member of the B7-CD28 family, is confirmed as a promising target after PD-L1 in clinical trials. Although the overexpression of B7-H3 has been associated with invasive metastatic potential and poor prognosis in multiple types of cancer, nothing is known regarding the expression profiles of B7-H3 in papillary thyroid carcinoma (PTC). In this study, we carried out a large-scale analysis of B7-H3 expression in PTC patients and evaluated the potential clinical significance of B7-H3. Methods: In total, data from 1,210 samples, including 867 cases from TCGA and four GEO datasets, were collected for B7-H3-related transcriptome analyses, and 343 postoperative, whole-tumor sections were collected from patients with PTC at our institute for B7-H3-specific immunohistochemistry (IHC) staining. The statistical analysis was primarily accomplished using the R project for statistical computing. Results: B7-H3 positivity was found in 84.8% of PTC patients (291/343), and the mRNA and protein expression levels of B7-H3 in PTC were markedly higher than those of para-tumor tissues (p < 0.001), demonstrating that B7-H3 can serve as a potential diagnostic biomarker for PTC. The significant upregulation of B7-H3 in PTC is caused by distinct patterns of CNVs and CpG DNA methylation. Functional enrichment analysis confirmed that high B7-H3 expression was significantly associated with specific immune features and angiogenesis. High B7-H3 protein expression was associated with tumor size (p = 0.022), extrathyroidal extension (ETE) (p = 0.003), and lymph node metastasis (LNM) (p < 0.001). More importantly, multivariate analysis confirmed that B7-H3 was an independent predictor of relapse-free survival (RFS) (p < 0.05). In the subgroup analysis, positive B7-H3 staining was associated with worse RFS in patients with primary tumor size ≥2 cm (p < 0.05), age ≥55 years (p < 0.05), LNM (p = 0.07), multifocality (p < 0.05), and ETE (p < 0.05). In addition, Circos plots indicated that B7-H3 was significantly associated with other immune checkpoints in the B7-CD28 family. Conclusion: This is the first comprehensive study to elucidate the expression profile of B7-H3 in PTC. Our observations revealed that B7-H3 is a novel independent biomarker for predicting LNM and disease recurrence for PTC patients, and it thus may serve as an indicator that could be used to improve risk-adapted therapeutic strategies and a novel target for immunotherapy strategies for patients who undergo an aggressive disease course.

Dataset Information

Dysregulated co-stimulatory molecule expression in a Sjogren's syndrome mouse model with potential implications by microRNA-146a.

Publications

Dysregulated co-stimulatory molecule expression in a Sjögren's syndrome mouse model with potential implications by microRNA-146a.

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