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J Pathol. 2016 Nov;240(3):329-340. doi: 10.1002/path.4781.

Exosomal miR-24-3p impedes T-cell function by targeting FGF11 and serves as a potential prognostic biomarker for nasopharyngeal carcinoma.

Ye SB1,2,3, Zhang H1,2,3, Cai TT1,2,3, Liu YN1,2,3, Ni JJ1,2,3, He J3, Peng JY3, Chen QY1,2,4, Mo HY1,2,4, Jun-Cui5, Zhang XS1,2,3, Zeng YX1,2,3, Li J6,7,8.

Author information

1
State Key Laboratory of Oncology in South China, Guangzhou, PR China.
2
Collaborative Innovation Centre for Cancer Medicine, Sun Yat-sen University Cancer Centre, Guangzhou, PR China.
3
Department of Biotherapy, Sun Yat-sen University Cancer Centre, Guangzhou, PR China.
4
Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Centre, Guangzhou, PR China.
5
Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, College of Life Sciences, Sun Yat-sen University, Guangzhou, PR China.
6
State Key Laboratory of Oncology in South China, Guangzhou, PR China. lijiang2@mail.sysu.edu.cn.
7
Collaborative Innovation Centre for Cancer Medicine, Sun Yat-sen University Cancer Centre, Guangzhou, PR China. lijiang2@mail.sysu.edu.cn.
8
Department of Biotherapy, Sun Yat-sen University Cancer Centre, Guangzhou, PR China. lijiang2@mail.sysu.edu.cn.

Abstract

Recent studies have shown that extracellular microRNAs are not only potential biomarkers but are also involved in cell interactions to regulate the intercommunication between cancer cells and their microenvironments in various types of malignancies. In this study, we isolated exosomes from nasopharyngeal carcinoma (NPC) cell lines and patient sera (T-EXOs), or control NP69 cells and healthy donor sera (HD-EXOs). We found that miR-24-3p was markedly enriched in T-EXOs as compared with HD-EXOs; the serum exosomal miR-24-3p level was correlated with worse disease-free survival of patients (p < 0.05). Knockdown of exosomal miR-24-3p (miR-24-3p-sponge-T-EXOs) by a sponge RNA targeting miR-24-3p restored the T-EXO-mediated (control-sponge-T-EXO) inhibition of T-cell proliferation and Th1 and Th17 differentiation, and the induction of regulatory T cells (Tregs). Mechanistic analyses revealed that administration of exosomal miR-24-3p increased P-ERK, P-STAT1 and P-STAT3 expression while decreasing P-STAT5 expression during T-cell proliferation and differentiation. Moreover, by in vivo and in vitro assessments, we found FGF11 to be a direct target of miR-24-3p. However, both miR-24-3p-sponge-T-EXOs and T-EXOs (control-sponge-T-EXOs) impeded proliferation and Th1 and Th17 differentiation, but induced Treg differentiation, of lenti-shFGF11-transfected T cells. The levels of phosphorylated ERK and STAT proteins were different in lenti-ScshRNA-transfected T cells and lenti-shFGF11-transfected T cells following administration of miR-24-3p-sponge-T-EXO. Interestingly, tumour FGF11 expression was positively correlated with the number of CD4+ and CD8+ T cells in vivo, and predicted favourable patient DFS (p < 0.05). Additionally, hypoxia increased cellular and exosomal miR-24-3p levels and enhanced the inhibitory effect of T-EXO on T-cell proliferation and differentiation. Collectively, our findings suggest that exosomal miR-24-3p is involved in tumour pathogenesis by mediating T-cell suppression via repression of FGF11, and may serve as a potential prognostic biomarker in NPC. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

KEYWORDS:

exosomes; immune regulation; miR-24-3p; nasopharyngeal carcinoma

PMID:
27538493
DOI:
10.1002/path.4781
[Indexed for MEDLINE]

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