Cell-free miR-17-5p as a diagnostic biomarker for gastric cancer inhibits dendritic cell maturation
Authors Cui ZJ, Xie XL, Qi W, Yang YC, Bai Y, Han J, Ding Q, Jiang HQ
Received 10 December 2018
Accepted for publication 15 February 2019
Published 9 April 2019 Volume 2019:12 Pages 2661—2675
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Justinn Cochran
Peer reviewer comments 3
Editor who approved publication: Dr Carlos E Vigil
Zi-Jin Cui,1,2 Xiao-Li Xie,1 Wei Qi,1 Yi-Chao Yang,1 Yun Bai,2 Jing Han,1 Qian Ding,1 Hui-Qing Jiang1
1Department of Gastroenterology, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Department of Gastroenterology, Hebei General Hospital, Shijiazhuang, People’s Republic of China
Purpose: Gastric cancer (GC) patients display aberrant miRNA expression and defective dendritic cell function. However, the role of cancer cell-derived oncomiR in GC detection and dendritic cell (DC) maturation remains largely elusive.
Methods: Candidate miRNAs were selected by deep sequencing (8 GC plasma samples vs 8 control plasma samples; 8 GC tissues vs 8 adjacent normal gastric tissues) and confirmed by PCR with 164 plasma samples and 72 formalin-fixed paraffin-embedded GC tissue samples. Their diagnostic performance was evaluated by receiver operating characteristic curve. Cy3 fluorescence signals in DCs, exposed to conditioned medium obtained from BGC-823 cells pre-transfected with Cy3-miR-17-5p, were determined by flow cytometry and visualized by confocal microscopy. Functional and phenotypical alterations of DCs were assayed when DCs were transfected with miR-17-5p in vitro.
Results: Deep sequencing and RT-PCR confirmed that five shared miRNAs were upregulated in plasma and tissue samples of GC patients. Cell-free miR-17-5p was superior to others in GC detection with an area under the curve of 0.82, and correlated with lymphatic metastasis and poor overall survival. GC cell-shuttled miR-17-5p can be delivered to immature DCs, and they significantly inhibited LPS-stimulated phenotypic maturation by diminishing the expression of maturation markers (MHC II, CD80 and CD86 molecules). In line with those alterations in the phenotypic markers, functional experiments demonstrated that miR-17-5p triggered an inhibitory effect on DCs endocytic activity and decreased tumor necrosis factor-α and IL-12 secretion, while enhancing IL-10 production. Mixed lymphocyte reaction showed that miR-17-5p inhibited the T cell stimulating effect of DCs and favored regulatory T cells expansion.
Conclusion: GC cell-derived miR-17-5p is a potential biomarker for GC detection. Taken up by DCs, miR-17-5p weakened antitumor immune responses via inhibiting the maturation of dendritic cells.
Keywords: gastric cancer, cell-free miRNA, biomarker, intracellular communication, dendritic cell
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