Gap Junctions Enhance the Antiproliferative Effect of MicroRNA-124-3p in Glioblastoma Cells.
MicroRNA (miRNA) holds promise as a novel therapeutic tool for cancer treatment. However, the transfection efficiency of current delivery systems represents a bottleneck for clinical applications. Here, we demonstrate that gap junctions mediate an augmentative effect on the antiproliferation mediated by miR-124-3p in U87 and C6 glioblastoma cells. The functional inhibition of gap junctions using either siRNA or pharmacological inhibition eliminated the miR-124-3p-mediated antiproliferation, whereas the enhancement of gap junctions with retinoic acid treatment augmented this miR-124-3p-mediated antiproliferation. A similar effect was observed in glioblastoma xenograft models. More importantly, patch clamp and co-culture assays demonstrated the transmission of miR-124-3p through gap junction channels into adjacent cells. In further exploring the impact of gap junction-mediated transport of miR-124-3p on miR-124-3p target pathways, we found that miR-124-3p inhibited glioblastoma cell growth in part by decreasing the protein expression of cyclin-dependent kinase 6, leading to cell cycle arrest at the G0 /G1 phase; moreover, pharmacological regulation of gap junctions affected this cell cycle arrest. In conclusion, our results indicate that the "bystander" effects of functional gap junctions composed of connexin 43 enhance the antitumor effect of miR-124-3p in glioblastoma cells by transferring miR-124-3p to adjacent cells, thereby enhancing G0 /G1 cell cycle arrest. These observations provide a new guiding strategy for the clinical application of miRNA therapy in tumor treatment.
Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, P.R. China.
Zhang
Z
Suzhi
Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, P.R. China.
Tao
T
Liang
Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, P.R. China.
Peng
P
Yuexia
Department of Cell and Systems Biology, University of Toronto, Ontario, Canada.
Liu
L
Lucy
Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, P.R. China.
Hong
H
Xiaoting
Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, P.R. China.
Zhang
Z
Yuan
Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, P.R. China.
Wang
W
Qin
D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D018920:Coculture Techniques; D017629:Gap Junctions / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*
C509207:MIRN124 microRNA, human; D035683:MicroRNAs; C540079:Mirn124 microRNA, mouse