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Pattern of cell-to-cell transfer of microRNA by gap junction and its effect on the proliferation of glioma cells.

ABSTRACT: MicroRNA is expected to be a novel therapeutic tool for tumors. Gap junctions facilitate the transfer of microRNA, which exerts biological effects on tumor cells. However, the length of microRNA that can pass through certain gap junctions composed of specific connexin remains unknown. To address this question, the present study investigated the permeability of gap junctions composed of various connexins, including connexin 43, connexin 32 or connexin 37, to microRNAs consisting of 18-27 nucleotides in glioma cells and cervical cancer cells. Results indicated that all of the microRNAs were able to be transferred from donor glioma cells to neighboring cells through the connexin 43 composed gap junction, but not the gap junctions composed of connexin 32 or connexin 37, in cervical cancer cells. Downregulation of the function of gap junctions comprising connexin 43 by pharmacological inhibition and shRNA significantly decreased the transfer of these microRNAs. In contrast, gap junction enhancers and overexpression of connexin 43 effectively increased these transfers. In glioma cells, cell proliferation was inhibited by microRNA-34a. Additionally, these effects of microRNA-34a were significantly enhanced by overexpression of connexin 43 in U251 cells, indicating that gap junctions play an important role in the antitumor effect of microRNA by transfer of microRNA to neighboring cells. Our data are the first to clarify the pattern of microRNA transmission through gap junctions and provide novel insights to show that antitumor microRNAs should be combined with connexin 43 or a connexin 43 enhancer, not connexin 32 or connexin 37, in order to improve the therapeutic effect.

SUBMITTER: Peng Y

PROVIDER: S-EPMC6549926 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Glioma is one of the most common, rapidly progressive and fatal brain tumors, and accumulating evidence shows that microRNAs (miRNAs) play important roles in the development of cancers, including glioma. Therapeutic applications of miRNAs in Ras-driven glioma have been proposed; however, their specific functions and mechanisms are poorly understood. Here, we report that miR-1301-3p directly targets the neuroblastoma Ras viral oncogene homolog (N-Ras) and functions as a tumor-suppressor in glioma. Quantitative reverse transcription-PCR was applied to detect the expression of miR-1301-3p in glioma specimens. The direct target genes of miR-1301-3p were predicted by bioinformatic analysis and further verified by immunoblotting and luciferase assays. The effects of miR-1301-3p on the proliferation and cell cycle of glioma cells were analyzed by cell-counting kit 8, colony formation, 5-ethynyl-2-deoxyuridine (EDU) and flow cytometry assays. A xenograft model was used to study the effect of miR-1301-3p on tumor growth and angiogenesis. The expression levels of miR-1301-3p in glioma specimens were significantly downregulated. N-Ras was confirmed as a direct target of miR-1301-3p. MiR-1301-3p inhibited glioma cell growth and blocked the cell cycle to G1 by negatively regulating N-Ras and its downstream signaling pathway, MEK-ERK1/2. Furthermore, the inhibitory effects of miR-1301-3p could be rescued by the overexpression of N-Ras. The protein levels of N-Ras were up-regulated in clinical glioma specimens and were negatively correlated with miR-1301-3p expression levels (r=-056, P=0.0002). In vivo studies revealed that increased levels of miR-1301-3p delayed the growth of intracranial tumors, which was accompanied by decreased Ki67 and CD31 expression. Taken together, our results demonstrate that miR-1301-3p plays a significant role in inactivating the Ras signaling pathway through the inhibition of N-Ras, which may provide a novel therapeutic strategy for treatment of glioma and other Ras-driven cancers.

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Pattern of cell-to-cell transfer of microRNA by gap junction and its effect on the proliferation of glioma cells.

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