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

Abstract

Micro RNA is expected to be a novel therapeutic tool for tumors. Gap junctions facilitate the transfer of micro RNA , which exerts biological effects on tumor cells. However, the length of micro RNA 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 micro RNA s consisting of 18‐27 nucleotides in glioma cells and cervical cancer cells. Results indicated that all of the micro RNA s 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 sh RNA significantly decreased the transfer of these micro RNA s. In contrast, gap junction enhancers and overexpression of connexin 43 effectively increased these transfers. In glioma cells, cell proliferation was inhibited by micro RNA ‐34a. Additionally, these effects of micro RNA ‐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 micro RNA by transfer of micro RNA to neighboring cells. Our data are the first to clarify the pattern of micro RNA transmission through gap junctions and provide novel insights to show that antitumor micro RNA s should be combined with connexin 43 or a connexin 43 enhancer, not connexin 32 or connexin 37, in order to improve the therapeutic effect.

Hypoxic Melanoma Cells Deliver microRNAs to Dendritic Cells and Cytotoxic T Lymphocytes through Connexin-43 Channels

“…Taking into consideration that Cx43 channels are permeable to miRNAs, that Cx43-GJs have been implicated in the transfer of miRNAs in other cellular and pathophysiological contexts [ 31 ], and the finding that Cx43-GJ inhibition impaired the levels of RNA molecules transferred from hypoxic melanoma to immune cells ( Figure 2 ), we hypothesized that hypoxic melanoma cells may transfer HRMs to immune cells via Cx43-GJs. In order to test this hypothesis, first, we identified HRMs in human melanoma cells by using a hypoxia signaling qRT-PCR array.…”

“…These miRNAs targeted the expression of stathmin-1 and insulin-like growth factor-1 receptor in the tumor cells, functionally inhibiting their proliferation level [ 62 ]. More recently, it was reported that the inhibition of glioma cell proliferation by miR34a can be increased by allowing its transfer via Cx43-GJs, which suggests that antitumor miRNAs can be combined with Cx43 enhancers in order to improve miRNA therapeutic effects [ 31 ].…”

Role of ROS/RNS in Preeclampsia: Are Connexins the Missing Piece?

“…There are several miRNAs that are associated with trophoblastic differentiation, migration and invasion [168]. Cx43 GJCs are permeable to several miRNAs [102,169]. Interestingly, Cx43 GJCs allows the exchange of miRNAs between bone-marrow-derived mesenchymal stem cells or cancer cells and endothelial cells [101,170,171].…”

Antagonistic Functions of Connexin 43 during the Development of Primary or Secondary Bone Tumors

“…Connexons are composed of six connexins that form a central pore of ~2 nm in diameter, allowing the diffusion of small molecules with a molecular mass of less than 1200 Da, such as second messengers (e.g., calcium, inositol triphosphate, adenosine monophosphate, glutathione, glucose, glutamate) [ 16 ]. More recently, studies have hypothesized that siRNA and miRNA can also pass through Gj despite having molecular masses of ~8 kDa [ 17 , 18 , 19 , 20 ].…”