Abstract
Connexins (Cxs) are a family of proteins that form two different types of ion channels: hemichannels and gap junction channels. These channels participate in cellular communication, enabling them to share information and act as a synchronized syncytium. This cellular communication has been considered a strong tumor suppressor, but it is now recognized that some type of Cxs can be pro-tumorigenic. For example, Cx46 expression is increased in human breast cancer samples and correlates with cancer stem cell (CSC) characteristics in human glioma. Thus, we explored whether Cx46 and glioma cells, can set up CSC and epithelial-to-mesenchymal transition (EMT) properties in a breast cancer cell line. To this end, we transfected MCF-7 cells with Cx46 attached to a green fluorescent protein (Cx46GFP), and we determined how its expression orchestrates both the gene-expression and functional changes associated with CSC and EMT. We observed that Cx46GFP increased Sox2, Nanog, and OCT4 mRNA levels associated with a high capacity to form monoclonal colonies and tumorspheres. Similarly, Cx46GFP increased the mRNA levels of n-cadherin, Vimentin, Snail and Zeb1 to a higher migratory and invasive capacity. Furthermore, Cx46GFP transfected in MCF-7 cells induced the release of higher amounts of VEGF, which promoted angiogenesis in HUVEC cells. We demonstrated for the first time that Cx46 modulates CSC and EMT properties in breast cancer cells and thus could be relevant in the design of future cancer therapies.
Highlights
Connexins (Cxs) are a family of transmembrane proteins that have the unique property to form two different types of ion channels: hemichannels and gap junction channels [1].Hemichannels are formed by six Cx subunits and, when they open, communicate the cytoplasm with the extracellular milieu [2]
We showed a potent effect of Cx46 on a cell line derived from breast cancer in terms of cancer stem cell (CSC) and epithelial-to-mesenchymal transition (EMT) induction, and these results are congruent with previous results obtained in glioma
Cx46 has been involved in the maintenance of CSCs in glioblastoma [9]; the effect of Cx46 on breast cancer stem cell properties was unknown
Summary
Connexins (Cxs) are a family of transmembrane proteins that have the unique property to form two different types of ion channels: hemichannels and gap junction channels [1].Hemichannels are formed by six Cx subunits and, when they open, communicate the cytoplasm with the extracellular milieu [2]. Almost all cell types in the human body express at least one type of Cx and have the capability to interconnect with other cells, share information and act as a synchronized syncytium This cellular communication has been considered as a tumor suppressor [3], and a decrease in Cx expression has been strongly correlated with the appearance of several types of cancer [4]. Currently it is recognized that there are some types of Cxs that seem to be pro-tumorigenic [4]; one of these, under physiological conditions, Cx46 is almost exclusively expressed in the eye lens [5] This Cx may have an important role in cancer progression.
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