Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago 7780272, Chile.
Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebastian, Santiago 7510157, Chile.
Int J Mol Sci. 2021 Nov 22;22(22):12604. doi: 10.3390/ijms222212604.
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.
间隙连接蛋白（Cxs）是一组形成两种不同类型离子通道的蛋白：半通道和间隙连接通道。这些通道参与细胞通讯，使它们能够共享信息并作为同步合胞体发挥作用。这种细胞通讯曾被认为是一种强大的肿瘤抑制因子，但现在人们认识到，某些类型的 Cxs 可能具有促肿瘤作用。例如，Cx46 在人乳腺癌样本中的表达增加，并且与人神经胶质瘤中的癌症干细胞（CSC）特征相关。因此，我们探讨了 Cx46 和神经胶质瘤细胞是否可以在乳腺癌细胞系中建立 CSC 和上皮-间充质转化（EMT）特性。为此，我们将 Cx46 与绿色荧光蛋白（Cx46GFP）连接转染 MCF-7 细胞，并确定其表达如何协调与 CSC 和 EMT 相关的基因表达和功能变化。我们观察到 Cx46GFP 增加了 Sox2、Nanog 和 OCT4 mRNA 水平，与形成单克隆集落和肿瘤球的高能力相关。同样，Cx46GFP 增加了 n-钙粘蛋白、波形蛋白、Snail 和 Zeb1 的 mRNA 水平，从而提高了迁移和侵袭能力。此外，Cx46GFP 在 MCF-7 细胞中转染诱导了更高量的 VEGF 的释放，从而促进了 HUVEC 细胞的血管生成。我们首次证明 Cx46 调节乳腺癌细胞中的 CSC 和 EMT 特性，因此在未来癌症治疗的设计中可能具有相关性。
