Extended synaptotagmins (E-Syts) are endoplasmic reticulum (ER)-associated proteins that facilitate the tethering of the ER to the plasma membrane (PM), participating in lipid transfer between the membranes and supporting the Orai1–STIM1 interaction at ER–PM junctions. Orai1 and STIM1 are the core proteins of store-operated Ca2+entry (SOCE), a major mechanism for Ca2+influx that regulates a variety of cellular functions. Aberrant modulation of SOCE in cells from different types of cancer has been reported to underlie the development of several tumoral features. Here we show that estrogen receptor-positive (ER+) breast cancer MCF7 and T47D cells and triple-negative breast cancer (TNBC) MDA-MB-231 cells overexpress E-Syt1 and E-Syt2 at the protein level; the latter is also overexpressed in the TNBC BT20 cell line. E-Syt1 and E-Syt2 knockdown was without effect on SOCE in non-tumoral MCF10A breast epithelial cells and ER+ T47D breast cancer cells; however, SOCE was significantly attenuated in ER+ MCF7 cells and TNBC MDA-MB-231 and BT20 cells upon transfection with siRNA E-Syt1 or E-Syt2. Consistent with this, E-Syt1 and E-Syt2 knockdown significantly reduced cell migration and viability in ER+ MCF7 cells and the TNBC cells investigated. To summarize, E-Syt1 and E-Syt2 play a relevant functional role in breast cancer cells.
扩展突触结合蛋白是内质网相关蛋白，能促进内质网与质膜之间的锚定连接，参与膜间脂质转运，并在内质网-质膜连接处支持Orai1–STIM1相互作用。Orai1和STIM1作为钙库操纵性钙内流的核心蛋白，是调节多种细胞功能的主要钙离子内流机制。已有研究表明，不同类型癌细胞中钙库操纵性钙内流的异常调控是多种肿瘤特征形成的基础。本研究发现，雌激素受体阳性乳腺癌细胞MCF7、T47D以及三阴性乳腺癌细胞MDA-MB-231在蛋白水平均过表达E-Syt1和E-Syt2；其中E-Syt2在三阴性乳腺癌BT20细胞系中也存在过表达现象。在非肿瘤性乳腺上皮细胞MCF10A和雌激素受体阳性乳腺癌细胞T47D中敲低E-Syt1或E-Syt2对钙库操纵性钙内流无显著影响；然而在雌激素受体阳性MCF7细胞及三阴性乳腺癌MDA-MB-231、BT20细胞中，转染E-Syt1或E-Syt2 siRNA能显著抑制钙库操纵性钙内流。与此一致的是，敲低E-Syt1和E-Syt2能显著抑制雌激素受体阳性MCF7细胞及所研究的三阴性乳腺癌细胞的迁移能力和存活率。综上所述，E-Syt1和E-Syt2在乳腺癌细胞中发挥着重要的功能作用。
肿瘤(癌症)患者之家