Li Haiyu, Chen Xingfeng, Gao Yue, Wu Jiayan, Zeng Fan, Song Fangzhou
Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China.
Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China.
Cell Signal. 2015 Jan;27(1):82-9. doi: 10.1016/j.cellsig.2014.09.018. Epub 2014 Oct 2.
Breast cancer is highly metastatic disease and the most lethal of the gynecologic malignancies. Epithelial-to-mesenchymal is a crucial process for the invasion of epithelial tumors. Recent studies revealed that breast cancer cells that have undergone EMT acquire aggressive malignant properties, but the molecular mechanisms underlying this transition are not well-understood. In this study, we report findings that human X-box binding protein1 (XBP1) acts as a novel regulator of EMT. We found that increased expression of XBP1 was associated with the progression of breast cancer and that XBP1 protein was significantly over-expressed in matched metastatic tumor. High XBP1 protein also predicts shorter overall survival of breast cancer patients. RNA interference-mediated knockdown of XBP1 expression restored E-cadherin expression and cell-cell junction formation in breast cancer cells, suppressing cell invasion, and tumor formation. In contrast, overexpression of XBP1 decreased the expression of the epithelial marker E-cadherin but increased the mesenchymal markers in breast cancer cells. Our finding demonstrates the upregulated expression of the key EMT regulator Snail and that it mediated EMT activation and cell invasion by XBP1.
乳腺癌是一种具有高度转移性的疾病，也是妇科恶性肿瘤中最致命的一种。上皮-间质转化是上皮性肿瘤侵袭的关键过程。最近的研究表明，经历上皮-间质转化的乳腺癌细胞具有侵袭性恶性特性，但其潜在的分子机制尚未完全明确。在本研究中，我们报告了人类X盒结合蛋白1（XBP1）作为上皮-间质转化新调节因子的研究结果。我们发现XBP1表达增加与乳腺癌进展相关，且XBP1蛋白在配对的转移瘤中显著过表达。高XBP1蛋白水平还预示着乳腺癌患者的总生存期较短。RNA干扰介导的XBP1表达下调可恢复乳腺癌细胞中E-钙黏蛋白的表达和细胞间连接的形成，抑制细胞侵袭和肿瘤形成。相反，XBP1的过表达降低了上皮标志物E-钙黏蛋白的表达，但增加了乳腺癌细胞中间质标志物的表达。我们的研究结果表明关键上皮-间质转化调节因子Snail的表达上调，且它介导了XBP1激活上皮-间质转化和细胞侵袭。
