Park Soon Young, Piao Yuji, Jeong Kang Jin, Dong Jianwen, de Groot John F
Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Mol Cancer Ther. 2016 Sep;15(9):2187-97. doi: 10.1158/1535-7163.MCT-15-0427. Epub 2016 Jun 15.
Periostin (POSTN) interacts with multiple integrins to coordinate a variety of cellular processes, including epithelial-to-mesenchymal transition (EMT) and cell migration. In our previous study, anti-VEGF-A therapy was associated with resistance and EMT. This study sought to determine the role of POSTN in the resistance of glioma stem cells (GSC) to antiangiogenic therapy. In mouse xenograft models of human glioma, POSTN expression was associated with acquired resistance to anti-VEGF-A therapy and had a synergistic effect with bevacizumab in prolonging survival and decreasing tumor volume. Resistance to anti-VEGF-A therapy regulated by POSTN was associated with increased expression of TGFβ1 and hypoxia-inducible factor-1α (HIF1α) in GSCs. At the molecular level, POSTN regulated invasion and expression of EMT (caveolin-1) and angiogenesis-related genes (HIF1α and VEGF-A) through activation of STAT3. Moreover, recombinant POSTN increased GSC invasion. Collectively, our findings suggest that POSTN plays an important role in glioma invasion and resistance to antiangiogenic therapy. Mol Cancer Ther; 15(9); 2187-97. ©2016 AACR.
骨膜蛋白（POSTN）与多种整合素相互作用，以协调包括上皮-间质转化（EMT）和细胞迁移在内的多种细胞过程。在我们之前的研究中，抗VEGF-A治疗与耐药性和EMT相关。本研究旨在确定POSTN在胶质瘤干细胞（GSC）对抗血管生成治疗耐药中的作用。在人胶质瘤的小鼠异种移植模型中，POSTN表达与对抗VEGF-A治疗的获得性耐药相关，并且在延长生存期和减小肿瘤体积方面与贝伐单抗具有协同作用。由POSTN调节的对抗VEGF-A治疗的耐药性与GSCs中TGFβ1和缺氧诱导因子-1α（HIF1α）表达增加相关。在分子水平上，POSTN通过激活STAT3调节EMT（小窝蛋白-1）和血管生成相关基因（HIF1α和VEGF-A）的侵袭和表达。此外，重组POSTN增加了GSC的侵袭。总体而言，我们的研究结果表明，POSTN在胶质瘤侵袭和抗血管生成治疗耐药中起重要作用。《分子癌症治疗》；15（9）；2187-2197。©2016美国癌症研究协会。
