TWIST1 promotes invasion through mesenchymal change in human glioblastoma.
TWIST1 promotes invasion through mesenchymal change in human glioblastoma.
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DOI：
10.1186/1476-4598-9-194
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发表时间：
2010-07-20
期刊：
影响因子：
37.3
通讯作者：
Rostomily RC
中科院分区：
文献类型：
--
作者：
Mikheeva SA;Mikheev AM;Petit A;Beyer R;Oxford RG;Khorasani L;Maxwell JP;Glackin CA;Wakimoto H;González-Herrero I;Sánchez-García I;Silber JR;Horner PJ;Rostomily RC
肿瘤细胞侵袭邻近正常脑组织是GBM的间质特征，也是导致其预后不良的主要因素。因此，更好地了解促进基底膜间充质改变的机制对于解决侵袭性具有重要的临床意义。我们之前的研究表明，bHLH转录因子Twist1在GBM中上调，并促进SF767 GBM细胞的体外侵袭。Twist1通过上皮间充质转化(EMT)协调肿瘤转移。为了进一步明确Twist1在GBM中的功能，我们测试了Twist1过表达对体内侵袭的影响及其对基因表达的影响。我们发现，Twist1显著增加了SNB19和T98G细胞在异种移植中的侵袭力，并增加了与黏附、细胞外基质蛋白、细胞运动和运动、细胞迁移和肌动蛋白细胞骨架组织相关的功能类别基因的表达。与此一致的是，Twist1减少了细胞聚集，促进了肌动蛋白细胞骨架的重组，并增强了对纤维连接蛋白底物的迁移和黏附。Twist1上调的单个已知促进EMT和/或GBM侵袭的基因包括SNAI2、MMP2、HGF、FAP和FN1。与癌EMT不同，Twist1不会在GBM细胞系中产生E-到N-钙粘素“开关”。体外鉴定的Twist靶基因SNAI2和成纤维细胞激活蛋白α(FAP)与Twist1在39例人类肿瘤中的表达高度相关，证实了它们与临床的相关性。抑制Twist1的潜在治疗重要性也通过减少细胞体外侵袭和GBM干细胞的生长而显示出来。总之，这些研究表明，Twist1增强了GBM的侵袭，与间质改变相一致，而不涉及癌EMT中典型的钙粘素开关。鉴于最近认识到间充质改变与恶性程度的增加有关，这些发现支持了颠覆Twist1介导的间充质改变的策略的潜在治疗重要性。
Tumor cell invasion into adjacent normal brain is a mesenchymal feature of GBM and a major factor contributing to their dismal outcomes. Therefore, better understandings of mechanisms that promote mesenchymal change in GBM are of great clinical importance to address invasion. We previously showed that the bHLH transcription factor TWIST1 which orchestrates carcinoma metastasis through an epithelial mesenchymal transition (EMT) is upregulated in GBM and promotes invasion of the SF767 GBM cell line in vitro. To further define TWIST1 functions in GBM we tested the impact of TWIST1 over-expression on invasion in vivo and its impact on gene expression. We found that TWIST1 significantly increased SNB19 and T98G cell line invasion in orthotopic xenotransplants and increased expression of genes in functional categories associated with adhesion, extracellular matrix proteins, cell motility and locomotion, cell migration and actin cytoskeleton organization. Consistent with this TWIST1 reduced cell aggregation, promoted actin cytoskeletal re-organization and enhanced migration and adhesion to fibronectin substrates. Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1. Distinct from carcinoma EMT, TWIST1 did not generate an E- to N-cadherin "switch" in GBM cell lines. The clinical relevance of putative TWIST target genes SNAI2 and fibroblast activation protein alpha (FAP) identified in vitro was confirmed by their highly correlated expression with TWIST1 in 39 human tumors. The potential therapeutic importance of inhibiting TWIST1 was also shown through a decrease in cell invasion in vitro and growth of GBM stem cells. Together these studies demonstrated that TWIST1 enhances GBM invasion in concert with mesenchymal change not involving the canonical cadherin switch of carcinoma EMT. Given the recent recognition that mesenchymal change in GBMs is associated with increased malignancy, these findings support the potential therapeutic importance of strategies to subvert TWIST1-mediated mesenchymal change.