Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Florida Hospital Cancer Institute, Orlando, Florida 32816, USA.
Cancer Res. 2010 Jan 1;70(1):418-27. doi: 10.1158/0008-5472.CAN-09-2654. Epub 2009 Dec 22.
Glioblastoma multiforme (GBM) is the most frequent and incurable type of brain tumor of adults. Hypoxia has been shown to direct GBM toward a more aggressive and malignant state. Here we show that hypoxia increases Notch1 activation, which in turn induces the expression of transient receptor potential 6 (TRPC6) in primary samples and cell lines derived from GBM. TRPC6 is required for the development of the aggressive phenotype because knockdown of TRPC6 expression inhibits glioma growth, invasion, and angiogenesis. Functionally, TRPC6 causes a sustained elevation of intracellular calcium that is coupled to the activation of the calcineurin-nuclear factor of activated T-cell (NFAT) pathway. Pharmacologic inhibition of the calcineurin-NFAT pathway substantially reduces the development of the malignant GBM phenotypes under hypoxia. Clinically, expression of TRPC6 was elevated in GBM specimens in comparison with normal tissues. Collectively, our studies indicate that TRPC6 is a key mediator of tumor growth of GBM in vitro and in vivo and that TRPC6 may be a promising therapeutic target in the treatment of human GBM.
多形性胶质母细胞瘤（GBM）是成人中最常见且无法治愈的脑肿瘤类型。缺氧已被证明可使 GBM 向更具侵袭性和恶性的状态发展。在这里，我们表明缺氧会增加 Notch1 的激活，进而在源自 GBM 的原代样本和细胞系中诱导瞬时受体电位 6（TRPC6）的表达。TRPC6 是侵袭性表型发展所必需的，因为 TRPC6 表达的敲低会抑制神经胶质瘤的生长、侵袭和血管生成。功能上，TRPC6 导致细胞内钙的持续升高，与钙调神经磷酸酶-活化 T 细胞核因子（NFAT）途径的激活偶联。钙调神经磷酸酶-NFAT 途径的药理学抑制可显著减少缺氧下恶性 GBM 表型的发展。临床上，与正常组织相比，GBM 标本中 TRPC6 的表达升高。总之，我们的研究表明，TRPC6 是体外和体内 GBM 肿瘤生长的关键介质，TRPC6 可能是治疗人类 GBM 的有前途的治疗靶点。
