Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target
Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target
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DOI：
10.1172/jci57147
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发表时间：
2011-10-01
影响因子：
15.9
通讯作者：
Soderberg-Naucler, Cecilia
中科院分区：
文献类型：
--
作者：
Baryawno, Ninib;Rahbar, Afsar;Soderberg-Naucler, Cecilia
髓母细胞瘤是儿童最常见的恶性脑肿瘤。它们表达高水平的考克斯-2并产生PGE（2），PGE（2）刺激肿瘤细胞增殖。人巨细胞病毒（HCMV）在人群中普遍存在，并且编码提供免疫逃避策略并促进致癌转化和肿瘤调节的蛋白质。特别地，HCMV诱导考克斯-2表达; STAT 3磷酸化; PGE 2、血管内皮生长因子和IL-6的产生;以及体内肿瘤形成。在这里，我们表明，一个大比例的原发性髓母细胞瘤和髓母细胞瘤细胞系感染HCMV和考克斯-2的表达，沿着PGE 2水平，在肿瘤中直接调制的病毒。我们的分析表明，HCMV立即早期蛋白和晚期蛋白在大多数原发性髓母细胞瘤中表达。值得注意的是，我们分析的所有人髓母细胞瘤细胞系都含有HCMV DNA和RNA，并在体外表达不同水平的HCMV蛋白。当移植到免疫功能低下的小鼠，人髓母细胞瘤细胞诱导HCMV蛋白的表达。HCMV和考克斯-2表达在原发肿瘤、细胞系和髓母细胞瘤异种移植物中相关。抗病毒药物缬更昔洛韦和特异性考克斯-2抑制剂塞来昔布在体外阻止HCMV复制，并在体外和体内抑制PGE 2产生和减少髓母细胞瘤肿瘤细胞生长。更昔洛韦不影响HCMV阴性肿瘤细胞系的生长。这些发现暗示了HCMV在髓母细胞瘤中的重要作用，并建议HCMV作为这种肿瘤的新的治疗靶点。
Medulloblastomas are the most common malignant brain tumors in children. They express high levels of COX-2 and produce PGE(2), which stimulates tumor cell proliferation. Human cytomegalovirus (HCMV) is prevalent in the human population and encodes proteins that provide immune evasion strategies and promote oncogenic transformation and oncomodulation. In particular, HCMV induces COX-2 expression; STAT3 phosphorylation; production of PGE2, vascular endothelial growth factor, and IL-6; and tumor formation in vivo. Here, we show that a large proportion of primary medulloblastomas and medulloblastoma cell lines are infected with HCMV and that COX-2 expression, along with PGE2 levels, in tumors is directly modulated by the virus. Our analysis indicated that both HCMV immediate-early proteins and late proteins are expressed in the majority of primary medulloblastomas. Remarkably, all of the human medulloblastoma cell lines that we analyzed contained HCMV DNA and RNA and expressed HCMV proteins at various levels in vitro. When engrafted into immunocompromised mice, human medulloblastoma cells induced expression of HCMV proteins. HCMV and COX-2 expression correlated in primary tumors, cell lines, and medulloblastoma xenografts. The antiviral drug valganciclovir and the specific COX-2 inhibitor celecoxib prevented HCMV replication in vitro and inhibited PGE2 production and reduced medulloblastoma tumor cell growth both in vitro and in vivo. Ganciclovir did riot affect the growth of HCMV-negative tumor cell lines. These findings imply an important role for HCMV in medulloblastoma and suggest HCMV as a novel therapeutic target for this tumor.