Development plan of the new treatment for malignant glioma using Monocyte Chemoattrctant Protein-1

单核细胞趋化蛋白-1治疗恶性胶质瘤新疗法的开发计划

• 批准号: 09671430
• 负责人: KURATSU Jun-ichi
• 金额: $ 1.92万
• 依托单位: Kagoshima University (1998)Kumamoto University (1997)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09671430/
• 关键词: MCP-1; Glioma; Angiogenesis; Macrophage; Macrophage; グリオーマ; マクロファージ; サイトカイン

We previously purified the human monocyte chemoattractant protein-1(MCP-1) from supernatant of cultured human glioma cell lines. MCP-1 is a member of the C-C chemokines that medicate monocyte chemotaxis. After cloning of the MCP-1 cDNA, ewe hacve analyzed the expression of the gene In a variety of brain tumors. We found the therewas a positive correatlon between the amount of MCP-1 expression of the tumors and the number of tumor associated macrophages. Furthermore, a transfection experiment demonstrated that excessive expression of this chemokine could induce macrophage infiltration and suppression In vivo tumor growth.The MCP-1 receptor, designated hCCR2, is an essential co-receptor In cell entry by the human immunodeficiency virus (HIV) as , well as a receptor for MCP-1. To elucidate the molecular mechanisms for transcriptional regulation of hCCR2, we cloned and sequenced the hCCR2 gene. In the 5-flanking region, there were the typical mammalian promotor consensus elements, a CAAT box and a TATA box resulting in a single transcription-Initiation site.Furthermore, we found that macraphages infiltrated into the glioma tissue express the tyrosine phosphorylase which play an important role on the neovascularization. We posit the regulation of MCP-1 activity and the control of the CCR2 expression of macrophages should lead to the growth control of glioma.

我们以前纯化的人单核细胞趋化蛋白-1（MCP-1）培养的人脑胶质瘤细胞系的上清液。MCP-1是C-C趋化因子的成员，其抑制单核细胞趋化性。克隆MCP-1 cDNA后，我们分析了该基因在多种脑肿瘤中的表达。发现肿瘤组织中MCP-1的表达量与肿瘤相关巨噬细胞的数量呈正相关。此外，转染实验表明，该趋化因子的过度表达可以诱导巨噬细胞浸润和抑制体内肿瘤生长。MCP-1受体，命名为hCCR 2，是人类免疫缺陷病毒（HIV）进入细胞的必需辅助受体，也是MCP-1的受体。为了阐明hCCR 2转录调控的分子机制，我们克隆了hCCR 2基因并进行了序列测定。在5-侧翼区有典型的哺乳动物启动子共有元件，一个CAAT盒和一个TATA盒，形成一个转录起始位点。此外，我们还发现浸润到胶质瘤组织中的巨噬细胞表达酪氨酸磷酸化酶，该酶在胶质瘤新生血管形成中起重要作用。我们认为调节巨噬细胞的MCP-1活性和控制CCR 2的表达可能导致胶质瘤的生长控制。

项目成果

Nishi T.: "Treatment of cancer using pulsed eletctric-field in combination with chemotherapeutic agents or genes" Human Cell. 10(1). 81-86 (1997)

Nishi T.：“使用脉冲电场结合化疗药物或基因治疗癌症”《人类细胞》。

Yamamoto Ket al.: "Cloning and functional characterization of the 5'-flanking region of the human monocyte chemoattractant protain-1 receptor(CCR2)gene.-Essential role of 5' untranslated region in tissue specific expression." J. Biol. Chem.274(in press).

Yamamoto Ket al.：“人单核细胞趋化蛋白 protain-1 受体 (CCR2) 基因 5 侧翼区域的克隆和功能表征。-5 非翻译区域在组织特异性表达中的重要作用。”