MicroRNA miR-29 modulates expression of immunoinhibitory molecule B7-H3: potential implications for immune based therapy of human solid tumors.
MicroRNA miR-29 modulates expression of immunoinhibitory molecule B7-H3: potential implications for immune based therapy of human solid tumors.
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DOI：
10.1158/0008-5472.can-08-4517
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发表时间：
2009-08-01
期刊：
影响因子：
11.2
通讯作者：
Cheung NK
中科院分区：
文献类型：
--
作者：
Xu H;Cheung IY;Guo HF;Cheung NK
B7-H3是一种表面免疫调节糖蛋白，抑制自然杀伤细胞和T细胞。单克隆抗体8H 9对4 Ig-B7-H3具有特异性，4 Ig-B7-H3是B7-H3的主要长型。使用8H 9的放射免疫疗法的早期结果已经显示出在患有转移到中枢神经系统的实体瘤的患者中的前景。虽然B7-H3转录物在人实体瘤和人正常组织中广泛表达，但B7-H3蛋白仅在肿瘤组织中优先表达。定量RT-PCR结果显示，miR-29的3种亚型（a，B，c）在正常组织中均高表达。然而，它们在广泛的实体瘤中下调，包括神经母细胞瘤、肉瘤、脑肿瘤和肿瘤细胞系。B7-H3蛋白表达与检测的细胞系和肿瘤组织中的miR-29水平呈负相关。荧光素酶报告基因检测结果显示，miR-29 a可直接靶向B7-H3的3′UTR，敲入和敲低miR-29 a分别导致B7-H3蛋白表达下调和上调。miR-29控制B7-H3蛋白表达的能力与实体瘤的免疫逃逸有关。这种关键免疫抑制分子在肿瘤与正常组织中的差异调节可以促进细胞介导的免疫治疗，以及使用B7-H3特异性单克隆抗体8H 9的基于抗体的靶向策略。
B7-H3, a surface immunomodulatory glycoprotein, inhibits natural killer cells and T cells. The monoclonal antibody 8H9 is specific for 4Ig-B7-H3, the long and principal form of B7-H3. Early results from radioimmunotherapy using 8H9 have shown promise in patients with metastatic solid tumors to the central nervous system. While B7-H3 transcript was ubiquitously expressed in a wide spectrum of human solid tumors as well as human normal tissues, B7-H3 protein was preferentially expressed only in tumor tissues. By quantitative RT-PCR, all 3 isoforms of microRNA miR-29 (a, b, c) were highly expressed in normal tissues. However, they were down-regulated in a broad spectrum of solid tumors, including neuroblastoma, sarcomas, brain tumors, and tumor cell lines. B7-H3 protein expression was correlated inversely with miR-29 levels in both cell lines and tumor tissues tested. Using luciferase reporter assay, miR-29a was shown to directly target B7-H3 3′UTR, and knock-in and knock-down of miR-29a led to down-regulation and up-regulation, respectively, of B7-H3 protein expression. The ability of miR-29 to control B7-H3 protein expression has implications in immune escape by solid tumors. Differential modulation of this key immunoinhibitory molecule in tumor versus normal tissues may advance both cell mediated immunotherapy, as well as antibody-based targeted strategies using the B7-H3 specific monoclonal antibody 8H9.