Peptide-based inhibition of the HOXA9/PBX interaction retards the growth of human meningioma
Peptide-based inhibition of the HOXA9/PBX interaction retards the growth of human meningioma
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DOI：
10.1007/s00280-013-2316-5
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发表时间：
2014-01-01
影响因子：
3
通讯作者：
Wakabayashi, Toshishiko
中科院分区：
文献类型：
--
作者：
Ando, Hitoshi;Natsume, Atsushi;Wakabayashi, Toshishiko
脑膜瘤是最常见的颅内肿瘤类型，占原发性颅内肿瘤的24%至30%。到目前为止，还没有生物标志物能够可靠地预测脑膜瘤的临床结果。先前的全基因组甲基化分析显示HOXA9是功能最相关的生物标志物之一。在这项研究中，我们利用一种抑制HOXA9与其辅助因子PBX相互作用的肽抑制剂HXR9，研究了HOXA9是否是脑膜瘤的潜在治疗靶点。我们测定了HOXA9在人脑膜瘤、脑膜瘤细胞系和正常脑组织中的表达水平。培养脑膜瘤和皮下肿瘤用HXR9治疗。我们还研究了HOXA9/PBX二聚体的破坏。我们首先证实HOXA9在脑膜瘤中高表达，而在正常脑组织中不表达。HXR9肽阻断HOXA9与PBX的结合，导致DNA结合的改变，进而调控其靶基因。HXR9明显抑制脑膜瘤细胞和皮下脑膜肿瘤的生长。目前脑膜瘤还没有有效的化疗方法，针对HOXA9/PBX的相互作用可能是一种新的治疗方案。
Meningiomas are the most common type of intracranial tumor, accounting for between 24 and 30 % of primary intracranial tumors. Thus far, no biomarkers exist to reliably predict the clinical outcome of meningiomas. A previous genome-wide methylation analysis revealed that HOXA9 is one of the most functionally relevant biomarkers. In this study, we have examined whether HOXA9 is a potential therapeutic target in meningiomas, using HXR9, a peptide inhibitor of the interaction between HOXA9 and its cofactor PBX.We determined the expression level of HOXA9 in human meningiomas, meningioma cell lines, and normal brain tissue. Meningioma in culture and in subcutaneous tumors was treated with HXR9. We also examined the disruption of HOXA9/PBX dimers.We first confirmed that HOXA9 is highly expressed in meningiomas, but not in normal brain tissue. The HXR9 peptide blocks the binding of HOXA9 to PBX, leading to an alteration of DNA binding, and subsequent regulation of their target genes. HXR9 markedly inhibited the growth of meningioma cells and subcutaneous meningeal tumors.There is no effective chemotherapy for meningiomas at present, and targeting the HOXA9/PBX interaction may represent a novel treatment option for this disease.