HoxC9影响神经母细胞瘤增殖与分化的分子机制研究

Neuroblastoma is a childhood malignant tumor of the sympathetic nervous system that accounts for approximately 10% of all childhood cancers and 15% of all childhood cancer death. Differentiation status in neuroblastoma strongly affects clinical outcomes: patients with poorly differentiated neuroblastoma have significantly poorer prognosis than those with differentiated tumor. The molecular mechanisms that control neuroblastoma differentiation status are largely unknown. .Our previous work has yielded two major findings that open new avenues of investigation into the molecular control of neuroblastoma differentiation and its impact on neuroblastoma pathogenesis. First, we have identified HOXC9 as a key regulator of neuroblastoma differentiation. Clinically, high HOXC9 expression is associated with neuroblastoma differentiation and is prognostic marker for better survival in neuroblastoma patients. In neuroblastoma cell lines, increased HOXC9 expression triggers neuronal differentiation, cell cycle exit and global attenuation of DNA damage response. At the molecular level, HOXC9 transcriptionally activates neuronal genes and represses cell cycle and DNA repair genes. Second, our investigation with MYCN mice, an animal model of human neuroblastoma, suggests that neuroblastoma development follows the cancer stem cell model. We have identified a minor population of nestin+ mouse neuroblastoma cells with self-renewal and differentiation potential, and developed an animal system that allows us to monitor the nestin+ cells during neuroblastoma initiation and progression in vivo, and to isolate and characterize them in vitro. The overall objective of this application is to test the hypothesis that HOXC9 transcriptionally activates and/or interacts with specific histone H3 methyltransferases and demethylases to coordinate the expression of neuronal, cell cycle and DNA repair genes during differentiation. We further hypothesize that HOXC9-induced differentiation is a key barrier to neuroblastoma initiation and/or progression.Our outcomes are anticipated to identify new drug targets for differentiation-based neuroblastoma therapy, advance our understanding of the molecular mechanism underlying the coordination between differentiation, cell cycle exit and global attenuation of DNA damage response, a central question in the field of developmental biology, advance our understanding of neuroblastoma pathogenesis and to identify a key cellular target for earlier detection of neuroblastoma, for better prediction of clinical outcomes, and for cancer stem cell-based drug discovery.

神经母细胞瘤是一种儿童常见的致死性肿瘤。肿瘤细胞的分化状态和临床预后有着直接和密切的联系。充分分化成熟的肿瘤细胞可自然消退。然而如何调控神经母细胞瘤细胞分化的分子机制还不清楚，有待进一步的深入研究。我们前期的工作已经证实HOXC9是调节神经母细胞瘤分化的关键基因之一，因此在前期工作的基础之上，将以MYCN转基因鼠、 nestin-GFP转基因鼠和HOXC9敲除小鼠为研究模型，阐释HOXC9调控神经母细胞瘤细胞分化的分子机制。本课题从表观修饰角度探索HOXC9调控细胞增殖、分化与细胞周期的机制，本课题的开展将为筛选以促进细胞分化为治疗基础的新药及标记物发现提供理论支撑，为肿瘤的早期诊断，病变进展及预后的判断打下基础。

围绕阐述HOXC9调控神经母细胞瘤细胞分化的分子机制这个重要的科学问题，我们利用基因芯片和chip-sequenc 技术，从细胞周期，DNA修复，神经母细胞瘤分化等几个层面暂开系统的研究，取得了一系列的创新成果。