AGGF1在肝细胞癌肿瘤血管生成中的作用及其分子机制研究

Sustained angiogenesis is a hallmark of most cancer types. Tumor growth, invasion and metastasis all rely on angiogenesis. Suppression of tumor angiogenesis is a promising strategy for cancer therapy. Hepatocellular carcinoma (HCC), a hypervascular tumor characterized by neovascularization, is a common malignancy worldwide with a high incidence in China. Aggressive angiogenesis promotes tumor growth, metastasis, rapid recurrence and heralds poor survival in HCC. Although anti-angiogenesis is considered an effective novel treatment for HCC, there are limited known targets for anti-angiogenic therapy. AGGF1 is a novel pro-angiogenic factor gene identified through genetic analysis of a congenital vascular disorder called Klippel-Trenaunay syndrome. The role of AGGF1 is largely unknown, especially in cancers. Our preliminary data show that AGGF1 is expressed and secreted by HCC tissues and cell lines, indicating that AGGF1 may play roles in HCC development and progression. We hypothesize that AGGF1 might regulate angiogenesis in the context of HCC. The aims of this project are to explore the role of AGGF1 in tumor angiogenesis for HCC, to elucidate its molecular mechanisms, and to translate the basic finding into possible anti-angiogenic strategy for treatment of HCC. We plan to investigate the expression of AGGF1 in tumor tissues in a cohort of specimens of HCC patients. Then the roles of AGGF1 in tumor angiogenesis will be determined in vitro by endothelial cell tube-formation assay, and then be analyzed in vivo in mice models of HCC xenografts including subcutaneous and orthotopic transplantation. Finally, the signaling pathway for AGGF1-mediated tumor angiogenesis will be elucidated. This project will clarify the roles and mechanisms of AGGF1 in angiogenesis during hepatocarcinogenesis and may lay the groundwork for rationalized development of novel anti-cancer strategies.

持续的血管生成是恶性肿瘤的主要特征之一，癌细胞的生长、侵袭和转移均依赖于血管。抑制肿瘤血管生成日趋成为肿瘤治疗的新策略。肝细胞癌(HCC)是我国高发的一种恶性肿瘤，血管生成被认为在HCC的生长、转移和复发中起重要作用。已证实抑制肿瘤血管生成对于治疗HCC非常有效，但已知的可作为HCC抗血管生成治疗的靶点较少。AGGF1是在先天性静脉畸形骨肥大综合征的遗传学研究中克隆到的一个新的血管生成基因，但其在肿瘤中的功能不清楚。申请者前期发现，AGGF1蛋白在HCC中高表达且可被分泌，这提示AGGF1可能在HCC中发挥作用。AGGF1的高表达是否与HCC中活跃的肿瘤血管生成有关？据此，本项目拟以HCC为模型，探究AGGF1在肿瘤血管生成中的作用。本课题将在临床标本、细胞和动物三个层面上揭示AGGF1对HCC肿瘤血管生成的影响，并解析其分子机制，为HCC的抗肿瘤血管生成治疗提供理论依据和新的靶点。

AGGF1（Angiogenic Factor with G Path and FHA domains 1）基因是通过对先天性静脉畸形骨肥大综合征进行精细的分子遗传学分析时，克隆到的一个新基因，该基因在所编码的蛋白在体外展现出强烈的促血管生成能力，初步被认定为一个新的血管生成因子。血管生成因子在转化医学应用中有巨大前景，如肿瘤抗血管生成治疗和缺血性疾病的促血管新生治疗等。AGGF1作为一个新的血管生成因子，为开发其转发医学应用潜能，有必要对其病理生理学功能及机制进行深入挖掘。本项目开展了两大方面的研究：第一部分，对AGGF1在血管损伤中功能作用进行了研究，发现AGGF1可保护血管血管损伤，其机制是通过调控Myocardin-SRF复合体稳定性从而影响血管平滑肌细胞形态转换，展示了其在动脉粥样硬化、高血压等重要心血管疾病中重要作用；第二部分，对AGGF1在肝脏损伤中病理生理学作用进行了研究，发现AGGF1可通过抑制TGF-beta信号通路活性，抑制肝星状细胞活化，从而减缓肝纤维化的发生，同时可拮抗NF-kB活性，减缓肝脏炎症；在脂肪性肝病中，AGGF1可影响AKT活性，调控肝脏对胰岛素的敏感性。上述研究成果揭示了AGGF1在心血管及肝脏病理生理学过程中有重要作用，为将来开发以AGGF1为靶标的分子医学治疗手段奠定了初步理论依据。