AFB1诱发的ADAMTS4表达通过调控ARNT/VEGF通路促进肝癌新生血管形成的研究

Our previous studies have shown that aflatoxin B1 (AFB1)-induced ADAMTS4 expression may involve in the development of hepatocellular carcinoma (HCC). However, the corresponding mechanisms are not clear..In pilot experiments of this project, we found the levels of ADAMTS4 expression in the tumor tissuelar samples with HCC were positively correlated with tumor micro-vessel density. Furthermore, ADAMTS4 expression was also associated with the expression of ARNT and VEGF. Based on the aforementioned findings, we will carry out the following research works: (1) studing and analyzing the network-modifying correlation between ADAMTS4 and ARNT/VEGF, their molecualr mechanisms, and possible change under the conditions of with or without AFB1; (2) researching the effects of ADAMTS4 on the HCC angiogenesis and correspondning actions such as proliferation and differentiation, the ability of tumor colony formation and drug tolerance, and the capacity of invasion and metastasis; (3) studing and analyzing the change of ADAMTS4/ARNT/VEGF in the tumor tissues with different differentiation and metastative potential HCC; and (4) analyzing the role of ADAMTS4/ARNT/VEGF in the HCC angiogenesis and their clinical values. This studies might help us not only to elucidate the molecular mechanisms of angiogenesis, invasion, and metastasis of HCC, but to provide new experimental data for targeting treatment of HCC.

课题组的前期研究发现黄曲霉毒素B1(AFB1)诱发的ADAMTS4表达涉及到肝细胞癌（HCC）的发生和发展过程，但机制不清楚。本课题的预实验发现：在HCC肿瘤组织中，ADAMTS4表达水平与血管密度正相关，也与ARNT和VEGF表达相关，我们将以此为线索开展如下研究：①研究与分析ADAMTS4和ARNT/VEGF间的网络调控关系、相关机制及在有无AFB1作用模式下的变化规律；②研究ADAMTS4对HCC新生血管形成的影响及相关生物学行为如增殖和分化能力、成瘤和耐药能力、浸润转移能力等的影响；③研究与分析ADAMTS4/ARNT/VEGF在不同分化程度和转移能力的HCC肿瘤组织中的变化情况；④分析ADAMTS4/ARNT/VEGF在HCC新生血管形成中的作用及临床价值。通过以上研究可有助于阐述HCC新生血管形成和侵袭转移的相关分子机制，为HCC靶向治疗提供新的实验依据，因而具有重要研究意义。

本立项课题是基于课题组前期所发现 “在HCC肿瘤组织中，ADAMTS4表达水平与血管密度正相关，也与ARNT和VEGF表达相关”的工作基础提出来，完成的主要研究内容包括：ADAMTS4在HCC新生血管形成及相关生物学行为的影响以及这种影响与AFB1的关系、ADAMTS4和ARNT/VEGF间的网络调控关系以及相关机制、ADAMTS4/ARNT/VEGF在不同分化程度和转移能力的HCC肿瘤组织中的变化情况以及临床价值。通过研究，我们发现AFB1诱发的ADAMTS4表达能通过调控ARNT表达并激活ARNT/VEGF信号通路而促进肝癌血管新生形成。这对阐明ADAMTS4/ARNT/VEGF在HCC新生血管形成和侵袭转移的地位具有重要科学价值，对进一步阐明肝癌发生发展提供了有价值的解释，也对指导肝癌的预防，为肝癌的生物治疗提供了新的理论依据，因而产生广泛的社会效益和经济效益。.针对以上所解决的科学问题涉及到的相关内容共在国外出版论文14篇，其中SCI收录5篇，出版专著1部，获得专利1项；培养研究生 10 名，超额完成了项目最初所提出的预期目标。