ADAMTS8在结直肠癌中的抑癌作用及其负调控MAPK/ERK通路的机制研究

项目名称： ADAMTS8在结直肠癌中的抑癌作用及其负调控MAPK/ERK通路的机制研究

项目编号： No.81201934

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学2

项目作者： 李际盛

作者单位： 山东大学

项目金额： 23万元

中文摘要： 新型金属蛋白酶ADAMTS家族某些成员近期被发现具有抑癌作用，但在结直肠癌中仍缺乏针对该家族的系统研究。前期在结直肠癌细胞系中对该家族进行的筛选研究发现成员ADAMTS8因启动子甲基化在癌细胞系中频繁沉默，恢复其表达可抑制肿瘤克隆形成并下调MAPK/ERK活性，提示它在结直肠癌中可能具有抑癌作用，但具体功能及机制不清。我们推测ADAMTS8可能通过负调控EGF、VEGF或Integrin通路下调MAPK/ERK活性而发挥抗增殖、促凋亡或抗血管生成等抑癌功能，并在原发结直肠癌组织中因甲基化沉默。为验证这一假设，拟利用癌细胞系及裸鼠模型开展体内、体外实验以研究ADAMTS8在结直肠癌细胞增殖、凋亡及血管生成中的抑癌功能及关键分子机制，并分析它在原发结直肠癌中的表达和甲基化状态及与肿瘤分期、预后等的相关性。结果将为研发新型结直肠癌治疗靶点和策略提供理论依据，并有可能发现新型结直肠癌标志物。

中文关键词： ADAMTS8；DNA甲基化；MAPK/ERK通路；EGFR；抑癌基因

英文摘要： Some members of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) metalloproteinase family have recently been reported to function as candidate tumor suppressor. However, there are still no systemic study carried out in the colorectal cancer (CRC) for this family by now. In our previous screening study for the 19 human ADAMTS genes, ADAMTS8 was revealed to be silenced by promoter CpG methylation in multiple CRC cell lines. Re-expression of ADAMTS8 could inhibit the colony formation ability of the HT29 CRC cell and meanwhile suppress its MAPK/ERK activity, suggesting that ADAMTS8 could be a functional tumor suppressor candidate in CRC. However, the biological role of ADAMTS8 and related molecular mechanism are still unknown. Based on our preliminary data, we presume that ADAMTS8 is a novel candidate tumor suppressor gene with multiple tumor-suppressing roles which is silenced by promoter methylation in CRC. ADAMTS8 may play its role through suppressing the MAPK/ERK signaling and it may mediate the MAPK/ERK inhibition via the EGF, VEGF or Integrin pathways. To prove above hypotheses, we plan to study the role of ADAMTS8 in the regulation of the proliferation, apoptosis and angiogenesis of CRC using in vitro and in vivo assays. Besides, we will also analyze if ADAMTS8 play its anti-tumorig

英文关键词： ADAMTS8；DNA methylation；MAPK/ERK signaling；EGFR；tumor suppressor gene