申请者基于前期研究发现LPS、IL-6明显增加原代培养人肝细胞DEC1的表达；肝癌患者肿瘤组织中的DEC1和survivin表达明显高于周围正常肝组织； DEC1增加Src对HepG2细胞集落（foci）形成作用，增加肿瘤细胞集落中STAT3磷酸化而促进肿瘤形成；DEC1参与8-MOP诱导肝肿瘤细胞株（HepG2、Huh7）凋亡；抗肿瘤药物CPT11在抗肿瘤的同时降低DEC1的表达的基础上，提出DEC1在肝脏肿瘤发生进程中可能发挥重要调控作用的假设。本项目应用DEC1基因敲除和过度表达模型，从整体、细胞、分子水平研究、阐明DEC1在肝脏肿瘤发生发展进程中的调控作用和机制以及DEC1在抗肿瘤药物抗肿瘤作用中的作用机制和意义。预期研究结果不仅在拓展DEC1肿瘤学的研究领域，且为基于DEC1为分子靶向性治疗和抗肿瘤药物的研发提供新的靶标。

Based on the following data we had gotten: (1) DEC1 expression increased induced by LPS and IL-6 in the primary culture human hepatocytes. (2) Both DEC1 and survivin were expressed markedly higher in the liver tumors than in the adjacent normal tissues. (3) DEC1 promoted the cell foci formation induced by Src in HepG2 cells and increased the phosphorylation of STAT3 in the foci. (4) DEC1 transcriptionally upregulate the expression of antiapoptotic protein survivin, especially without serum (minmic tumor microenvironment). (5) Down regulation of DEC1 is involved in 8-methoxypsoralen-induced apoptosis in HepG2 cells. Therefore, it is hyothesized that DEC1 probably plays a crucial role in liver tumor genesis, progression, invasiveness and metastasis. This study will investigate the regulation and mechanism of DEC1 in liver tumor genesis, progression, invasiveness and metastasis and the mechanism and significance of the antitumor effects by antitumor drugs using the overexpression and knockout DEC1 models from the whole, the cell and molecule levels. Expected outcome will reveal the regulation and mechanism of DEC1 in oncogenesis, tumor progression, invasiveness and metastasis, and the mechanism and significance of DEC1 in the antitumor effects by antitumor drugs. This study not only expands DEC1 oncology field academically, but also provides the molecular target therapy and the antitumor drugs development based on DEC1.

基于前期研究发现LPS、IL-6明显增加原代培养人肝细胞DEC1的表达；肝癌患者肿瘤组织中的DEC1和survivin表达明显高于周围正常肝组织； DEC1增加Src对HepG2细胞集落（foci）形成作用，增加肿瘤细胞集落中STAT3磷酸化而促进肿瘤形成；DEC1参与8-MOP诱导肝肿瘤细胞株（HepG2、Huh7）凋亡；抗肿瘤药物CPT11在抗肿瘤的同时降低DEC1的表达的基础上，提出DEC1在肝脏肿瘤发生进程中可能发挥重要调控作用的假设。本项目应用DEC1基因敲除小鼠、HepG2细胞过度表达等模型，在整体、细胞、分子水平研究、阐明DEC1在肝脏肿瘤发生发展进程中的调控作用和机制以及DEC1在抗肿瘤药物抗肿瘤作用（8-MOP、知母皂苷III）中的作用机制和意义。结果发现：（1）8-MOP（8-methoxypsoralen）具有诱导肝肿瘤细胞株（HepG2）凋亡，其机制通过降低肿瘤细胞DEC1表达；（2）8-MOP具有抗肝肿瘤细胞转移，其机制是下调DEC1表达而抑制EMT；（3）知母皂苷A III（Timosaponin AIII, TAIII）抑制乳腺癌侵袭和转移，通过降低DEC1表达，抑制EMT，ECM和血管生成；（4）通过在两种基因型（DEC1+/+、DEC1-/-）小鼠制备结肠炎及结肠炎性结肠癌模型发现：DEC1敲除小鼠可抑制小鼠结肠炎的发生，抑制小鼠结肠炎性结肠癌的发生，其机制主要DEC1缺乏可抑制致炎因子（IL-6、IL-1β）产生、促进抑炎因子（IL-10），影响免疫系统功能。本研究表明DEC1不仅在肝肿瘤发生发展中发挥重要作用，而且在肿瘤的侵袭和转移、炎症-肿瘤转化过程中发挥重要作用，为基于DEC1为分子靶向性治疗和抗肿瘤药物的研发提供新的靶标。