DMBT1基因在胆囊癌发生发展中的作用及分子机制研究

候选抑癌基因DMBT1在多种恶性肿瘤中表达下调或缺失，但在多数慢性炎症中却呈高表达。国外研究主要集中于DMBT1对肿瘤进展的影响,而对其在肿瘤发生早期的作用及调控机制却鲜有报道。我们前期研究发现：胆囊癌组织中DMBT1表达明显下调，而癌旁组织(多合并慢性炎症)中呈高表达；体外实验证明DMBT1高表达能显著抑制胆囊癌细胞增殖、迁移，并促进其凋亡。故推测DMBT1在胆囊癌发生早期被诱导表达，参与机体免疫防护；随着肿瘤进展其表达下调或缺失，转而有利于肿瘤生长。本研究将在前期工作基础上，利用DMBT1基因敲除鼠模型和人胆囊癌裸鼠原位移植瘤模型，通过RNA干扰、基因芯片等技术，从体外到体内，旨在探讨DMBT1在胆囊癌发生、发展过程中所起的作用及其分子机制；并对DMBT1在两个不同表达阶段的调控机制进行初步研究。其科学意义在于：丰富胆囊癌发生发展的理论体系，为临床治疗提供新的高效靶点。

DMBT1 has been considered as a candidate tumor suppressor gene, whose expression is down-regulated or depleted in multiple types of malignant tumor, and yet DMBT1 is usually over-expressed when chronic inflammation occurs. Research overseas concentrates on the effect of EMBT1 during tumor development, while rarely did scientists mention of its role and regulation mechanism in early stage of tumor. In previous studies, we find that expression of DMBT1 dramatically down-regulated in gallbladder carcinoma, while the converse is true in normal adjacent tissues, usually with chronic inflammation. In vitro, high-expression of DMBT1 remarkably inhibits proliferation and migration in gallbladder carcinoma cells, and induces apoptosis. Therefore, we presumed that the expression of DMBT1 has been induced in the early stage of gallbladder carcinoma for immunological protection. Down-regulation or depletion of DMBT1, occurring as tumor advances, contributes to tumor growth. On the basis of prior experiments, this study is intended to illustrate the role and molecular mechanism of DMBT1 in process of tumorigenesis and development from in vitro to in vivo by establishing DMBT1-gene knockout mouse model and human gallbladder carcinoma orthotopic grafting model, taking advantage of RNA interference technology and microarray technology. Moreover, we intend to primarily indicate the regulation mechanisms involved in the process of tumorigenesis and development. The scientific meaning of this study lays emphases on enriching the understanding of tumorigenesis and development of gallbladder carcinoma, providing new target with high-effecacy for clinical treatment.