Metadherin通过Wnt/β-catenin信号通路对于弥漫大B细胞淋巴瘤发病机制的调控研究

Metadherin (MTDH) involved in aberrant proliferation, survival, and increased migration, invasiveness, and metastasis of tumor cells, has been demonstrated as a potentially crucial mediator of various types of human malignancies. MTDH promotes tumor progression by modulating Wnt/β-catenin pathways in hepatocellular and gastric carcinomas.Our preliminary studies found that MTDH and β-catenin were aberrantly expressed in DLBCL,and there was significant correlation between them. These results suggested that they might have connection with each other in the pathogenesis of DLBCL.Our study will expand sample size and detect the expression of MTDH and β-catenin in different levels to further analyze their correlation and the clinical meaning. Meanwhile,the test both in vitro and vivo will be carried on to clarify the biological impact of MTDH downexpression on DLBCL tumor cells and the regulation to Wnt/β-catenin pathway. This novel study may contribute to further investigation on the useful biomarkers，prognostic factors and potential therapeutic target in the DLBCL patients.

Metadherin（MTDH）与肿瘤的生长、侵袭、转移等生物学行为有关，是促进肿瘤发生发展的关键因子。已证实在肝细胞肝癌和胃癌中MTDH通过调控Wnt/β-catenin信号通路促进肿瘤进展。我们前期实验发现弥漫大B细胞淋巴瘤（DLBCL）患者肿瘤组织中存在MTDH和β-catenin蛋白的异常表达，且二者的表达具有相关性，提示在DLBCL的发病过程中MTDH和Wnt/β-catenin通路可能存在调控关系。本研究拟扩大样本量，从不同水平检测DLBCL中MTDH和β-catenin的表达情况，进一步分析二者表达的相关性，研究两者的异常表达与DLBCL患者的临床特征及预后等的相关性；同时开展细胞株体外试验和动物体内实验，研究MTDH表达下调对DLBCL细胞生物学行为及体内播散的影响及其与Wnt/β-catenin通路的调控关系，并探讨其机制，为DLBCL的诊断、治疗提供理论依据。

Metadherin（MTDH）通过调控Wnt/β-catenin通路参与了弥漫大B细胞淋巴瘤（DLBCL）的发生发展，本研究扩大样本量，进一步检测了MTDH和β-catenin蛋白在DLBCL肿瘤组织中异常表达，且MTDH高表达和β-catenin核内表达与DLBCL临床分期呈正相关，生存分析发现MTDH阳性组患者预后较差，但MTDH高表达不是DLBCL患者的总生存期（OS）的独立预后因素。细胞株体外实验证实慢病毒载体介导的MTDH基因沉默可以促进DLBCL细胞株凋亡并下调Wnt/β-catenin通路的激活程度，且本研究进一步建立了DLBCL的SCID/Beige裸鼠模型，动物模型体内实验的部分工作目前正在进行。综合上述结果，本研究为DLBCL的发病机制研究提供新的思路，并探讨了MTDH作为DLBCL的新的分子标志物、预后因素和治疗靶点的可行性及其与Wnt/β-catenin通路的调控关系。项目资助发表SCI论文1篇，待发表两篇。培养硕士生2名，其中1名已经取得硕士学位，1名在读。项目投入经费23万元，支出17.33396万元，各项支出基本与预算相符。剩余经费5.66604万元，剩余经费计划用于本项目研究后续支出。