Metadherin通过BCR信号通路对慢性淋巴细胞白血病的发病机制的调控研究

Chronic lymphocytic leukemia (CLL) is a disease caused by a clonal expansion of small, mature B lymphocytes. Despite improved in complete remission rate and long-term survival of CLL patient by chemo-immune therapy, there are still need to explore new therapy strategy for patients with poor prognostic factors, refractory and chemoresistance. More recently, Metadherin (MTDH) involved in aberrant proliferation, survival, and increased migration, invasiveness, and metastasis of tumor cells, has been demonstrated as a potential crucial mediator of various types of human malignancies. MTDH promotes tumor progression by modulating multiple oncogenic signaling pathways such as NF-kB, PI3K/Akt and NF-κB, etc. However, there was no report about the role of MTDH in CLL. Our previous studies have confirmed MTDH abnormally high expression in CLL cells and related with cell proliferation and apoptosis, partially by regulating the activity of Wnt signaling. BCR signaling activation can further heighten MTDH expression in CLL, blocking MTDH can inhibit the cell proliferation effect mediated by BCR signaling pathways, and Btk inhibitors can cut MTDH expression level. The study elaborates that MTDH involved in the pathogenesis of CLL and may have a regulation role with BCR signaling pathways. The objective of this study was to investigate the role of MTDH in CLL and the regulatory mechanism between MTDH and BCR signaling pathway. This study intends to enlarge the sample size to assess MTDH expression and clinical characteristics of CLL patients to explore the potential of MTDH for clinical application as diagnosis, therapy response and prognosis biomarkers. CLL cell line (MEC-1 and EHEB) were infected by lentivirus to interfere MTDH expression and cells were injected to NOD/SCID mice to build animal models to exploring the mechanism of MTDH in CLL in vitro and vivo, as well as its relation with BCR signaling pathway. The study may contribute to provide the theoretical basis for individual therapy and prognosis judgement in CLL.

Metadherin(MTDH)参与肿瘤的增殖、迁移和耐药等多种生物学行为，被认为是肿瘤的治疗靶点，并与部分种肿瘤患者预后相关。其促肿瘤作用通过调控Wnt，PI3K及NF-κB等信号通路的活性实现。在慢性淋巴细胞白血病（CLL）中MTDH表达未见报道。为此我们进行了MTDH在CLL细胞中表达及作用机制的研究。结果表明MTDH在CLL细胞中异常增高，活化Wnt通路发挥促瘤作用。BCR活化伴有MTDH表达进一步增高，干扰MTDH表达可以抑制BCR活化介导的细胞增殖，BCR抑制剂部分下调MTDH的表达，提示MTDH参与CLL发病并与BCR信号通路存在调控关系。本研究拟扩大样本量，分析MTDH表达与CLL临床特征与预后因子的相关性，并通过构建细胞株及动物模型进行体内外实验探索MTDH在CLL中的作用机制及其与BCR信号通路的调控关系，拟进一步阐明CLL的发病机制，并为CLL的诊断及治疗提供新思路。

Metadherin(MTDH)参与肿瘤的增殖、迁移和耐药等多种生物学行为，被认为是肿瘤的治疗靶点，并与部分肿瘤患者预后相关。其促肿瘤作用通过调控Wnt，PI3K及NF-κB等信号通路的活性实现。但其在慢性淋巴细胞白血病中的作用尚不明确。课题组对慢性淋巴细胞白血病中MTDH的表达及对慢淋生物学行为影响进行研究。同时探讨MTDH与BCR信号通路，肿瘤微环境的相互关系。研究数据表明，在慢性淋巴细胞白血病细胞中存在MTDH高表达，其参与了肿瘤的抗凋亡机制。MTDH在慢淋中的作用部分通过Wnt通路发挥促瘤作用，除此之外，MTDH参与BCR信号通路的活化。进一步研究数据证实，两者之间存在协同作用。通过体外模拟慢淋微环境，课题组进一步验证MTDH参与微环境介导的促瘤机制，该机制部分通过NF-kB通路发挥作用，沉默MTDH可以逆转微环境的促瘤作用。铁死亡是近年发现的新的细胞死亡方式，有研究报道MTDH促进铁死亡的发生。 本研究初步探讨在CLL中铁死亡的发生机制，结果证实铁死亡诱导剂可以部分逆转微环境介导的促肿瘤作用。 课题深入研究MTDH在CLL中的作用机制及其与BCR信号通路、铁死亡之间的调控关系，进一步阐明了慢淋的发病机制，为CLL的诊断及治疗提供新思路。