LATS2低表达活化Wnt/β-catenin信号通路在慢性淋巴细胞白血病耐药中的机制研究

慢性淋巴细胞白血病（CLL）是一种异质性很强的不可治愈性肿瘤，晚期或复发后多耐药。我们前期研究证明抑癌基因LATS2在CLL中显著低表达，复发耐药患者更为明显，是CLL新的不良预后因素；功能研究初步显示LATS2低表达可导致Wnt/β-catenin信号通路活化，并可导致肿瘤细胞耐药。已知Wnt/β-catenin通路在CLL中持续活化，是多种肿瘤耐药的主要原因。本课题拟进一步探讨①CLL中LATS2低表达是否导致Wnt/β-catenin通路持续活化；②CLL中LATS2低表达或Wnt/β-catenin通路持续活化是否导致CLL耐药；③LATS2是否通过Wnt/β-catenin通路导致CLL耐药；④小鼠体内及CLL患者原代标本中验证相关结果。本课题研究结果将揭示LATS2在CLL中的具体作用机制以及CLL的耐药原因，为研究CLL的治疗提供一个新靶标，具有重要的理论意义和实用价值。

Chronic lymphocytic leukemia (CLL) is still a incurable disease with heterogeneous course and always resistant to chemotherapy at advance or relapsed stage. Our previous study had proved that tumor suppressed gene LATS2 was down-regulated in CLL, especially in the relapsed or resistant patients. Low expression of LATS2 is a new poor prognostic factor of CLL. Knock-down of LATS2 by siRNA in HeLa cell made the Wnt/β-catenin signaling pathway constitutively activated and reduce the sensitivity of HeLa cell to chemotherapeutic drug. Wnt/β-catenin signaling pathway is known to play important role in drug-resistance in many cancer, and is constitutively actived in CLL. In this project, we will further investigate ① whether the low expression of LATS2 will make the constitutive activation of Wnt/β-catenin signaling pathway in CLL. ② Whether the low expression of LATS2 or the constitutive activation of Wnt/β-catenin signaling pathway will cause the drug resistance of CLL. ③ Whether low expression of LATS2 will cause the drug resistance through constitutively activating the Wnt/β-catenin signaling pathway in CLL. ④ We will identify the above outcomes in NOD/SCID mouse model and in the primary CLL cells. This project will elucidate the mechanism of down-regulated LATS2 in the of drug resistance of CLL, and provide the evidence to explore LATS2 as a valuable therapeutic target for the treatment of CLL. So this project has great academic and applicative value.