Wnt5a/Ror2信号通过BCR-ABL和中心体上β-catenin抑制CML细胞增殖机制研究

Wnt5a is a leukemia suppressor, but the mechanism was unknown. Our previous study showed that Wnt5a/Ror2 signal inhibited β-catenin and suppressed the proliferation of CML (Chronic Myelogenous Leukemia)cell line K562 .But whether Wnt5a also regulates "BCR-ABL",the oncogene of CML? Besides we found that Wnt5a/Ror2 seem located in the site of centrosome,and β-catenin is relative to the separation of centrosome .Dose Wnt5a also regulate the separation of centrosome through β-catenin ? All of these remains unknown.This project attempts to verify the following hypothesis by research: 1.Wnt5a/Ror2 inhibits the function of BCR-ABL and downregulats the activity of β-catenin，and then suppresses the proliferation of CML cells and enhances the efficacy of Imatinib killing CML cells.2.Wnt5a/Ror2 blocks centrosome separation and mitosis progress and then play antitumor effect by regulating β-catenin on centrosome. The study result is helpful to further understand the double mechanism of Wnt5a anti-leukemia by regulating both of β-catenin and BCR-ABL, and provides a new perspective for the therapy of leukemia. Furthermore the study result will enriching the correlation theory of the relationship between Wnt signaling and tumorigenesis.

Wnt5a是白血病抑制因子，但确切机制不明。我们前期研究发现：CML细胞K562中Wnt5a/Ror2信号抑制β-catenin，阻止细胞恶性增殖。但Wnt5a是否也调控了CML 的特异癌基因"BCR-ABL"？另外还发现Wnt5a/Ror2定位于似中心体位置，而β-catenin与中心体分离有关，那么Wnt5a是否通过β-catenin调控中心体的分离？这些问题至今未见报道。本项目通过研究拟验证如下假设：1.Wnt5a/Ror2可拮抗BCR-ABL功能，进而下调β-catenin活性，抑制CML细胞增殖并增强抗CML药-伊马替尼的效力。2.Wnt5a/Ror2通过调控中心体上β-catenin，阻滞中心体分离和有丝分裂进程，发挥抑癌作用。研究结果有助于深入认识Wnt5a调控β-catenin和BCR-ABL抗白血病"双重"机制，为CML治疗提供新思路，并丰富Wnt信号与肿瘤发生相关理论。

Wnt5a是白血病抑制因子，CML细胞K562中Wnt5a/Ror2信号不但抑制β-catenin，阻止细胞恶性增殖，而且Wnt5a也调控了CML 的特异癌基因“BCR-ABL”，另外还发现Wnt5a/Ror2定位于似中心体位置，而β-catenin与中心体分离有关，研究发现：Wnt5a也通过β-catenin调控了中心体的分离。本项目通过研究验证了如下假设：1.Wnt5a/Ror2可拮抗BCR-ABL功能，进而下调β-catenin活性，抑制CML细胞增殖并增强伊马替尼杀灭白血病细胞的药效。2.Wnt5a/Ror2通过调控中心体上β-catenin，阻滞中心体分离和有丝分裂进程，发挥抑癌作用。研究结果有助于深入认识Wnt5a调控β-catenin和BCR-ABL抗白血病的双重机制，并丰富了Wnt信号与肿瘤发生相关理论，也为CML治疗提供了新思路，为诊断CML提供了新靶标。