肿瘤细胞获得干细胞样特性是肿瘤耐药生成的重要原因，而干细胞样表型的转化需要多重信号介导。虽然人们已证实Wnt信号是干细胞样表型转化的关键，但仍无法解释细胞内多重信号的协同方式。散乱蛋白Dishevelled(DVL)通过自身多个功能结构域参与多重信号的传导，是Wnt信号通路的核心调控因子。我们前期研究发现，在结直肠癌耐药细胞中广泛存在DVL3的异构体DVL3-X2，并证实其密切参与了干细胞样表型转化及耐药过程。由此，我们推测DVL3-X2由于缺乏DIX及Dishevelled结构域，选择性活化旁路信号，协同调控了结直肠癌干细胞样特性的维持，诱发耐药的生成。本项目拟在此基础上，通过多种干预措施从分子、细胞及动物模型等层面系统解析DVL3-X2与DVL3协同驱动结直肠癌干细胞样表型转化的内在机制，并评价相关干预措施对改善结直肠癌化疗疗效的有效性，最终为逆转结直肠癌耐药开辟一条有价值的新途径。

Cancer cells gain stem cell-like properties is a key factor of cancer chemoresistance. The stem cell-like phenotype transformation is mediated by multiple signaling. Although it has been confirmed that Wnt signaling is critical for stem cell-like phenotypic transformation, the synergistical mode of multiple signaling in cell remains unexplained. Dishevelled (DVL) with multiple functional domain is involved in signals transduction, and regarded as a key regulator of Wnt signaling pathway. Our preliminary studies have showed that a isomer of DVL3 (DVL3-X2) was overexpressed in drug-resistant colorectal cancer cells, and participated in stem cell-like phenotype transformation and chemoresistance. Therefore, we hypothesized that DVL3-X2 selectively activates bypass signaling due to the lack of DIX and Dishevelled domains, and synergistically mediates the maintenance of colorectal cancer stem cell-like properties and induction of chemoresistance. Therefore, our present proposal will reveal the role and mechanism underlying synergistical driving effect of DVL3-X2 and DVL3 on colorectal cancer stem cell-like phenotype transformation using RNAi, specific anti-agonist, and evaluate the efficiency of improve colorectal cancer chemosensitivity by double-targeting DVL3-X2 and DVL3，and finally supplying a valuable new method for reversing chemoresistance in colorectal cancer.