Dishevelled3及其异构体协同驱动干细胞样表型转化参与结直肠癌耐药的机制与干预策略

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.