DIXDC1调控Wnt通路影响肺腺癌生物学功能的研究

Wnt signaling pathway involved in embryonic development, neural differentiation and development of tumor. Currently, more and more research results showed that the Wnt signaling pathway also plays an important role in the procession of human non-small cell lung cancer. DIXDC1 is a regulator in the Wnt signaling pathway. The relationship between DIXDC1 and Wnt signaling pathway in human lung cancer has not been clear. We found that the expression of DIXDC1 in lung adenocarcinoma tissue increased, and correlated with tumor invasion and metastasis. In lung adenocarcinoma cell line, DIXDC1 up-regulated the phosphorylation of GSK-3β（Ser9）, and the expression of DIXDC1 was correlated with the cytoplasm and nucleus expression of β-catenin. We also found that DIXDC1 can up-regulate the phosphorylation of JNK, and DIXDC1 protein sequence analysis suggested that there is a binding domain of Rock in DIXDC1 MTH structure. Therefore, we supposed that DIXDC1 influent the development of lung adenocarcinoma through canonical and/or non-canonical wnt signaling pathway. Experiments in vitro will be performed to explore the effect of DIXDC1 on lung adenocarcinoma cell line, the interaction of DIXDC1 and GSK-3β, the mechanism of regulation of downstream genes. The mechanism of DIXDC1 activating RhoA or Rac signaling pathway will also be investigated, which will indicate DIXDC1 affect the invasion and migration of lung adenocarcinoma through non-canonical Wnt signaling pathway. Finally, we will confirm the role of DIXDC1 in the development of lung adenocarcinoma in vivo. Our study will further reveal the DIXDC1 biological function and Wnt signaling pathway in the procession of human tumor development, and provide new molecular targets of Wnt signaling pathway for tumor treatment.

越来越多研究显示Wnt通路在肺癌发生发展中发挥重要作用。DIXDC1是人类Wnt通路的基因，该基因是否通过Wnt通路影响肺癌发生发展尚未清楚。我们预实验结果显示，DIXDC1在肺腺癌组织中高表达，且与侵袭转移相关；并能上调GSK-3β(Ser9)和JNK的磷酸化水平，同时与β-catenin胞浆和胞核的表达有一定相关性；蛋白序列分析提示，其MTH结构域上可能存在Rock结合位点，因此我们推测DIXDC1有可能通过经典和/或非经典Wnt通路影响肺腺癌发生发展。本课题将进一步探讨DIXDC1对肺腺癌生物学功能的影响，及其与GSK-3β的相互作用和对下游基因的调控，探讨DIXDC1对RhoA或Rac通路活化的影响，明确该基因通过Wnt通路在肺腺癌发生发展中的作用。本研究将进一步明确DIXDC1在肿瘤中的生物学功能，深入了解Wnt通路在肿瘤中的作用机理，为靶向Wnt通路的分子治疗提供新靶和依据。