title: Dishevelled-1 and dishevelled-3 affect cell invasion mainly through canonical and noncanonical Wnt pathway, respectively, and associate with poor prognosis in nonsmall cell lung cancer.
abstract: Dishevelled (Dvl) family proteins are overexpressed in nonsmall cell lung cancer (NSCLC), but the correlation between Dvl overexpression and patient prognosis is not clear. The underlying mechanisms of Dvl-1 and Dvl-3 promoting lung cancer cell invasion require further research. We used immunohistochemistry to assess the presence of Dvl-1, Dvl-3, beta-catenin, and p120ctn, and compared their expression to the prognosis in 102 specimens from NSCLC patients. We also examined the effect of Dvl-1 and Dvl-3 on Tcf-dependent transcriptional activity, as well as on the invasiveness in A549 and LTEP-alpha-2 lung cancer cells. The results showed that Dvl-1 correlated to the abnormal expression of beta-catenin, while Dvl-3 correlated to p120ctn. Both Dvl-1 and Dvl-3 were related to the poor prognosis of patient. Dvl-1 overexpression enhanced the Tcf-dependent transcriptional activity and beta-catenin expression significantly. However, Dvl-3 had little effect on the Tcf-dependent transcriptional activity and beta-catenin expression, which was accompanied by p38 and JNK phosphorylation. Furthermore, the invasiveness of Dvl-3-enhanced cells was inhibited by p38 and JNK inhibitors. Exogenous expression of both Dvl-1 and Dvl-3 increased the p120ctn protein expression, while only Dvl-3 upregulated p120ctn mRNA. We conclude that both protein and mRNA of Dvl-1 and Dvl-3 are overexpressed in NSCLC in a manner related to poor prognosis. Dvl-1 may affect the biological behavior of lung cancer cells mainly through beta-catenin (canonical Wnt pathway), while Dvl-3 mainly through p38 and JNK pathway (noncanonical Wnt pathway).
authors.affiliation: Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhao
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Yang
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Miao
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Shun-Dong
authors.initials: SD
authors.lastname: Dai
authors.forename: Yang
authors.initials: Y
authors.lastname: Han
authors.forename: En-Hua
authors.initials: EH
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism*; D051177:Catenins / Q000235:genetics / Q000378:metabolism; D000072261:Dishevelled Proteins; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins; D010766:Phosphorylation; D011379:Prognosis; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051177:Catenins; C000606578:DVL1 protein, human; C000606584:DVL3 protein, human; D000072261:Dishevelled Proteins; D010750:Phosphoproteins; D011506:Proteins; D051176:beta Catenin