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.
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).
Zhao
Yue
Y
Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China.
Yang
Zhi-Qiang
ZQ
Wang
Yan
Y
Miao
Yuan
Y
Liu
Yang
Y
Dai
Shun-Dong
SD
Han
Yang
Y
Wang
En-Hua
EH
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*
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