Wnt3a Promotes Epithelial-mesenchymal Transition In Lung Adenocarcinoma And Its Clinical Significance

Background:Epithelial-Mesenchymal Transition(EMT)has been associated with the invasion and dissemination steps during cancer metastasis.Wnt3a is one of the ligands in canonical Wnt/β-catenin signal pathway,which is well established in the progression of lung cancer cell lines.The aim of this study was to evaluate the association between Wnt3a expression and EMT-related proteins(E-cadherin and N-cadherin),and to further investigate its impact on prognosis of lung adenocarcinoma patients.Methods:A total of 147 stage Ⅰ-Ⅲ lung adenocarcinoma patients were included and their clinicopathological characteristics were collected in this retrospective study.The expression levels of Wnt3a,E-cadherin and N-cadherin in post-surgery cancerous and adjacent normal tissues were assessed by immunohistochemistry.Pearson Chi-square test was adopted to assess the association between Wnt3a and EMT-related proteins.Cox regression analyses and Kaplan-Meier curves were conducted to further evaluate the prognostic value of these markers.Experiments in vitro,transwell invasion and migration assays were conducted to test the motility of lung adenocarcinoma cells when activated by wnt3a.Western blot assay were used to explore the mechanism of EMT by wnt3a activating.Results:High Wnt3a expression level was significantly associated with low E-cadherin(P<0.001)and high N-cadherin(P<0.001)expression level in lung adenocarcinoma tissues.Besides,high Wnt3a level predicted poorer lung adenocarcinoma survival by univariate Cox analysis(P=0.001),while the multivariate result was not significant(P=0.355).Subgroup analysis suggested that the prognostic value of Wnt3a expression level was significant in Stage T1-T2(log rank P=0.003)and Stage N0(log rank P=0.031)patients.Besides,the multivariate Cox analysis suggested that N-cadherin was an independent prognostic factor for lung adenocarcinoma patients(P=0.012).Results in vitro experiments showed that,the motility of adenocarcinoma cell were increased by wnt3a activation.Wnt3a up-regulate the expression of mesenchymal cell protein such as vimentin and snail,and down-regulate the expression of epithelial protein E-cadherin.Also Wnt3a up-regulate the expression of related proteins in the wnt/p-catenin signaling pathway.Conclusions:The expression level of wnt3a was higher in lung adenocarcinoma than in normal lung tissue,patients with high level of Wnt3a in their lung cancer tissue had a poor prognosis,especially in those T1-2 stage and NO stage patients.Wnt3a was significantly associated with EMT related proteins,and it is through canonical wnt/β-catenin signal pathway.