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Neural precursor cell expressed, developmentally down-regulated 9 (NEDD9) is overexpressed in multiple tumor types, where it is thought to regulate tumor cell metastasis and act as a trigger of the epithelial-mesenchymal transition (EMT). Loss of E-cadherin/β-catenin and upregulation of N-cadherin are hallmarks of the EMT. The expression and correlation of NEDD9 with E-cadherin, β-catenin and N-cadherin in lung cancer are poorly characterized. We examined NEDD9, E-cadherin, β-catenin and N-cadherin protein expression in 105 cases of non-small cell lung carcinoma (NSCLC), including 43 cases of squamous cell carcinoma and 62 cases of lung adenocarcinoma, and the corresponding normal lung tissues using immunohistochemistry. NEDD9 was overexpressed in 56.2 % (59/105) of the NSCLC samples compared to normal lung tissue. Overexpression of NEDD9 correlated with abnormal expression of E-cadherin, β-catenin and N-cadherin (P < 0.001, P = 0.008 and P = 0.027, respectively). Additionally, overexpression of NEDD9 correlated positively with lymph node metastasis in NSCLC (Chi-square test; P = 0.015). The mean overall survival of NSCLC patients overexpressing NEDD9 (39.10 ± 6.49 months) was markedly shorter than patients with normal NEDD9 expression (56.67 ± 7.44 months; Log-Rank, P = 0.001). Moreover, for patients with adenocarcinoma or squarmous cell carcinoma, the survival is also dramatically poorer upon overexpression of NEDD9. In multivariate analysis, overexpression of NEDD9 (P = 0.013) and TNM stage (P = 0.001) were significant independent prognostic factors for overall survival in NSCLC. In conclusion, overexpression of NEDD9 correlates with altered expression of EMT markers, increased lymph node metastasis and poorer survival in lung cancer.

Disabled-2 (Dab2) is considered a tumor suppressor and is downregulated in cancers. We examined the promoter methylation status and expression levels of Dab2, and investigated their roles in the development of lung cancers. Methylation-specific PCR was employed to analyze the methylation status of Dab2 in 100 lung cancer tissues. The cytoplasmic and nuclear expression of the Dab2 protein was determined using western blot analysis. Demethylation treatment using 5-Aza-2-deoxycytidine (5-Aza-dC) was performed in three lung cancer cell lines. Dab2 expression was upregulated by Dab2 transfection or interrupted by Dab2 siRNA in lung cancer cells. Proliferative and invasive ability tests were performed with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTS) and a Matrigel invasion assay, respectively. The methylation rate of Dab2 was significantly higher in lung cancer tissues compared to normal lung tissues. Dab2 methylation correlated with the reduced nuclear and cytoplasmic expression of Dab2, as well as the TNM stage and lymphatic metastasis of lung cancers. Treatment with 5-Aza-dC was able to eliminate the hypermethylation of Dab2, enhance Dab2 expression, and inhibit β-catenin expression, and the proliferative and invasive ability of lung cancer cells. Upregulation of Dab2 expression reduced β-catenin expression and proliferation and invasiveness of lung cancer cells. However, interruption of Dab2 expression induced the opposite results. Dab2 methylation is common in lung cancers, and is one of the most important factors responsible for the reduced expression of Dab2. Aberrant hypermethylation and reduced expression of Dab2 promote the development of lung cancers.

HDPR1 (human homologue of Dapper) is considered as a Dishevelled (DVL) antagonist in WNT signaling. We recently reported that DVL was associated with cytoplasmic accumulation of beta-catenin in nonsmall cell lung cancer (NSCLC). Whether cytoplasmic accumulation of beta-catenin is correlated with HDPR1 is unclear. Xenopus Dapper (XDpr) was found to stabilize p120-catenin (p120ctn) in Xenopus embryogenesis. However, whether HDPR1 can regulate p120ctn expression level is not reported. Furthermore, how HDPR1 influences invasiveness in lung carcinogenesis is also not well understood. In this study, our aims were to explore the effects of HDPR1 on the lung carcinogenesis and to examine the relationship among HDPR1, beta-catenin, and p120ctn. Immunohistochemical analysis in 120 NSCLC tissues showed that HDPR1 was significantly lower in 82 specimens (68.3%). Reverse transcription (RT)-polymerase chain reaction (PCR) and Western blotting analysis showed that the mRNA and protein expression of HDPR1 were lower in tumor tissues as compared to corresponding nontumorous tissues. Moreover, reduced HDPR1 expression was related to the clinicopathological factors and was an independent risk factor for prognosis of the patients with NSCLC. In addition, HDPR1 expression was also associated with the expression of p120ctn and beta-catenin in lung cancer tissues. Knockdown of HDPR1 gene enhanced the invasive ability of lung cancer cells, which was dependent on p120ctn and independent of beta-catenin. In conclusion, the function of HDPR1 on regulating p120ctn may play an important role in human lung carcinogenesis. Restoration of HDPR1 gene may be a new therapeutic target of lung cancer.