Down-regulation of NKD1 increases the invasive potential of non-small-cell lung cancer and correlates with a poor prognosis

• Published in: BMC cancer Vol. 11; no. 1; p. 186
• Main Authors: Zhang, Sheng, Wang, Yan, Dai, Shun-Dong, Wang, En-Hua
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 20.05.2011; BioMed Central; BMC
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; beta Catenin - metabolism; Carcinoma, Non-Small-Cell Lung - diagnosis; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - mortality; Carcinoma, Non-Small-Cell Lung - pathology; Care and treatment; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line, Tumor; Cellular signal transduction; Dishevelled Proteins; Down-Regulation; Genetic aspects; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Lung cancer, Non-small cell; Lung Neoplasms - diagnosis; Lung Neoplasms - metabolism; Lung Neoplasms - mortality; Lung Neoplasms - pathology; Matrix Metalloproteinase 7 - genetics; Matrix Metalloproteinase 7 - metabolism; Middle Aged; Neoplasm Invasiveness; Phosphoproteins - metabolism; Prognosis; Proportional Hazards Models; Risk factors; RNA Interference; Transcription, Genetic; China
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/1471-2407-11-186

As a negative modulator of the canonical Wnt signaling pathway, Naked1 (NKD1) is widely expressed in many normal tissues. However, the expression pattern and clinicopathological significance of NKD1 in patients with non-small-cell lung cancer (NSCLC) is still unclear. Immunohistochemical studies were performed on 35 cases of normal lung tissues and 100 cases of NSCLC, including 66 cases with complete follow-up records. The NKD1 protein and mRNA expressions were detected by western blot and Real-time PCR, respectively. To examine the effect of NKD1 on the invasiveness of lung cancer cells, NKD1 was down-regulated by siRNA in lung cancer cell lines and the invasive ability was then evaluated by the Matrigel invasion assay. In addition, the expressions of Dishevelled-1 and β-catenin proteins, as well as MMP mRNA were also examined in NKD1 knockdown cells. In 35 fresh lung cancer tissues examined, 27(79%) of them exhibited lower levels of NKD1 protein in comparison with their corresponding normal tissue (P = 0.009). However, the NKD1 mRNA level was significantly higher in cancerous lung tissues, compared with the adjacent normal tissues. In 100 NSCLC tissues, NKD1 was significantly lower in 78 cases (78%) than in the normal specimens, determined by immunohistochemical staining. The reduced NKD1 expression was correlated with histological type (P = 0.003), poor differentiation (P = 0.004), lymph node metastasis (P = 0.013), TNM stage (P = 0.002) and poor survival (62.88 ± 3.23 versus 23.61 ± 2.18 months, P = 0.03). In addition, NKD1 knockdown could up-regulate Dishevelled-1 and β-catenin protein levels, as well as increased MMP-7 transcription and the invasive ability of lung cancer cells. Furthermore, when the NKD1-knockdown cells were treated with Dishevelled-1 antibody, their invasive potential was significantly reduced. NKD1 protein is reduced but NKD1 mRNA is elevated in NSCLC. Reduced NKD1 protein expression correlates with a poor prognosis in NSCLC. NKD1 might inhibit the activity of the canonical Wnt pathway through Dishevelled-1.