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

abstract: ...Background 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. Methods 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 -catenin proteins, as well as MMP mRNA were also examined in NKD1 knockdown cells. Results 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 -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. Conclusion 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.

...BMC Cancer BMC Cancer 1471-2407 BioMed Central 21599923 3118196 1471-2407-11-186 10.1186/1471-2407-11-186 Research Article Down-regulation of NKD1 increases the invasive potential of non-small-cell lung cancer and correlates with a poor prognosis Zhang Sheng 1 zhangshengcmu@163.com Wang Yan 1 julia2003320@hotmail.com Dai Shun-Dong 1 dddsddd111@yahoo.com.cn Wang En-Hua 1 wangeh@hotmail.com 1 Department of Pathology, the First Affiliated Hospital and College of Basic Medical Sciences of China

... 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. Methods 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 -catenin proteins, as well as MMP mRNA were also examined in NKD1 knockdown cells. Results 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 -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. Conclusion 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. Background dNKD (Naked Cuticle Drosophila) was first found in Drosophila and mutation of the Naked gene could induce the loss of segmentation of Drosophila [ 1 ]. Subsequently, NKD1 and NKD2, two homologues of drosophila naked cuticle, were also detected in mammalians [ 2 ]. These two genes are located on chromosome 16q12.1 and 5p15.3, respectively, in human beings, and share 43.8% amino-acid sequence homology. NKD1 has been proposed to interact with Dishevelled (Dvl) through its conservative domain which forms an EF-hand-like motif, functioning as a negative regulator of the canonical Wnt/-catenin signaling pathway [ 3 - 6 ]. Dishevelled (Dvl) is a positive regulatory factor located upstream of the Wnt pathway, and plays a role in regulating at least two intracellular Wnt signal pathways, such as the canonical Wnt/-catenin pathway and JNK/PCP pathway [ 7 ]. NKD1 is an antagonist of the canonical Wnt/-catenin pathway. When it directly

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Gene: NKD1 - naked cuticle homolog 1 (Drosophila) - (NCBI)

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