Abstract
Previous studies suggested Ataxia-telangiectasia group D complementing gene (ATDC) as an oncogene in many types of cancer. However, its expression and biological functions in non-small cell lung cancer (NSCLC) remain unclear. Herein, we investigated its expression pattern in 109 cases of human NSCLC samples by immunohistochemistry and found that ATDC was overexpressed in 62 of 109 NSCLC samples (56.88%). ATDC overexpression correlated with histological type (p<0.0001), tumor status (p = 0.0227) and histological differentiation (p = 0.0002). Next, we overexpressed ATDC in normal human bronchial epithelial cell line HBE and depleted its expression in NSCLC cell lines A549 and H1299. MTT and colony formation assay showed that ATDC overexpression promoted cell proliferation while its depletion inhibited cell growth. Furthermore, cell cycle analysis showed that ATDC overexpression decreased the percentage of cells in G1 phase and increased the percentage of cells in S phase, while ATDC siRNA treatment increased the G1 phase percentage and decreased the S phase percentage. Further study revealed that ATDC overexpression could up-regulate cyclin D1 and c-Myc expression in HBE cells while its depletion down-regulated cyclin D1 and c-Myc expression in A549 and H1299 cells. In addition, ATDC overexpression was also associated with an increased proliferation index, cyclin D1 and c-Myc expression in human NSCLC samples. Further experiments demonstrated that ATDC up-regulated cyclin D1 and c-Myc expression independent of wnt/β-catenin or p53 signaling pathway. Interestingly, ATDC overexpression increased NF-κB reporter luciferase activity and p-IκB protein level. Correspondingly, NF-κB inhibitor blocked the effect of ATDC on up-regulation of cyclin D1 and c-Myc. In conclusion, we demonstrated that ATDC could promote lung cancer proliferation through NF-κB induced up-regulation of cyclin D1 and c-Myc.
Highlights
Lung cancer is one of the leading causes of all cancer-related deaths worldwide and, in particular, non-small-cell lung cancer (NSCLC) constitutes the majority of the diagnosed cases [1,2]
Expression of Ataxia-telangiectasia group D complementing gene (ATDC) was analyzed by real-time PCR and western blot assays in a panel of lung cancer cell lines and in a normal bronchial epithelial cell line HBE (Figure 2A–B). We found that both ATDC mRNA and protein expression levels in NSCLC cell lines were much higher than that in HBE, especially in A549 and H1299 cell lines
ATDC Expression Correlates with Ki67 Labeling Index, Cyclin D1 and c-Myc Levels in NSCLC Tissues We examined the relationship between the level of total ATDC
Summary
Lung cancer is one of the leading causes of all cancer-related deaths worldwide and, in particular, non-small-cell lung cancer (NSCLC) constitutes the majority of the diagnosed cases [1,2]. Epigenetic and microenvironmental, play important roles in the survival and colonization of tumor cells at a distant tissue site, leading to the metastasis [3]. TRIM proteins typically have a series of conserved domains including multiple zinc finger motifs and a leucine zipper motif. These proteins have been demonstrated to participate in cell growth regulation and development and have been implicated in several human diseases such as HIV infection and leukemia [6,7]. One report described increased ATDC mRNA expression in association with high histological grade, large tumor size, extent of tumor invasion and lymph node metastasis in gastric cancer [15]. To the best of our knowledge, the protein expression of ATDC and its relationship with clinicopathological factors in primary lung cancers have never been characterized
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