Abstract
β-catenin is a major component of the Wnt/β-catenin signaling pathway, and is known to play a role in lung tumorigenesis. β-catenin-interacting protein 1 (CTNNBIP1) is a known repressor of β-catenin transactivation. However, little is known about the role of CTNNBIP1 in lung cancer. The aim of this study was to carry out a molecular analysis of CTNNBIP1 and its effect on β-catenin signaling, using samples from lung cancer patients and various lung cancer cell lines. Our results indicate a significant inverse correlation between the CTNNBIP1 mRNA expression levels and the CTNNBIP1 promoter hypermethylation, which suggests that the promoter hypermethylation is responsible for the low levels of CTNNBIP1 present in many lung cancer patient samples. The ectopic expression of CTNNBIP1 is able to reduce the β-catenin transactivation; this then brings about a decrease in the expression of β-catenin-targeted genes, such as matrix metalloproteinase 7 (MMP7). Conversely, CTNNBIP1 knockdown is able to increase β-catenin transactivation and the expression of MMP7. In agreement with these findings, a low level of CTNNBIP1 was found to be correlated with a high level of MMP7 when a publicly available microarray dataset for lung cancer was analyzed. Also, in agreement with the above, the ectopic expression of CTNNBIP1 inhibits the migration of lung cancer cells, whereas the CTNNBIP1 knockdown increases cancer cell migration. Our findings suggest that CTNNBIP1 is a suppressor of cancer migration, thus making it a potential prognostic predictor for lung cancer.
Highlights
Lung cancer is one of the leading causes of cancer deaths worldwide, including in Taiwan, with a five-year survival rate of less than 15%; this is despite significant advances in both the diagnostic and therapeutic approaches to this disease [1]
To validate whether the epigenetic silencing of the CTNNBIP1 gene is involved in lung cancer, we first analyzed a cohort of patients with lung adenocarcinoma tumors, obtained from the GSE66836 and GSE66863 projects, and stored in the Gene Expression Omnibus (GEO) database [17]
The results indicated that 45% (10/22) showed CTNNBIP1 promoter hypermethylation (Figure 1B)
Summary
Lung cancer is one of the leading causes of cancer deaths worldwide, including in Taiwan, with a five-year survival rate of less than 15%; this is despite significant advances in both the diagnostic and therapeutic approaches to this disease [1]. Our genome-wide loss of heterozygosity (LOH) study showed that a high frequency of LOH affecting the chromosomal region 1p36.2 was present in lung cancer patients [2] This deleted region is close to the gene locus encoding the β-catenin-interacting protein 1 (CTNNBIP1) protein, which is a tumor suppressor-like protein that is known to be involved in regulating β-catenin signaling. The activated Wnt signaling causes β-catenin to accumulate in the cytoplasm, and the protein is translocated to the nucleus, where it binds to T-cell factor/lymphoid enhancer-binding factor (TCF/LEF-1) This binding activates the expression of a range of target genes, including c-Myc and MMP7 [5,6,7]. CTNNBIP1 would seem to possibly function as a tumor suppressor by inhibiting Wnt/β-catenin signaling, and blocking the oncogenic phenotype
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