Abstract
NK2 homeobox 5 (Nkx2.5), a homeobox-containing transcription factor, is associated with a spectrum of congenital heart diseases. Recently, Nkx2.5 was also found to be differentially expressed in several kinds of tumors. In colorectal cancer (CRC) tissue and cells, hypermethylation of Nkx2.5 was observed. However, the roles of Nkx2.5 in CRC cells have not been fully elucidated. In the present study, we assessed the relationship between Nkx2.5 and CRC by analyzing the expression pattern of Nkx2.5 in CRC samples and the adjacent normal colonic mucosa (NCM) samples, as well as in CRC cell lines. We found higher expression of Nkx2.5 in CRC compared with NCM samples. CRC cell lines with poorer differentiation also had higher expression of Nkx2.5. Although this expression pattern makes Nkx2.5 seem like an oncogene, in vitro and in vivo tumor suppressive effects of Nkx2.5 were detected in HCT116 cells by establishing Nkx2.5-overexpressed CRC cells. However, Nkx2.5 overexpression was incapacitated in SW480 cells. To further assess the mechanism, different expression levels and mutational status of p53 were observed in HCT116 and SW480 cells. The expression of p21WAF1/CIP1, a downstream antitumor effector of p53, in CRC cells depends on both expression level and mutational status of p53. Overexpressed Nkx2.5 could elevate the expression of p21WAF1/CIP1 only in CRC cells with wild-type p53 (HCT116), rather than in CRC cells with mutated p53 (SW480). Mechanistically, Nkx2.5 could interact with p53 and increase the transcription of p21WAF1/CIP1 without affecting the expression of p53. In conclusion, our findings demonstrate that Nkx2.5 could act as a conditional tumor suppressor gene in CRC cells with respect to the mutational status of p53. The tumor suppressive effect of Nkx2.5 could be mediated by its role as a transcriptional coactivator in wild-type p53-mediated p21WAF1/CIP1 expression.
Highlights
Colorectal cancer (CRC) is one of the most common malignancies with high rates of morbidity and mortality [1,2,3,4]
To indicate whether Nkx2.5 expression differs between CRC and normal colonic mucosa (NCM) samples, microarray data that were extracted from ONCOMINE database were analyzed
The findings in our present study indicates that Nkx2.5 serves as a conditional tumor suppressor in CRC cells
Summary
Colorectal cancer (CRC) is one of the most common malignancies with high rates of morbidity and mortality [1,2,3,4]. The formation of CRC is a multistep process that arises from accumulation of genetic and epigenetic alterations [5, 6], including silencing of tumor suppressor genes with aberrant methylations, as well as activating oncogenes by mutations and/ or chromosomal deletions [7]. This has led to the hypothesis that aberrant methylation could be used as a marker to identify candidate tumor suppressor genes in neoplasia [7, 8]. Nkx2.5 is a homeobox-containing transcription factor that belongs to the NK2 class of homeobox proteins [11, 12]. Nkx2.5 may act as a tumor suppressor in CRC through making an interaction with a p53 and/or cell cycle-related pathway
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