Abstract
The presence of an activating mutation of the Wnt/β-catenin signaling pathway is found in ~90% of colorectal cancer (CRC) cases. Death domain-associated protein (DAXX), a nuclear protein, interacts with β-catenin in CRC cells. We investigated DAXX expression in 106 matched sample pairs of CRC and adjacent normal tissue by Western blotting. This study evaluated DAXX expression and its clinical implications in CRC. The results revealed that DAXX expression was significantly lower in the patients with the positive serum carcinoembryonic antigen (CEA) screening results compared to the patients with negative CEA screening levels (p < 0.001). It has been reported that CD24 is a Wnt target in CRC cells. Here, we further revealed that DAXX expression was significantly correlated with CD24 expression (rho = 0.360, p < 0.001) in 106 patients. Consistent with this, in the CEA-positive subgroup, of which the carcinomas expressed DAXX at low levels, they were significantly correlated with CD24 expression (rho = 0.461, p < 0.005). Therefore, reduced DAXX expression is associated with reduced CD24 expression in CRC. Notably, in the Hct116 cells, DAXX knockdown using short-hairpin RNA against DAXX (shDAXX) not only caused significant cell proliferation, but also promoted metastasis. The DAXX-knockdown cells also demonstrated significantly decreased CD24 expression, however the intracellular localization of CD24 did not change. Thus, DAXX might be considered as a potential regulator of CD24 or β-catenin expression, which might be correlated with proliferative and metastatic potential of CRC.
Highlights
IntroductionGenetic mutations and epigenetic alterations contribute to tumor development through oncogene activation and tumor suppressor gene inactivation
Colorectal cancer (CRC) is the most common malignancy in the Western world
3-kinase pathway activation [4]; adenomatous polyposis coli (APC) inactivation is observed in 70%–80% of sporadic colorectal adenomas and carcinoma cases, and gain-of-function β-catenin mutations have been identified in nearly 50% of the colon tumors with intact APC [5]. β-catenin is a transcriptional activator, activating the expression of many different genes, enhancing T-cell factor (TCF)/lymphoid enhancer family expression, and translocating to the nucleus to combine with DNA-binding sites
Summary
Genetic mutations and epigenetic alterations contribute to tumor development through oncogene activation and tumor suppressor gene inactivation. Genetic mutations including adenomatous polyposis coli (APC), TP53, KRAS, and β-catenin (CTNNB1) participate in CRC carcinogenesis [2,3]. KRAS, a protooncogene, is a downstream effector from the epidermal growth factor receptor (EGFR) family, which plays a role in mitogen-activated protein kinase and phosphoinositide. 3-kinase pathway activation [4]; APC inactivation is observed in 70%–80% of sporadic colorectal adenomas and carcinoma cases, and gain-of-function β-catenin mutations have been identified in nearly 50% of the colon tumors with intact APC [5]. Β-catenin is a transcriptional activator, activating the expression of many different genes, enhancing T-cell factor (TCF)/lymphoid enhancer family expression, and translocating to the nucleus to combine with DNA-binding sites.
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