Abstract
Objective To investigate methylation of the adenomatosis polyposis coli homologue (APC2) promoter and its correlation with prognostic implications in Chinese colorectal cancer (CRC). Methods The mRNA expression of APC2 in colorectal tissues was evaluated using the database of The Cancer Genome Atlas (TCGA). Methylation analysis of APC2 in tumor (n = 66) and corresponding adjacent formalin-fixed and paraffin-embedded (FFPE) tissues (n = 44) was performed by Sequenom EpiTYPER® and verified by cloning-based bisulfite sequencing analysis. Demethylation and retrieval of APC2 expression in cell lines HT29, HCT116, and SW480 were treated with 5-aza-2′-deoxycytidine (5-AZC). Results Analysis of TCGA showed that APC2 mRNA was significantly downregulated in primary tumors when compared to normal tissues (p < 0.05). APC2 methylation was upregulated (43.93% vs 7.31%, p < 0.05) in tumors compared to adjacent FFPE tissues. In vitro experiments demonstrated that 5-AZC downregulated the methylation of APC2 and retrieved its expression of mRNA and protein levels (p < 0.05). Multivariate Cox regression indicated that APC2_CPG_14 was an independent risk factor for overall survival (HR = 6.38, 95% CI: 1.59–25.64, p < 0.05). Conclusion This study indicates that APC2 is hypermethylated and may be a tumorigenesis biomarker for Chinese CRC patients.
Highlights
Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality with high incidence worldwide [1]
The mRNA expression of APC2 in a number of CRC tissues was evaluated by The Cancer Genome Atlas (TCGA) in Oncomine, a database of RNA and DNA sequencing information originated from the Gene Expression Omnibus, The Cancer Genome Atlas, and other published literature database
The mRNA expression of APC2 in CRC was explored in TCGA database
Summary
Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality with high incidence worldwide [1]. Despite advances in efficient surgical techniques and novel chemoradiotherapeutic interventions, the long-term survival rate of CRC patients remains poor [2]. Promising epigenetic therapies for cancer have been put forward [3]. Methylation of CpG sites is a common epigenetic modification in cancers and results in gene silencing and oncogenesis [4, 5]. The classic tumor suppressor gene adenomatosis polyposis coli (APC) has been well studied in many malignancies [6,7,8]. APC2/APCL, located on chromosome 19p13.3 [9], plays a significant role in several human cancers, including retinoblastoma (RB) tumor, lymphocytic leukemia, and ovarian cancer [10,11,12,13]. APC2 has been found to be hypermethylated in both RB tumor samples and the Y79 cell line, mediating the reduction of β-catenin levels
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