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Received Oct 15, 2017; Revised Mar 3, 2018; Accepted May 23, 2018
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1. Introduction
Colorectal cancer (CRC) is the development of cancer in the colon or rectum. It is one of the most common fatal malignancies in the world; globally, more than 1 million people get colorectal cancer every year [1]. The incidence of CRC in China is lower than that in the west countries but has increased in recent years and has become a substantial cancer burden in China, particularly in the more developed areas [2].
Tregs are considered to be a major cell population involved in tumor immune tolerance [3, 4]. The transcription factor forkhead box P3 (FOXP3) is a subfamily member of forkhead transcription factor, which is specifically expressed in CD4+CD25+ Tregs, and it is regarded as a critical developmental and functional factor for Tregs [5]. Treg-specific demethylated region (TSDR) is a CpG dinucleotide-rich and highly conserved region within the conserved noncoding sequences 2 (CNS2) at the FOXP3 locus [6]. TSDR demethylation is necessary for stable FOXP3 expression and maintenance of the suppressive phenotype for nTregs [7].
Recently, investigators have evaluated that the tumor-infiltrating FOXP3+ Tregs are linked to colorectal cancer progression and outcome [8–10]. Zhuo et al. found significantly higher FOXP3-TSDR demethylation rates in tumor sites versus normal sites in patients with CRC, as well as significantly more FOXP3 mRNA expression and higher protein synthesis in tumor tissues [11]. However, the molecular mechanism of FOXP3-TSDR excessive demethylation in patients with CRC has not been fully understood.
Ten-eleven translocation proteins (TET1, TET2, and TET3) catalyze 5-methylcytosine (5mC) conversion to 5-hydroxymethylcytosine (5hmC) to mediate DNA demethylation [12]. It has been found that TET1 and TET2 bind to the FOXP3 CNS2 region in Tregs, suggesting a role for the TET proteins in the maintenance of Tregs identity [13]. Moreover, IL2 can maintain the high level of TET2 during the thymic Treg development, and downregulation of TET2 expression prevents FOXP3-TSDR demethylation [14]. Nevertheless, the molecular mechanism of TET2 targeting regulation of FOXP3-TSDR demethylation is still unclear. STAT5 is an important transcription...