Abstract
BackgroundsColorectal cancer (CRC) results from the accumulation of epigenetic and genetic changes in colon cells during neoplasic transformation, which the activation of Wingless (Wnt) signaling pathway is a common mechanism for CRC initiation. The Wnt pathway is mainly regulated by Wnt antagonists, as secreted frizzled-related protein (SFRP) family. Indeed, SFRP2 is proposed as a noninvasive biomarker for CRC diagnosis. Vitamin D also antagonizes Wnt signaling in colon cancers cells. Several studies showed that vitamin D was able to alter DNA methylation, although this mechanism is not yet clear. Therefore, the aim of this study was to find an association between circulating 25-OH vitamin D (30th percentile of vitamin D) and the SFRP2 methylation.MethodsA total of 67 CRC patients were included in the study. These patients were subdivided into two groups based on their 30th percentile vitamin D (20 patients were below, and 47 participants were above the 30th percentile of vitamin D). We investigated the SFRP2 methylation in peripheral blood mononuclear cells (PBMCs), visceral adipose tissue (VAT), CRC tumor tissue, and adjacent tumor-free area. We also determined the relationship between SFRP2 methylation and methylation of carcinogenic and adipogenic genes. Finally, we tested the effect of vitamin D on the SFRP2 methylation in human colorectal carcinoma cell lines 116 (HCT116) and studied the association of neoadjuvant therapy under the 30th percentile vitamin D with SFRP2 promoter methylation.ResultsSFRP2 methylation in tumor area was decreased in patients who had higher levels of vitamin D. SFRP2 promoter methylation was positively correlated in tumor area with insulin and homeostasis model assessment of insulin resistance (HOMA-IR) but negatively correlated with HDL-c. SFRP2 methylation was also correlated with T cell lymphoma invasion and metastasis 1 (TIAM1) methylation in tumor area and CCAAT/enhancer-binding protein alpha (C/EBPα) in VAT. Treatment with vitamin D did not affect SFRP2 methylation in HCT116 cell line. Finally, neoadjuvant treatment was correlated with higher circulating 25-OH vitamin D and SFRP2 methylation under linear regression model.ConclusionOur results showed that higher circulating vitamin D is associated with low SFRP2 promoter methylation. Therefore, our results could suggest that vitamin D may have an epigenetic effect on DNA methylation. Finally, higher vitamin D could contribute to an improvement response to neoadjuvant treatment.
Highlights
Colorectal cancer (CRC) is one of the most common cancers worldwide
Our results showed that higher circulating vitamin D is associated with low SFRP2 promoter methylation
Our results showed that not significant differences were observed in SFRP2 promoter methylation between < 30th and > 30th groups in peripheral blood mononuclear cells (PBMCs) and visceral adipose tissue (VAT) from non-CRC subjects (Fig. 1a)
Summary
Colorectal cancer (CRC) is one of the most common cancers worldwide. Combined, in both sexes, CRC is the third most commonly diagnosed cancer and one of the leading causes of cancer-related mortality [1]. It is well known that genetic and epigenetic alterations in cell crypt foci lead to activation of Wingless (Wnt) signaling pathway [2]. Aberrant activation of Wnt signaling is a hallmark of CRC and is one of the most investigated target for preventive and therapeutic intervention [3]. Uninterrupted activation of the Wnt pathway is often caused by alterations in any of their components, either by mutational or epigenetic changes and leads to uncontrolled cancer cell proliferation and differentiation [4, 5]
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