8-Oxoguanine DNA Glycosylase 1 Upregulation as a Risk Factor for Obesity and Colorectal Cancer

Abstract

DNA damage has been extensively studied as a potentially helpful tool in assessing and preventing cancer, having been widely associated with the deregulation of DNA damage repair (DDR) genes and with an increased risk of cancer. Adipose tissue and tumoral cells engage in a reciprocal interaction to establish an inflammatory microenvironment that enhances cancer growth by modifying epigenetic and gene expression patterns. Here, we hypothesize that 8-oxoguanine DNA glycosylase 1 (OGG1)-a DNA repair enzyme-may represent an attractive target that connects colorectal cancer (CRC) and obesity. In order to understand the mechanisms underlying the development of CRC and obesity, the expression and methylation of DDR genes were analyzed in visceral adipose tissue from CRC and healthy participants. Gene expression analysis revealed an upregulation of OGG1 expression in CRC participants (p < 0.005) and a downregulation of OGG1 in normal-weight healthy patients (p < 0.05). Interestingly, the methylation analysis showed the hypermethylation of OGG1 in CRC patients (p < 0.05). Moreover, expression patterns of OGG1 were found to be regulated by vitamin D and inflammatory genes. In general, our results showed evidence that OGG1 can regulate CRC risk through obesity and may act as a biomarker for CRC.

Keywords: CRC; DNA repairs; OGG1; colorectal cancer; inflammation; methylation; obesity; repair genes.

Figure 1

Gene expression and methylation profile of OGG1 in visceral adipose tissue from patients with obesity and colorectal cancer: (A) Normalized gene expression of OGG1 comparing healthy participants (N = 54) and patients with CRC (N = 65). (B) Normalized gene expression of OGG1 comparing healthy lean participants (N = 13) with overweight/obese participants (N = 41). In addition, we compared lean (N = 22) and overweight/obese patients with CRC (N = 43). (C) Promoter methylation of OGG1 comparing healthy participants (N = 24) and patients with CRC (N = 23). The promoter contained the following CpG sites: cg11841349, cg14201528, cg15357639, cg17285536, cg17319894, cg19391888, cg25415932, and cg05439191. (D) Promoter methylation of OGG1 comparing healthy lean participants (N = 7) with overweight/obese participants (N = 17). In addition, we compared lean (N = 11) and overweight/obese patients with CRC (N = 12). Gene expression was normalized using the PPIA gene and the formula: 2^−ΔCt. Abbreviations: CRC: colorectal cancer; OGG1: OGG1 8-oxoguanine DNA glycosylase 1; Ow/Ob: overweight/obese; ns: non-significant. Asterisks indicate significant values according to the test (* p < 0.05; ** p < 0.01).

Figure 2

OGG1 expression in adipose tissue and metabolic and DNA repair genes: (A) Heatmap of Pearson’s correlation between OGG1 expression and methylation, and anthropometric and biochemical variables in all participants. (B) Heatmap of Pearson’s correlation between OGG1 expression and methylation and gene expression of inflammatory genes in visceral adipose tissue in all participants. (C) Heatmap of Pearson’s correlation between OGG1 expression and methylation and gene expression of DNA repair genes in visceral adipose tissue from healthy participants (D) Kaplan–Meier estimates for overall survival according to gene expression of OGG1 (low vs. high under the median value) in whole blood. The asterisks indicate a significant correlation between variables according to Pearson’s correlation test (* p < 0.05). Abbreviations: AT: adipose tissue; WB: whole blood.

Figure 3

In vitro validation of the OGG1 gene profile in the adipose tissue and adipocytes: Total RNA from explants was extracted, and gene expression was measured. Normalized gene expression of (A) OGG1 and (C) CYP24A1 was calculated by comparing explants from healthy lean participants (N = 3), healthy obese participants (N = 3), and patients with CRC (N = 4). Adipocytes were treated with 0.5 µM of calcitriol for 24 h. (B) OGG1 and (D) CYP24A1 was calculated by comparing control and treated adipocytes. The asterisks indicate significant values according to the test (** p < 0.01; *** p < 0.001). Gene expression was normalized using the PPIA gene and the formula 2^−ΔCt. ns: no significant.