Effects of selenium on colon carcinogenesis induced by azoxymethane and dextran sodium sulfate in mouse model with high-iron diet

Jun-Hyeong Kim, Jin-Joo Hue, Bong Su Kang, Hyunji Park, Sang Yoon Nam, Young Won Yun, Jong-Soo Kim, Beom Jun Lee, Jun-Hyeong Kim, Jin-Joo Hue, Bong Su Kang, Hyunji Park, Sang Yoon Nam, Young Won Yun, Jong-Soo Kim, Beom Jun Lee

Abstract

Selenium (Se) is known to prevent several cancers while the relationship between high iron and the risk of colorectal cancer is controversial. To investigate the effects of Se in colon carcinogenesis, we subjected three different levels of Se and high-iron diet to a mouse model of colon cancer in which animals were treated with three azoxymethane (AOM) injections followed by dextran sodium sulfate (DSS) administration. There were five experimental groups including vehicle group [normal-Fe (NFe, 45 ppm)+medium-Se (MSe, 0.1 ppm)], positive control group (AOM/DSS+NFe+MSe), AOM/DSS+high-Fe (HFe, 450 ppm)+low-Se (LSe, 0.02 ppm), AOM/DSS+HFe+MSe, and AOM/DSS+HFe+high-Se (HSe, 0.5 ppm). The animals were fed on the three different Se diets for 24 weeks. The incidence of colon tumor in the high-Se diet group (AOM/DSS+HFe+HSe) showed 19.4% lower than positive control group, 5.9% lower than AOM/DSS+HFe+MSe diet group, and 11.1% lower than AOM/DSS+HFe+LSe group. The tumor multiplicity was significantly higher in the low-Se diet group (AOM/DSS+HFe+LSe) compare to all other AOM/DSS treated groups. In the high-Se diet group, the activity of hepatic GPx was comparable to that of positive control group, and significantly higher than those of low-Se or medium-Se diet groups. Expression level of hepatic GPx-1 showed similar results. Hepatic malondialdehyde (MDA) level (indicator of oxidative stress) in the low-Se diet group showed the highest compared to the other groups, and it was significantly higher than positive control group. In the high-Se diet group the level of MDA in the liver was significantly lower than all other AOM/DSS treated groups. High-Se diet group showed significantly lower proliferative index than low-Se and medium-Se groups. The apoptotic indices in low-Se group and medium-Se group were significantly lower than positive control group. However, apoptotic index of high-Se diet group was significantly higher than all other AOM/DSS treated groups. These findings suggest that dietary Se supplement may have protective effect against colon cancer by decreasing proliferation, increasing apoptosis of tumor cells, and reducing oxidative stress in mice with high iron diet.

Keywords: Azoxymethane (AOM); colon cancer; dextran sodium sulfate (DSS); iron; selenium.

Figures

Figure 1
Figure 1
Change in the body weights of mice fed the high Fe diet. All AOM/DSS-treated groups showed a low body weight compared with the vehicle group during experimental periods. AOM: azoxymethane, DSS: dextran sodium sulfate, HFe: high-Fe diet (450 ppm), LSe: low-Se diet (0.02 ppm), MSe: medium-Se diet (0.1 ppm), HSe: high-Se diet (0.5 ppm). Data were represented as mean±SE. abMeans not sharing common superscript letters are significantly different at P<0.05.
Figure 2
Figure 2
Hepatic Fe levels in mice fed the high Fe diet. Fe concentration was determined using an inductively coupled plasma spectrophotometer. High Fe diet significantly increased hepatic Fe levels compared with the control group. AOM: azoxymethane, DSS: dextran sodium sulfate, HFe: high-Fe diet (450 ppm), LSe: low-Se diet (0.02 ppm), MSe: medium-Se diet (0.1 ppm), HSe: high-Se diet (0.5 ppm). Data were represented as mean±SE. abcMeans not sharing common superscript letters are significantly different at P<0.05.
Figure 3
Figure 3
Hepatic Se levels in mice fed the high Fe diet with different Se levels. The Se concentration was determined using an inductively coupled plasma mass spectrophotometer. The hepatic Se levels were dependent on dietary Se levels. AOM: azoxymethane, DSS: dextran sodium sulfate, HFe: high-Fe diet (450 ppm), LSe: low-Se diet (0.02 ppm), MSe: medium-Se diet (0.1 ppm), HSe: high-Se diet (0.5 ppm). Data were represented as mean±SE. abMeans not sharing common superscript letters are significantly different at P<0.05.
Figure 4
Figure 4
Effect of Se on hepatic GPx activity in mice fed the high Fe diet with different Se levels. The activity of GPx was dependent on dietary Se levels. AOM: azoxymethane, DSS: dextran sodium sulfate, HFe: high-Fe diet (450 ppm), LSe: low-Se diet (0.02 ppm), MSe: medium-Se diet (0.1 ppm), HSe: high-Se diet (0.5 ppm). Data were represented as mean±SE. abcMeans not sharing common superscript letters are significantly different at P<0.05.
Figure 5
Figure 5
Effect of Se on hepatic GPx-1 by western blot in mice fed the high Fe diet with different Se levels. The expression of GPx-1 was up-regulated in the high-Se group compared with the low-Se group. AOM: azoxymethane, DSS: dextran sodium sulfate, HFe: high-Fe diet (450 ppm), LSe: low-Se diet (0.02 ppm), MSe: medium-Se diet (0.1 ppm), HSe: high-Se diet (0.5 ppm). Data were represented as mean±SE. abcMeans not sharing common superscript letters are significantly different at P<0.05.
Figure 6
Figure 6
Effect of Se on hepatic MDA levels in mice fed the high Fe diet with different Se levels. The MDA levels were decreased by dietary Se in a dose-dependent manner. AOM: azoxymethane, DSS: dextran sodium sulfate, HFe: high-Fe diet (450 ppm), LSe: low-Se diet (0.02 ppm), MSe: medium-Se diet (0.1 ppm), HSe: high-Se diet (0.5 ppm). Data were represented as mean±SE. abcdMeans not sharing common superscript letters are significantly different at P<0.05.
Figure 7
Figure 7
Immunohistochemistry of PCNA in the colon of mice fed the low Fe diet with different Se levels. The PCNA-positive cells were increased by treatment with AOM/DSS, but they were reduced by co-administration of a high concentration of Se. Vehicle (A), AOM/DSS+NFe+MSe (positive control, B), AOM/DSS+HFe+LSe (C), AOM/DSS+HFe+MSe (D), AOM/DSS+HFe+HSe (E).
Figure 8
Figure 8
TUNEL assay for apoptotic nuclei in distal colon sections of mice fed high-Fe diet with different Se levels. The TUNEL-positive cells were increased by dietary Se in a dose-dependent manner. Vehicle (A), AOM/DSS+NFe+MSe (positive control, B), AOM/DSS+HFe+LSe (C), AOM/DSS+HFe+MSe (D), AOM/DSS+HFe+HSe (E).

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