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Loss of sulfiredoxin renders mice resistant to azoxymethane/dextran sulfate sodium-induced colon carcinogenesis.

ABSTRACT: Sulfiredoxin (Srx) is the enzyme that reduces the hyperoxidized inactive form of peroxiredoxins. To study the function of Srx in carcinogenesis in vivo, we tested whether loss of Srx protects mice from cancer development. Srx null mice were generated and colon carcinogenesis was induced by an azoxymethane (AOM) and dextran sulfate sodium (DSS) protocol. Compared with either wild-type (Wt) or heterozygotes, Srx(-/-) mice had significantly reduced rates in both tumor multiplicity and volume. Mechanistic studies reveal that loss of Srx did not alter tumor cell proliferation; however, increased apoptosis and decreased inflammatory cell infiltration were obvious in tumors from Srx null mice compared with those from Wt control. In addition to the AOM/DSS model, examination of Srx expression in human reveals a tissue-specific expression pattern. Srx expression was also demonstrated in tumors from colorectal cancer patients and the levels of expression were associated with patients' clinic stages. These data provide the first in vivo evidence that loss of Srx renders mice resistant to AOM/DSS-induced colon carcinogenesis, suggesting that Srx has a critical oncogenic role in cancer development, and Srx may be used as a marker for human colon cancer pathogenicity.

SUBMITTER: Wei Q

PROVIDER: S-EPMC3670259 | biostudies-other | 2013 Jun

REPOSITORIES: biostudies-other

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Loss of sulfiredoxin renders mice resistant to azoxymethane/dextran sulfate sodium-induced colon carcinogenesis.

Wei Qiou Q Jiang Hong H Baker Alyson A Dodge Lisa K LK Gerard Matthieu M Young Matthew R MR Toledano Michel B MB Colburn Nancy H NH

Carcinogenesis 20130207 6

Sulfiredoxin (Srx) is the enzyme that reduces the hyperoxidized inactive form of peroxiredoxins. To study the function of Srx in carcinogenesis in vivo, we tested whether loss of Srx protects mice from cancer development. Srx null mice were generated and colon carcinogenesis was induced by an azoxymethane (AOM) and dextran sulfate sodium (DSS) protocol. Compared with either wild-type (Wt) or heterozygotes, Srx(-/-) mice had significantly reduced rates in both tumor multiplicity and volume. Mecha ...[more]

PMID: 23393226

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Project description:This study aims to investigate the antitumor effect and the possible mechanism of a microecological preparation (JK5G) in mice. The mice treated with AOM/DSS were then randomly divided into the two model groups and the JK5G group, and the blank control group was included. Fecal samples were used for liquid chromatography-mass spectrometry and 16S rRNA gene sequencing analyses to reveal metabolic perturbations and gut flora disorders to demonstrate the effects of JK5G. Compared with the mice in the control group, the weight and food intake of mice after JK5G treatment were both upregulated. Moreover, JK5G could inhibit the growth of colon tumors and prolong the survival rate of mice, as well as inhibit the levels of cytokines in serum. The proportions of lymphocytes, T cells, CD3+CD4+ T cells, and CD3+CD8+ T cells in the spleen of the JK5G mice were all significantly increased compared to those in the control group (p < 0.05). Similarly, compared with the model group, the proportions of lymphocytes, B cells, T cells, natural killer T cells, CD3+CD4+ T cells, and CD3+CD8+ T cells in the intestinal tumors of the JK5G mice were significantly increased (p < 0.05). Furthermore, 16S rRNA high-throughput sequencing data revealed that Alloprevotella in the JK5G group was significantly upregulated, and Ruminiclostridium, Prevotellaceae_UCG_001, and Acetitomaculum were significantly downregulated. Fecal and serum metabolite analysis detected 939 metabolites, such as sildenafil and pyridoxamine, as well as 20 metabolites, including N-Palmitoyl tyrosine and dihydroergotamine, which were differentially expressed between the JK5G and model groups. Integrated analysis of 16s rRNA and metabolomics data showed that there were 19 functional relationship pairs, including 8 altered microbiota, such as Ruminiclostridium and Prevotellaceae_UCG_001, and 16 disturbed metabolites between the JK5G and model groups. This study revealed that JK5G treatment was involved in the growth of colorectal cancer, which may be associated with the role of JK5G in improving the nutritional status of mice and regulating the tumor microenvironment by regulating the changes of intestinal microbiota and metabolite bands on different pathways.

Dataset Information

Loss of sulfiredoxin renders mice resistant to azoxymethane/dextran sulfate sodium-induced colon carcinogenesis.

Publications

Loss of sulfiredoxin renders mice resistant to azoxymethane/dextran sulfate sodium-induced colon carcinogenesis.

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