Abstract 1557: The iron-overload genetic disease hemochromatosis potentiates colonic inflammation and colon carcinogenesis

Abstract

Abstract Hemochromatosis is a highly prevalent genetic disease associated with excessive iron accumulation in a variety of tissues in an age-dependent manner. In a majority of patients (>85%) with hemochromatosis, mutations in the iron-regulatory gene HFE are the cause. Iron, when present in excess, is an inducer of oxidative stress and suppresses mitochondrial function. Patients with hemochromatosis show evidence of colonic inflammation. Further, some studies have shown increased risk for colon cancer associated with genetic mutations known to cause hemochromatosis. Based on these findings in the literature, we hypothesized that hemochromatosis is an important determinant of disease progression in patients with colitis and colon cancer. We tested this hypothesis by comparing progression of experimentally induced colitis and colon cancer between wild type mice and Hfe-null mice, a model for hemochromatosis. We also compared the transcriptome profile between wild type and Hfe-null colonic epithelial cells. In addition, we analyzed fecal bacteria in wild type mice and Hfe-null mice because colonic microbiome is an important determinant of colonic inflammation and colon cancer. With dextran sulfate sodium-induced colitis, Hfe-null mice suffered more weight loss and exhibited more severe bleeding and diarrhea scores than wild type mice. With ApcMin-driven colon and intestinal cancer, Hfe-null mice had more polyps in the small intestine and colon than wild type mice. Transcriptome analysis showed that Hfe-null colonic epithelial cells, compared to wild type cells, had increased expression of the cytokines Ccl3 and Ccl5 and the interferon-stimulated gene 15 (ISG15 or Usp18), which are all known to promote inflammation and cancer. Hfe-null colonic epithelial cells also had decreased expression of Erdr1 (erythroid differentiation regulator 1), whose expression is known to suppress tumor cell proliferation, invasion, migration and metastasis. Analysis of fecal microbiome indicated that the prevalence of Bacteroidetes and Firmicutes decreased while that of Proteobacteria increased in Hfe-null mice compared to wild type mice, a finding particularly striking in male mice. These studies demonstrate that hemochromatosis enhances the progression of colonic inflammation and colon carcinogenesis. This conclusion is further supported by xenograft studies using the colon cancer cell line HCT116 with and without shRNA-induced downregulation of HFE. When HFE was silenced, there was a significant increase in the growth of HCT116 cells in mouse xenografts, demonstrating that inactivation of HFE promotes colon cancer progression. Based on these data, we conclude that the iron-overload disease hemochromatosis is a promoter of disease progression in colitis and colon cancer, and that use of iron chelators might have a logical basis for inclusion in therapeutic modalities in the treatment of colonic inflammation and colon cancer. Citation Format: Vadivel Ganapathy, Ashish Gurav, Jaya P. Gnanaprakasam, Ellappan Babu, Yangzom D. Bhutia, Cynthia Reinoso Webb, Matthew B. Grisham. The iron-overload genetic disease hemochromatosis potentiates colonic inflammation and colon carcinogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1557. doi:10.1158/1538-7445.AM2015-1557