Hypercholesterolemia Increases Colorectal Cancer Incidence by Reducing Production of NKT and {gamma}{delta} T Cells from Hematopoietic Stem Cells

In this study, we show that hypercholesterolemia increases the incidence and pathologic severity of colorectal neoplasia in two independent mouse models. Hypocholesterolemia induced an oxidant stress–dependent increase in miR101c, which downregulated Tet1 in hematopoietic stem cells (HSC), resulting in reduced expression of genes critical to natural killer T cell (NKT) and γδ T-cell differentiation. These effects reduced the number and function of terminally differentiated NKT and γδ T cells in the thymus, the colon submucosa, and during early tumorigenesis. These results suggest a novel mechanism by which a metabolic disorder induces epigenetic changes to reduce lineage priming of HSC toward immune cells, thereby compromising immunosurveillance against cancer. Cancer Res; 77(9); 2351–62. ©2017 AACR.
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Molecular and Cellular Pathobiology Source Type: research