Hypercholesterolemia Increases Colorectal Cancer Incidence by Reducing Production of NKT and γδ T Cells from Hematopoietic Stem Cells

Cancer Res. 2017 May 1;77(9):2351-2362. doi: 10.1158/0008-5472.CAN-16-1916. Epub 2017 Mar 1.

Abstract

Obesity will soon surpass smoking as the most preventable cause of cancer. Hypercholesterolemia, a common comorbidity of obesity, has been shown to increase cancer risk, especially colorectal cancer. However, the mechanism by which hypercholesterolemia or any metabolic disorder increases cancer risk remains unknown. 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carcinogenesis
  • Cell Differentiation / genetics
  • Cell Line, Tumor
  • Cell Lineage / genetics
  • Colorectal Neoplasms / etiology
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Hematopoietic Stem Cells / pathology
  • Humans
  • Hypercholesterolemia / complications
  • Hypercholesterolemia / genetics*
  • Hypercholesterolemia / pathology
  • Lymphocyte Activation / genetics
  • Mice
  • MicroRNAs / biosynthesis
  • MicroRNAs / genetics*
  • Mixed Function Oxygenases / biosynthesis
  • Mixed Function Oxygenases / genetics*
  • Natural Killer T-Cells / pathology
  • Obesity / complications
  • Obesity / genetics*
  • Obesity / pathology
  • Oxidative Stress / genetics
  • Proto-Oncogene Proteins / biosynthesis
  • Proto-Oncogene Proteins / genetics*
  • Receptors, Antigen, T-Cell, gamma-delta
  • Xenograft Model Antitumor Assays

Substances

  • MIRN101 microRNA, human
  • MicroRNAs
  • Proto-Oncogene Proteins
  • Receptors, Antigen, T-Cell, gamma-delta
  • Mixed Function Oxygenases
  • TET1 protein, human