title: Hypercholesterolemia Increases Colorectal Cancer Incidence by Reducing Production of NKT and γδ T Cells from Hematopoietic Stem Cells.
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.
authors.affiliation: Diabetes Center of Excellence and Division of Vascular and Endovascular Surgery, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Guodong
authors.initials: G
authors.lastname: Tie
authors.affiliation: Diabetes Center of Excellence and Division of Vascular and Endovascular Surgery, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Jinglian
authors.initials: J
authors.lastname: Yan
authors.affiliation: Diabetes Center of Excellence and Division of Vascular and Endovascular Surgery, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Lyne
authors.initials: L
authors.lastname: Khair
authors.affiliation: Division of Infectious Diseases, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Messina
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: April
authors.initials: A
authors.lastname: Deng
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Joonsoo
authors.initials: J
authors.lastname: Kang
authors.affiliation: Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fazzio
authors.affiliation: Diabetes Center of Excellence and Division of Vascular and Endovascular Surgery, University of Massachusetts Medical School, Worcester, Massachusetts. Louis.Messina@umassmemorial.org.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Messina
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics; D015179:Colorectal Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000235:genetics*; D055611:Natural Killer T-Cells / Q000473:pathology; D009765:Obesity / Q000150:complications / Q000235:genetics* / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D016692:Receptors, Antigen, T-Cell, gamma-delta; D023041:Xenograft Model Antitumor Assays
chemical_list: C534072:MIRN101 microRNA, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D016692:Receptors, Antigen, T-Cell, gamma-delta; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human