title: Effects of calorie restriction and diet-induced obesity on murine colon carcinogenesis, growth and inflammatory factors, and microRNA expression.
abstract: Obesity is an established colon cancer risk factor, while preventing or reversing obesity via a calorie restriction (CR) diet regimen decreases colon cancer risk. Unfortunately, the biological mechanisms underlying these associations are poorly understood, hampering development of mechanism-based approaches for preventing obesity-related colon cancer. We tested the hypotheses that diet-induced obesity (DIO) would increase (and CR would decrease) colon tumorigenesis in the mouse azoxymethane (AOM) model. In addition, we established that changes in inflammatory cytokines, growth factors, and microRNAs are associated with these energy balance-colon cancer links, and thus represent mechanism-based targets for colon cancer prevention. Mice were injected with AOM once a week for 5 weeks and randomized to: 1) control diet; 2) 30% CR diet; or 3) DIO diet. Mice were euthanized at week 5 (n = 12/group), 10 (n = 12/group), and 20 (n = 20/group) after the last AOM injection. Colon tumors were counted, and cytokines, insulin-like growth factor 1 (IGF-1), IGF binding protein 3 (IGFBP-3), adipokines, proliferation, apoptosis, and expression of microRNAs (miRs) were measured. The DIO diet regimen induced an obese phenotype (∼36% body fat), while CR induced a lean phenotype (∼14% body fat); controls were intermediate (∼26% body fat). Relative to controls, DIO increased (and CR decreased) the number of colon tumors (p = 0.01), cytokines (p<0.001), IGF-1 (p = 0.01), and proliferation (p<0.001). DIO decreased (and CR increased) IGFBP-3 and apoptosis (p<0.001). miRs including mir-425, mir-196, mir-155, mir-150, mir-351, mir-16, let-7, mir34, and mir-138 were differentially expressed between the dietary groups. We conclude that the enhancing effects of DIO and suppressive effects of CR on colon carcinogenesis are associated with alterations in several biological pathways, including inflammation, IGF-1, and microRNAs.
authors.affiliation: Laboratory of Human Carcinogenesis, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland, United States of America; Division of Epidemioogy, The Ohio State University College of Public Health, Columbus, Ohio, United States of America.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Olivo-Marston
authors.affiliation: Department of Nutritional Sciences, University of Texas-Austin, Austin, Texas, United States of America; Department of Molecular Carcinogenesis, University of Texas-MD Anderson Cancer Center, Smithville, Texas, United States of America.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Hursting
authors.affiliation: Center for Cancer Training, The National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Susan N
authors.initials: SN
authors.lastname: Perkins
authors.affiliation: Laboratory of Human Carcinogenesis, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Aaron
authors.initials: A
authors.lastname: Schetter
authors.affiliation: Laboratory of Human Carcinogenesis, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Khan
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University College of Medicine, Columbus, Ohio, United States of America.
authors.forename: Carlo
authors.initials: C
authors.lastname: Croce
authors.affiliation: Laboratory of Human Carcinogenesis, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Curtis C
authors.initials: CC
authors.lastname: Harris
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, United States of America.
authors.forename: Jackie
authors.initials: J
authors.lastname: Lavigne
mesh_terms: D054392:Adipokines / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001823:Body Composition; D001835:Body Weight; D031204:Caloric Restriction; D063646:Carcinogenesis; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000150:complications* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004032:Diet; D015972:Gene Expression Regulation, Neoplastic; D005951:Glucose Tolerance Test; D007249:Inflammation / Q000378:metabolism; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D009765:Obesity / Q000150:complications*; D011897:Random Allocation; D012307:Risk Factors
chemical_list: D054392:Adipokines; D016207:Cytokines; D018972:Insulin-Like Growth Factor Binding Protein 3; D035683:MicroRNAs; D007334:Insulin-Like Growth Factor I
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