title: Combined inadequacies of multiple B vitamins amplify colonic Wnt signaling and promote intestinal tumorigenesis in BAT-LacZxApc1638N mice.
abstract: The Wnt pathway is a pivotal signaling cascade in colorectal carcinogenesis. The purpose of this work is to determine whether depletion of folate and other metabolically related B vitamins induces in vivo activation of intestinal Wnt signaling and whether this occurs in parallel with increased tumorigenesis. A hybrid mouse was created by crossing a Wnt-reporter animal (BAT-LacZ) with a model of colorectal cancer (Apc1638N). A mild depletion of folate and vitamins B₂, B₆, and B₁₂ was induced over 16 wk, and the control animals in each instance were pair fed a diet containing the basal requirement of these nutrients. The multiplicity of macroscopic tumors and aberrant crypt foci both increased by ~50% in the hybrid mice fed the depletion diet (P<0.05). A 4-fold elevation in Wnt signaling was produced by the depletion diet (P<0.05) and was accompanied by significant changes in the expression of a number of Wnt-related genes in a pattern consistent with its activation. Proliferation and apoptosis of the colonic mucosa both changed in a protransformational direction (P<0.05). In summary, mild depletion of multiple B vitamins produces in vivo activation of colonic Wnt signaling, implicating it as a key pathway by which B-vitamin inadequacies enhance intestinal tumorigenesis.
authors.affiliation: Vitamins and Carcinogenesis Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA. zhenhua.liu@tufts.edu
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Liu
authors.forename: Eric D
authors.initials: ED
authors.lastname: Ciappio
authors.forename: Jimmy W
authors.initials: JW
authors.lastname: Crott
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Brooks
authors.forename: Jared
authors.initials: J
authors.lastname: Nesvet
authors.forename: Donald E
authors.initials: DE
authors.lastname: Smith
authors.forename: Sang-Woon
authors.initials: SW
authors.lastname: Choi
authors.forename: Joel B
authors.initials: JB
authors.lastname: Mason
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle; D049109:Cell Proliferation; D003106:Colon / Q000166:cytology / Q000473:pathology; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D004032:Diet; D004847:Epithelial Cells; D005786:Gene Expression Regulation / Q000502:physiology; D017930:Genes, Reporter; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D007763:Lac Operon / Q000235:genetics / Q000502:physiology*; D051379:Mice; D015398:Signal Transduction / Q000502:physiology*; D014804:Vitamin B Deficiency / Q000097:blood / Q000150:complications* / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D051153:Wnt Proteins