title: Nuclear adenomatous polyposis coli suppresses colitis-associated tumorigenesis in mice.
abstract: Mutation of tumor suppressor adenomatous polyposis coli (APC) initiates most colorectal cancers and chronic colitis increases risk. APC is a nucleo-cytoplasmic shuttling protein, best known for antagonizing Wnt signaling by forming a cytoplasmic complex that marks β-catenin for degradation. Using our unique mouse model with compromised nuclear Apc import (Apc(mNLS)), we show that Apc(mNLS/mNLS) mice have increased susceptibility to tumorigenesis induced with azoxymethane (AOM) and dextran sodium sulfate (DSS). The AOM-DSS-induced colon adenoma histopathology, proliferation, apoptosis, stem cell number and β-catenin and Kras mutation spectra were similar in Apc(mNLS/mNLS) and Apc(+/+) mice. However, AOM-DSS-treated Apc(mNLS/mNLS) mice showed more weight loss, more lymphoid follicles and edema, and increased colon shortening than treated Apc(+/+) mice, indicating a colitis predisposition. To test this directly, we induced acute colitis with a 7 day DSS treatment followed by 5 days of recovery. Compared with Apc(+/+) mice, DSS-treated Apc(mNLS/mNLS) mice developed more severe colitis based on clinical grade and histopathology. Apc(mNLS/mNLS) mice also had higher lymphocytic infiltration and reduced expression of stem cell markers, suggesting an increased propensity for chronic inflammation. Moreover, colons from DSS-treated Apc(mNLS/mNLS) mice showed fewer goblet cells and reduced Muc2 expression. Even in untreated Apc(mNLS/mNLS) mice, there were significantly fewer goblet cells in jejuna, and a modest decrease in colonocyte Muc2 expression compared with Apc(+/+) mice. Colonocytes from untreated Apc(mNLS/mNLS) mice also showed increased expression of inflammatory mediators cyclooxygenase-2 (Cox-2) and macrophage inflammatory protein-2 (MIP-2). These findings reveal novel functions for nuclear Apc in goblet cell differentiation and protection against inflammation-induced colon tumorigenesis.
authors.affiliation: Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA, Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt and.
authors.forename: Maged
authors.initials: M
authors.lastname: Zeineldin
authors.affiliation: Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Miller
authors.affiliation: Carbone Cancer Center and Research Animal Resources Center, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Sullivan
authors.affiliation: Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA, klneuf@ku.edu.
authors.forename: Kristi L
authors.initials: KL
authors.lastname: Neufeld
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001397:Azoxymethane / Q000633:toxicity; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D003092:Colitis / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D051546:Cyclooxygenase 2; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009154:Mutation / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D002273:Carcinogens; D012333:RNA, Messenger; D051176:beta Catenin; D016264:Dextran Sulfate; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D001397:Azoxymethane