Mathematics56

http://www.sciencedaily.com/releases/2014/08/140821102433.htm

Nuclear adenomatous polyposis coli suppresses colitis-associated tumorigenesis in mice
Maged Zeineldin1,2, Matthew A. Miller1, Ruth Sullivan3 and Kristi L. Neufeld1,*
+ Author Affiliations

1 Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA,
2 Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt and
3 Carbone Cancer Center and Research Animal Resources Center, University of Wisconsin, Madison, WI 53706, USA
↵*To whom correspondence should be addressed. Department of Molecular Biosciences, University of Kansas, 7049 Haworth Hall, 1200 Sunnyside Avenue, Lawrence, KS 66045, USA. Tel: +1 785 864 5079; Fax: +1 785 864 5294; Email: klneuf@ku.edu
Received December 5, 2013.
Revision received May 9, 2014.
Accepted May 24, 2014.
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 (ApcmNLS), we show that ApcmNLS/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 ApcmNLS/mNLS and Apc+/+ mice. However, AOM–DSS-treated ApcmNLS/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 ApcmNLS/mNLS mice developed more severe colitis based on clinical grade and histopathology. ApcmNLS/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 ApcmNLS/mNLS mice showed fewer goblet cells and reduced Muc2 expression. Even in untreated ApcmNLS/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 ApcmNLS/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.

Abbreviations:
APC
adenomatous polyposis coli
AOM
azoxymethane
Cox
cyclooxygenase
CRC
colorectal cancer
CXCR-2
CXC cytokine receptor-2
DSS
dextran sodium sulfate
Gro-α
growth-related oncogene-α
IL
interleukin
MIP-2
macrophage inflammatory protein-2
mRNA
messenger RNA
NLS
nuclear localization signals
OPN
osteopontin
PBS
phosphate-buffered saline
TUNEL
terminal deoxynucleotidyl transferase dUTP nick end labeling.
© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

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