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Carcinogenesis Advance Access published online on November 12, 2008
Carcinogenesis, doi:10.1093/carcin/bgn256
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Inducible Heat Shock Protein70 Prevents Multifocal Flat Dysplastic Lesions and Invasive Tumors in an Inflammatory Model of Colon Cancer

Yun Tao, John Hart*, Lev Lichtenstein, Loren Joseph, Mae Ciancio, Shien Hu, Eugene B. Chang{ddagger} and Marc Bissonnette{ddagger},{dagger}

* Departments of Medicine and Pathology, University of Chicago, Chicago, IL USA

{dagger} To whom correspondence should be addressed: Marc Bissonnette, M.D, Department of Medicine, MC 4076, University of Chicago Hospitals and Clinics, 5841 S. Maryland Ave, Chicago, IL 60637; Telephone: (773) 702-8597 FAX: (773) 702-2182 e-mail: mbissonn{at}medicine.bsd.uchicago.edu

Background: Heat shock protein70 (Hsp70)1 regulates protein biosynthesis and refolding of denatured proteins. Since Hsp70 participates in recovery from stress injury, we examined the effect of Hsp70 genetic deletion in the azoxymethane/dextran sulfate sodium (AOM/DSS) model of inflammation and colon cancer. Methods: Hsp70 mutant mice (Hsp70.1-/-/70.3-/-) and wild type (WT) littermates received AOM and 3 cycles of DSS and were sacrificed 24 wks later. Tumors were graded for histology and immunostained for p53, APC, β-catenin, Cox-2 and iNOS and sequenced for p53 mutations. Results: Elevated adenomas developed in 4/10 WT mice with no dysplasia in adjacent mucosa. In contrast, 7/8 Hsp70 KO mice developed chronic mucosal inflammation and multifocal areas of flat dysplasia and 4/8 progressed to invasive carcinomas arising in a background of flat dysplastic mucosa. These differences in the incidence of flat dysplasia and invasive cancers were significant (p<0.05). Nuclear p53 was stronger in Hsp70 KO tumors compared to WT tumors, and sequencing confirmed p53 mutations in 2/5 tumors from Hsp70-/- vs. 0/5 in WT mice. In Hsp70 WT tumors β-catenin was predominantly nuclear, compared with membranous β-catenin in Hsp70-/- tumors, suggesting that Hsp70 regulates β-catenin in colonic tumorigenesis. Cox-2 and iNOS levels were increased in tumors from Hsp70-/- mice compared to Hsp70 wild type tumors. Conclusions: Hsp70-deleted mice treated with AOM/DSS develop flat invasive colonic tumors that mimic many histological and molecular features of UC colon cancer. This model will be useful to dissect the role of Hsp70 in IBD colon cancer.

Key Words: azoxymethane • dextran sulfate sodium • inflammatory bowel diseases • inflammation • colonic carcinogenesis

{ddagger} Equal roles as principal investigators

Received August 18, 2008; revised October 23, 2008; accepted November 6, 2008.


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[Abstract] [Full Text] [PDF]


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