Carcinogenesis Advance Access originally published online on November 12, 2008
Carcinogenesis 2009 30(1):175-182; doi:10.1093/carcin/bgn256
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Inducible heat shock protein 70 prevents multifocal flat dysplastic lesions and invasive tumors in an inflammatory model of colon cancer
Department of Medicine
1 Department of Pathology, University of Chicago, Chicago, IL 60637, USA
* To whom correspondence should be addressed. Department of Medicine, MC 4076, University of Chicago Hospitals and Clinics, 5841 South Maryland Avenue, Chicago, IL 60637, USA. Tel: +1 773 702 8597; Fax: +1 773 702 2182; Email: mbissonn{at}medicine.bsd.uchicago.edu
Background: Heat shock protein 70 (Hsp70) 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 (AOM)/dextran sulfate sodium (DSS) model of inflammation and colon cancer. Methods: Hsp70 mutant mice (Hsp70.1–/–/70.3–/–) and wild-type (WT) littermates received AOM and three cycles of DSS and were killed 24 weeks later. Tumors were graded for histology and immunostained for p53, adenomatous polyposis coli, β-catenin, cyclooxygenase-2 (Cox-2) and inducible nitric oxide synthase (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 knock out (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 with WT tumors, and sequencing confirmed p53 mutations in 2/5 tumors from Hsp70–/– versus 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 with Hsp70 WT tumors. Conclusions: Hsp70-deleted mice treated with AOM/DSS develop flat invasive colonic tumors that mimic many histological and molecular features of ulcerative colitis colon cancer. This model will be useful to dissect the role of Hsp70 in inflammatory bowel disease colon cancer.
Abbreviations: AOM, azoxymethane; Apc, adenomatous polyposis coli; Cox-2, cyclooxygenase-2; DSS, dextran sulfate sodium; Hsp70, heat shock protein 70; IBD, inflammatory bowel disease; IL, interleukin; iNOS, inducible nitric oxide synthase; PCR, polymerase chain reaction; UC, ulcerative colitis; WT, wild-type
These authors contributed equally to this work. Received August 18, 2008; revised October 23, 2008; accepted November 6, 2008.
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