Inducible heat shock protein 70 prevents multifocal flat dysplastic lesions and invasive tumors in an inflammatory model of colon cancer.
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, beta-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, beta-catenin was predominantly nuclear, compared with membranous beta-catenin in Hsp70(-/-) tumors, suggesting that Hsp70 regulates beta-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.
Tao
Yun
Y
Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Hart
John
J
Lichtenstein
Lev
L
Joseph
Loren J
LJ
Ciancio
Mae J
MJ
Hu
Shien
S
Chang
Eugene B
EB
Bissonnette
Marc
M
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D003092:Colitis / Q000473:pathology*; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D017931:DNA Primers; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009361:Neoplasm Invasiveness; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D017931:DNA Primers; D018840:HSP70 Heat-Shock Proteins; D016159:Tumor Suppressor Protein p53