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Conditional loss of TGF-beta signalling leads to increased susceptibility to gastrointestinal carcinogenesis in mice.

Authors
Hahm, KB; Lee, KM; Kim, YB; Hong, WS; Lee, WH; Han, SU; Kim, MW; Ahn, BO; Oh, TY; Lee, MH; Green, J; Kim, SJ
Citation
Alimentary pharmacology & therapeutics, 16(suppl.2):115-127, 2002
Journal Title
Alimentary pharmacology & therapeutics
ISSN
0269-28131365-2036
Abstract
BACKGROUND: Downregulation of TGF-beta receptors is implicated in colon cancer development. Inactivation of either of the two transmembrane serine/threonine kinases, TGF-beta1 types I/II receptors, is now implicated in carcinogenesis, especially gastrointestinal carcinogenesis.



METHODS: We generated transgenic mice, called pS2-dnRII or ITF-dnRII, of which the dominant negative mutant of the TGF-beta type II receptor was expressed under the control of tissue-specific promoters, the pS2 promoter for stomach and ITF for intestine. They were either infected with H.pylori (ATCC 43504 strain, CagA+ and VacA+) or administered with azoxymethane to determine the significance of loss of TGF-beta signalling in gastrointestinal carcinogenesis.



RESULTS: Gastric adenocarcinoma developed in pS2-dnRII mice, whereas only chronic active gastritis was noted in wild-type littermates after 36 weeks of H.pylori infection. Mice lacking in TGF-beta signalling specifically in the stomach showed a significantly higher proliferation cell nuclear antigen-labelling index when infected with H.pylori than wild-type littermates (P < 0.01). Development of colonic aberrant crypt foci was provoked in mice by intraperitoneal injections of azoxymethane, and ITF-dnRII mice showed significantly higher incidences of ACF and colon cancers than wild-type littermates.



CONCLUSIONS: Maintaining normal TGF-beta signalling in the gastrointestinal tract seems to be important either for preventing abnormal mucosal proliferation, or for suppressing or retarding carcinogenesis.
MeSH terms
AnimalsAzoxymethane/toxicityCarcinogens/toxicityCarcinoma/etiology/genetics/*metabolism/pathologyColonic Neoplasms/genetics/*metabolism/pathologyDisease SusceptibilityGastritis/etiology/genetics/metabolism/pathologyHelicobacter Infections/complications/genetics/metabolism/pathologyHelicobacter pyloriMiceMice, TransgenicReceptors, Transforming Growth Factor beta/genetics/*metabolismSignal TransductionStomach Neoplasms/etiology/genetics/*metabolism/pathologyTransforming Growth Factor beta/genetics/*metabolism
PMID
11966532
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Gastroenterology
AJOU Authors
함, 기백이, 기명
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