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Induction of cyclooxygenase-2 in a mouse model of Peutz-Jeghers polyposis
Derrick J Rossi1, Antti Ylikorkala, Nina Korsisaari
1Haartman Institute and Helsinki University Central Hospital, Biomedicum Helsinki, P.O. Box 63, University of Helsinki, 00014 Helsinki, Finland.
Abstract:
Inactivating germ-line mutations of LKB1 lead to Peutz-Jeghers syndrome (PJS). We have generated mice heterozygous for a targeted inactivating allele of Lkb1 and found that they develop severe gastrointestinal polyposis. In all cases, the polyps arising in the Lkb1+/- mice were found to be hamartomas that were histologically indistinguishable from polyps resected from PJS patients, indicating that Lkb1+/- mice model human PJS polyposis. No evidence for inactivation of the remaining wild-type Lkb1 allele in Lkb1+/- -associated polyps was observed. Moreover, polyps and other tissues in heterozygote animals exhibited reduced Lkb1 levels and activity, indicating that Lkb1 was haploinsufficient for tumor suppression. Analysis of the molecular mechanisms characterizing Lkb1+/- polyposis revealed that cyclooxygenase-2 (COX-2) was highly up-regulated in murine polyps concomitantly with activation of the extracellular signal-regulated kinases 1 and 2 (Erk1/2). Subsequent examination of a large series of human PJS polyps revealed that COX-2 was also highly up-regulated in the majority of these polyps. These findings thereby identify COX-2 as a potential target for chemoprevention in PJS patients.
Insights
Inactivating the LKB1 gene causes Peutz-Jeghers syndrome (PJS). Lkb1+/- mice develop PJS-like polyps, showing LKB1 haploinsufficiency and identifying COX-2 as a potential therapeutic target for PJS.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Peutz-Jeghers syndrome (PJS) is a rare inherited disorder.
- Germ-line mutations in the LKB1 gene are the primary cause of PJS.
- PJS is characterized by the development of hamartomatous polyps in the gastrointestinal tract.
Purpose of the Study:
- To develop and validate a mouse model for Peutz-Jeghers syndrome (PJS).
- To investigate the role of LKB1 haploinsufficiency in PJS polyposis.
- To identify molecular mechanisms underlying PJS pathogenesis and potential therapeutic targets.
Main Methods:
- Generation of mice heterozygous for a targeted inactivating Lkb1 allele (Lkb1+/-).
- Histological analysis of polyps from Lkb1+/- mice and comparison with human PJS polyps.
- Assessment of LKB1 levels and activity in polyps and other tissues.
- Molecular analysis, including evaluation of cyclooxygenase-2 (COX-2) and extracellular signal-regulated kinases 1 and 2 (Erk1/2) expression.
Main Results:
- Lkb1+/- mice developed severe gastrointestinal polyposis, modeling human PJS.
- Murine polyps were histologically indistinguishable from human PJS hamartomas.
- LKB1 was haploinsufficient for tumor suppression, with reduced LKB1 levels and activity in polyps.
- Cyclooxygenase-2 (COX-2) was significantly upregulated in Lkb1+/- polyps, along with activated Erk1/2 signaling.
- Human PJS polyps also showed high COX-2 upregulation.
Conclusions:
- Lkb1+/- mice serve as a valid model for studying human PJS polyposis.
- LKB1 haploinsufficiency drives PJS-associated tumor development.
- Upregulation of COX-2 is a key molecular event in PJS polyposis, suggesting it as a target for chemoprevention.