TRANSGENIC EXPRESSION OF 15-LIPOXYGENASE 2 (15-LOX2) IN MOUSE PROSTATE LEADS TO HYPERPLASIA AND CELL SENESCENCE
| Autor: | Carlos J. Maldonado, Tammy Davis, Robert A. Newman, Mahipal Suraneni, Hangwen Li, Jiemiao Hu, John R. Moore, Peiying Yang, Donna Frances Kusewitt, Robin Schneider-Broussard, Dean G. Tang |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Genetically modified mouse
Male Cancer Research medicine.medical_specialty senescence Prostatic Hyperplasia Mice Transgenic Biology medicine.disease_cause Article 15-lipoxygenase 2 03 medical and health sciences Prostate cancer Mice 0302 clinical medicine Prostate stem cells Internal medicine Genetics medicine Animals Arachidonate 15-Lipoxygenase Progenitor cell Molecular Biology Cellular Senescence 030304 developmental biology Cell Proliferation 0303 health sciences prostate Gene Expression Profiling Intracellular Signaling Peptides and Proteins hyperplasia Hyperplasia medicine.disease 3. Good health Endocrinology medicine.anatomical_structure Ki-67 Antigen 030220 oncology & carcinogenesis Cancer research Stem cell tumor suppression Carcinogenesis Cell aging Cyclin-Dependent Kinase Inhibitor p27 |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | 15-Lipoxygenase 2 (15-LOX2), a lipid-peroxidizing enzyme, is mainly expressed in the luminal compartment of the normal human prostate, and is often decreased or lost in prostate cancer. Previous studies from our lab implicate 15-LOX2 as a functional tumor suppressor. To better understand the biological role of 15-LOX2 in vivo, we generated prostate-specific 15-LOX2 transgenic mice using the ARR2PB promoter. Unexpectedly, transgenic expression of 15-LOX2 or 15-LOX2sv-b, a splice variant that lacks arachidonic acid-metabolizing activity, resulted in age-dependent prostatic hyperplasia and enlargement of the prostate. Prostatic hyperplasia induced by both 15-LOX2 and 15-LOX2sv-b was associated with an increase in luminal and Ki-67(+) cells; however, 15-LOX2-transgenic prostates also showed a prominent increase in basal cells. Microarray analysis revealed distinct gene expression profiles that could help explain the prostate phenotypes. Strikingly, 15-LOX2, but not 15-LOX2sv-b, transgenic prostate showed upregulation of several well-known stem or progenitor cell molecules including Sca-1, Trop2, p63, Nkx3.1 and Psca. Prostatic hyperplasia caused by both 15-LOX2 and 15-LOX2sv-b did not progress to prostatic intraprostate neoplasia or carcinoma and, mechanistically, prostate lobes (especially those of 15-LOX2 mice) showed a dramatic increase in senescent cells as revealed by increased SA-betagal, p27(Kip1) and heterochromatin protein 1gamma staining. Collectively, our results suggest that 15-LOX2 expression in mouse prostate leads to hyperplasia and also induces cell senescence, which may, in turn, function as a barrier to tumor development. |
| Databáze: | OpenAIRE |
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