TY - JOUR
T1 - Transgenic expression of 15-lipoxygenase 2 (15-LOX2) in mouse prostate leads to hyperplasia and cell senescence
AU - Suraneni, M. V.
AU - Schneider-Broussard, R.
AU - Moore, J. R.
AU - Davis, T. C.
AU - Maldonado, C. J.
AU - Li, H.
AU - Newman, R. A.
AU - Kusewitt, D.
AU - Hu, J.
AU - Yang, P.
AU - Tang, D. G.
N1 - Funding Information:
We thank Dr R Matusik (Vanderbilt University) for providing the ARR2PB promoter, D Holowell for transgenic studies, Dr H Thames and K Lin for assistance in statistics, the Histology Core for help in IHC, Animal Facility Core for animal-related experiments, Molecular Biology Core, especially J Repass, for assistance in qPCR analysis, C Perez for assistance in LCM, S Gaddis, L Shen and S Tsavachidis for assistance in microarray analysis, Drs S Fischer and C Jeter for critically reading the paper and other members of the Tang lab for support and helpful discussions. This work was supported in part by grants from NIH (R01-AG023374, R01-ES015888 and R21-ES015893-01A1), American Cancer Society (RSG MGO-105961), Department of Defense (W81XWH-07-1-0616 and W81XWH-08-1-0472) and Elsa Pardee Foundation (DGT) and by two Center Grants (CCSG-5 P30 CA016672 and ES07784).
PY - 2010/7/29
Y1 - 2010/7/29
N2 - 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-Βgal, p27 Kip1 and heterochromatin protein 1γ 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.
AB - 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-Βgal, p27 Kip1 and heterochromatin protein 1γ 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.
KW - 15-lipoxygenase 2
KW - hyperplasia
KW - prostate
KW - senescence
KW - stem cells
KW - tumor suppression
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U2 - 10.1038/onc.2010.197
DO - 10.1038/onc.2010.197
M3 - Article
C2 - 20514017
AN - SCOPUS:77955176918
SN - 0950-9232
VL - 29
SP - 4261
EP - 4275
JO - Oncogene
JF - Oncogene
IS - 30
ER -