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Transgenic expression of 15-lipoxygenase 2 (15-LOX2) in mouse prostate leads to hyperplasia and cell senescence

Oncogene volume 29, pages 4261–4275 (2010)Cite this article

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Abstract

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, p27Kip1 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.

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Accession codes

Accessions

Gene Expression Omnibus

Abbreviations

15-LOX2:

15-lipoxygenase 2

15(S)-HETE:

15(S)-hydroxyeicosatetraenoic acid

AA:

arachidonic acid

AP:

anterior prostate

CK5:

cytokeratin 5

DP:

dorsal prostate

ECM:

extracellular matrix

HP1-γ:

heterochromatin protein-1 γ

LP:

lateral prostate

NHP:

normal human prostate epithelial cells

PCa:

prostate cancer

PPARs:

peroxisome proliferator-activated receptors

SA-βgal:

senescence associated β-galactosidase

VP:

ventral prostate

wt:

wild type

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Acknowledgements

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).

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Authors and Affiliations

  1. Department of Carcinogenesis, Science Park-Research Division, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA

    M V Suraneni, R Schneider-Broussard, J R Moore, T C Davis, C J Maldonado, H Li, D Kusewitt & D G Tang

  2. Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    R A Newman & P Yang

  3. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J Hu

  4. Program in Molecular Carcinogenesis, The University of Texas Graduate School of Biomedical Sciences (GSBS), Houston, TX, USA

    D G Tang

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  1. M V Suraneni
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  2. R Schneider-Broussard
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Correspondence to D G Tang.

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Suraneni, M., Schneider-Broussard, R., Moore, J. et al. Transgenic expression of 15-lipoxygenase 2 (15-LOX2) in mouse prostate leads to hyperplasia and cell senescence. Oncogene 29, 4261–4275 (2010). https://doi.org/10.1038/onc.2010.197

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