Loss of 15-hydroxyprostaglandin dehydrogenase indicates a tumor suppressor role in pituitary adenomas

Bai,Ji-Wei; Wang,Zhe; Gui,Song-Bai; Zhang,Ya-Zhuo

doi:10.3892/or.2012.1806

Loss of 15-hydroxyprostaglandin dehydrogenase indicates a tumor suppressor role in pituitary adenomas

Authors:
- Ji-Wei Bai
- Zhe Wang
- Song-Bai Gui
- Ya-Zhuo Zhang
View Affiliations

Affiliations: Beijing Neurosurgical Institute, Capital Medical University, Dongcheng District, Beijing 100050, P.R. China, Neurosurgical Department, Beijing Tiantan Hospital, Dongcheng District, Beijing 100050, P.R. China
Published online on: May 9, 2012 https://doi.org/10.3892/or.2012.1806
Pages: 714-720

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

15-hydroxyprostaglandin dehydrogenase (15-PGDH) may function as a tumor suppressor that antagonizes the action of the cyclooxygenase-2 (COX-2) oncogene in several types of tumors. However, it is unknown if it has a role in the pituitary. Recently, our group found that 15-PGDH expression was low in prolactin (PRL) secreting adenomas (prolactinomas) and growth hormone (GH) secreting adenomas (GHomas) using fiber-optic BeadArray technology. In this study, we examined the relative expression of 15-PGDH and COX-2 mRNA in clinical specimens and examined the effects of 15-PGDH on GH3 rat pituitary tumor cell proliferation, apoptosis and hormone secretion. 15-PGDH expression was lower and COX-2 expression was higher in prolactinomas and GHomas compared with normal controls. Overexpressed 15-PGDH inhibited tumor cell proliferation and induced apoptosis. It had a significant suppressive effect on mRNA levels and on the secretion of PRL and GH in GH3 cells. The inhibition of cell proliferation was accompanied by the decreased expression of cox-2, matrix metalloproteinase-9 (MMP-9) and B cell leukemia/lymphoma-2 (Bcl-2). These data are suggestive of a previously unrecognized pathway in pituitary tumorigenesis, and this novel observation may shed light on therapeutic strategies for pituitary tumors.

View Figures

View References

1	Asa SL and Ezzat S: The pathogenesis of pituitary tumors. Annu Rev Pathol. 4:97–126. 2009. View Article : Google Scholar : PubMed/NCBI
2	Osamura RY, Kajiya H, Takei M, et al: Pathology of the human pituitary adenomas. Histochem Cell Biol. 130:495–507. 2008. View Article : Google Scholar : PubMed/NCBI
3	Jiang Z, Gui S and Zhang Y: Analysis of differential gene expression by fiber-optic BeadArray and pathway in prolactinomas. Endocrine. 38:360–368. 2010. View Article : Google Scholar : PubMed/NCBI
4	Jiang Z, Gui S and Zhang Y: Analysis of differential gene expression by bead-based fiber-optic array in growth-hormone-secreting pituitary adenomas. Exp Ther Med. 1:905–910. 2010.PubMed/NCBI
5	Tai HH, Cho H, Tong M and Ding Y: NAD⁺-linked 15-hydroxyprostaglandin dehydrogenase: structure and biological functions. Curr Pharm Des. 12:955–962. 2006.
6	Tseng-Rogenski S, Gee J, Ignatoski KW, et al: Loss of 15-hydroxyprostaglandin dehydrogenase expression contributes to bladder cancer progression. Am J Pathol. 176:1462–1468. 2010. View Article : Google Scholar
7	Liu Z, Wang X, Lu Y and Han S: Expression of 15-PGDH is downregulated by COX-2 in gastric cancer. Carcinogenesis. 29:1219–1227. 2008. View Article : Google Scholar : PubMed/NCBI
8	Lodygin D, Epanchintsev A, Menssen A, Diebold J and Hermeking H: Functional epigenomics identifies genes frequently silenced in prostate cancer. Cancer Res. 65:4218–4227. 2005. View Article : Google Scholar : PubMed/NCBI
9	Tai HH, Tong M and Ding Y: 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and lung cancer. Prostaglandins Other Lipid Mediat. 83:203–208. 2007. View Article : Google Scholar : PubMed/NCBI
10	Wolf I, O’Kelly J, Rubinek T, et al: 15-hydroxyprostaglandin dehydrogenase is a tumor suppressor of human breast cancer. Cancer Res. 66:7818–7823. 2006. View Article : Google Scholar : PubMed/NCBI
11	Myung SJ, Rerko RM, Yan M, et al: 15-Hydroxyprostaglandin dehydrogenase is an in vivo suppressor of colon tumorigenesis. Proc Natl Acad Sci USA. 103:12098–12102. 2006. View Article : Google Scholar : PubMed/NCBI
12	Wakimoto N, Wolf I, Yin D, et al: Non-steroidal anti-inflammatory drugs suppress glioma via 15-hydroxyprostaglandin dehydrogenase. Cancer Res. 68:6978–6986. 2008. View Article : Google Scholar : PubMed/NCBI
13	Tai HH: Prostaglandin catabolic enzymes as tumor suppressors. Cancer Metastasis Rev. 30:409–417. 2011. View Article : Google Scholar : PubMed/NCBI
14	DeLellis RA, Lloyd RV, Heitz PU and Eng C: Pathology and Genetics of Tumours of Endocrine Organs. WHO Classification of Tumours. The International Agency for Research on Cancer; Lyon: 2004
15	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
16	Kaliberova LN, Kusmartsev SA, Krendelchtchikova V, et al: Experimental cancer therapy using restoration of NAD⁺-linked 15-hydroxyprostaglandin dehydrogenase expression. Mol Cancer Ther. 8:3130–3139. 2009. View Article : Google Scholar : PubMed/NCBI
17	Greenland KJ, Jantke I, Jenatschke S, Bracken KE, Vinson C and Gellersen B: The human NAD⁺-dependent 15-hydroxyprostaglandin dehydrogenase gene promoter is controlled by Ets and activating protein-1 transcription factors and progesterone. Endocrinology. 141:581–597. 2000.
18	Yang L, Amann JM, Kikuchi T, et al: Inhibition of epidermal growth factor receptor signaling elevates 15-hydroxyprostaglandin dehydrogenase in non-small cell lung cancer. Cancer Res. 67:5587–5593. 2007. View Article : Google Scholar : PubMed/NCBI
19	Vidal S, Kovacs K, Bell D, Horvath E, Scheithauer BW and Lloyd RV: Cyclooxygenase-2 expression in human pituitary tumors. Cancer. 97:2814–2821. 2003. View Article : Google Scholar : PubMed/NCBI
20	Liu JK, Patel SK, Gillespie DL, Whang K and Couldwell WT: R-flurbiprofen, a novel nonsteroidal anti-inflammatory drug, decreases cell proliferation and induces apoptosis in pituitary adenoma cells in vitro. J Neurooncol. 106:561–569. 2012. View Article : Google Scholar : PubMed/NCBI
21	Frank GR, Brar AK, Cedars MI and Handwerger S: Prostaglandin E2 enhances human endometrial stromal cell differentiation. Endocrinology. 134:258–263. 1994.PubMed/NCBI
22	Matzkin ME, Ambao V, Carino MH, et al: Prolactin (PRL) induction of cyclooxygenase 2 (COX2) expression and prostaglandin (PG) production in hamster Leydig cells. Mol Cell Endocrinol. 348:33–46. 2012. View Article : Google Scholar : PubMed/NCBI
23	Hashizume T and Kanematsu S: Effects of prostaglandins E₂, F_2α, and D₂ on the release of growth hormone, prolactin, and luteinizing hormone from cultured bovine anterior pituitary cells. J Reprod Dev. 41:41–46. 1995.
24	Canete SR, Gui YH, Linask KK and Muschel RJ: MMP-9 (gelatinase B) mRNA is expressed during mouse neurogenesis and may be associated with vascularization. Brain Res Dev Brain Res. 88:37–52. 1995. View Article : Google Scholar : PubMed/NCBI
25	Turner HE, Nagy Z, Esiri MM, Harris AL and Wass JA: Role of matrix metalloproteinase 9 in pituitary tumor behavior. J Clin Endocrinol Metab. 85:2931–2935. 2000. View Article : Google Scholar : PubMed/NCBI
26	Paez PM, Ledda MF, Goldberg V, et al: High levels of matrix metalloproteinases regulate proliferation and hormone secretion in pituitary cells. J Clin Endocrinol Metab. 85:263–269. 2000.PubMed/NCBI
27	Kulig E, Jin L, Qian X, et al: Apoptosis in non-tumorous and neoplastic human pituitaries: expression of the Bcl-2 family of proteins. Am J Pathol. 154:767–774. 1999. View Article : Google Scholar : PubMed/NCBI
28	Ozer E, Canda MS, Ulukus C, Guray M and Erbayraktar S: Expression of Bcl-2, Bax and p53 proteins in pituitary adenomas: an immunohistochemical study. Tumori. 89:54–59. 2003.PubMed/NCBI