Top

Published in:

Open Access 01-12-2007 | Research article

Kisspeptin and GPR54 immunoreactivity in a cohort of 518 patients defines favourable prognosis and clear cell subtype in ovarian carcinoma

Authors: Leah M Prentice, Christian Klausen, Steve Kalloger, Martin Köbel, Steven McKinney, Jennifer L Santos, Challayne Kenney, Erika Mehl, C Blake Gilks, Peter Leung, Ken Swenerton, David G Huntsman, Samuel AJ Aparicio

Published in: BMC Medicine | Issue 1/2007

Abstract

Background

Kisspeptins and their G-protein coupled receptor, GPR54 are required for GnRH release and have been associated with anti-metastatic tumour cell behaviour in model systems. The latter might suggest that their overexpression would be associated with a better prognosis in cancer. However, kisspeptin/GPR54 interactions (autocrine, paracrine, and/or endocrine) could also impact tumour behaviour in a negative manner. Here, for the first time, we associate the immunoreactivity of the kisspeptin/GPR54 ligand-receptor pair with favourable prognosis in a large cohort of ovarian carcinomas.

Methods

Immunohistochemical analysis for kisspeptin and GPR54 was performed on a tissue microarray (TMA) consisting of 518 early stage ovarian carcinomas, all with linked clinical outcome data. The TMA was scored using a staining intensity scale of 0 (negative), +1 (mild-moderate), and +2 (strong). Strong staining cases were considered either kisspeptin or GPR54 positive and designated as 1, while all other cases were considered negative and designated 0. All statistical analysis was conducted using two-sided tests and a p value equal to or less than 0.05 was considered significant.

Results

Kisspeptin and GPR54 immunoreactive cases show a favourable prognosis in univariable disease specific survival (p = 0.0023, p = 0.0092), as well as in overall survival (p = 0.0006, p = 0.0002). Furthermore, kisspeptin is an independent marker for favourable prognosis as determined by multivariable disease specific (p = 0.0046) and overall survival analysis (p = 0.0170), while GPR54 is an independent marker for overall survival only (p = 0.0303). Both kisspeptin positive and GPR54 positive cases are strongly associated with the ovarian carcinoma clear cell subtype (p < 0.0001, p < 0.0001), and GPR54 is significantly associated with favourable prognosis in overall survival within the clear cell subtype (p = 0.0102).

Conclusion

Kisspeptin and GPR54 immunoreactivity are significantly associated with favourable prognosis in both disease specific and overall survival, as well as being significantly associated with the clear cell ovarian carcinoma subtype, thereby creating the first independent prognostic biomarkers specific for ovarian clear cell carcinomas.

Available only for authorised users

Lee JH, Welch DR: Suppression of metastasis in human breast carcinoma MDA-MB-435 cells after transfection with the metastasis suppressor gene, KiSS-1. Cancer Res. 1997, 57: 2384-2387.PubMed

Lee JH, Miele ME, Hicks DJ, Phillips KK, Trent JM, Weissman BE, Welch DR: KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. J Natl Cancer Inst. 1996, 88: 1731-1737. 10.1093/jnci/88.23.1731.CrossRefPubMed

Bilban M, Ghaffari-Tabrizi N, Hintermann E, Bauer S, Molzer S, Zoratti C, Malli R, Sharabi A, Hiden U, Graier W, et al: Kisspeptin-10, a KiSS-1/metastin-derived decapeptide, is a physiological invasion inhibitor of primary human trophoblasts. J Cell Sci. 2004, 117: 1319-1328. 10.1242/jcs.00971.CrossRefPubMed

Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K, Terao Y, Kumano S, Takatsu Y, Masuda Y, et al: Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature. 2001, 411: 613-617. 10.1038/35079135.CrossRefPubMed

Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Le Poul E, Brezillon S, Tyldesley R, Suarez-Huerta N, Vandeput F, et al: The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem. 2001, 276: 34631-34636. 10.1074/jbc.M104847200.CrossRefPubMed

Hori A, Honda S, Asada M, Ohtaki T, Oda K, Watanabe T, Shintani Y, Yamada T, Suenaga M, Kitada C, et al: Metastin suppresses the motility and growth of CHO cells transfected with its receptor. Biochem Biophys Res Commun. 2001, 286: 958-963. 10.1006/bbrc.2001.5470.CrossRefPubMed

Jiang Y, Berk M, Singh LS, Tan H, Yin L, Powell CT, Xu Y: KiSS1 suppresses metastasis in human ovarian cancer via inhibition of protein kinase C alpha. Clin Exp Metastasis. 2005, 22: 369-376. 10.1007/s10585-005-8186-4.CrossRefPubMed

Aparicio SA: Kisspeptins and GPR54 – the new biology of the mammalian GnRH axis. Cell Metab. 2005, 1: 293-296. 10.1016/j.cmet.2005.04.001.CrossRefPubMed

Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG, et al: The GPR54 gene as a regulator of puberty. N Engl J Med. 2003, 349: 1614-1627. 10.1056/NEJMoa035322.CrossRefPubMed

10.

d'Anglemont de Tassigny X, Fagg LA, Dixon JP, Day K, Leitch HG, Hendrick AG, Zahn D, Franceschini I, Caraty A, Carlton MB, et al: Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 gene. Proc Natl Acad Sci USA. 2007, 104: 10714-10719. 10.1073/pnas.0704114104.CrossRefPubMedPubMedCentral

11.

Semple RK, Achermann JC, Ellery J, Farooqi IS, Karet FE, Stanhope RG, O'Rahilly S, Aparicio SA: Two novel missense mutations in g protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2005, 90: 1849-1855. 10.1210/jc.2004-1418.CrossRefPubMed

12.

Funes S, Hedrick JA, Vassileva G, Markowitz L, Abbondanzo S, Golovko A, Yang S, Monsma FJ, Gustafson EL: The KiSS-1 receptor GPR54 is essential for the development of the murine reproductive system. Biochem Biophys Res Commun. 2003, 312: 1357-1363. 10.1016/j.bbrc.2003.11.066.CrossRefPubMed

13.

de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E: Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci USA. 2003, 100: 10972-10976. 10.1073/pnas.1834399100.CrossRefPubMedPubMedCentral

14.

Patterson M, Murphy KG, Thompson EL, Patel S, Ghatei MA, Bloom SR: Administration of kisspeptin-54 into discrete regions of the hypothalamus potently increases plasma luteinising hormone and testosterone in male adult rats. J Neuroendocrinol. 2006, 18: 349-354. 10.1111/j.1365-2826.2006.01420.x.CrossRefPubMed

15.

Nazian SJ: Role of metastin in the release of gonadotropin-releasing hormone from the hypothalamus of the male rat. J Androl. 2006, 27: 444-449. 10.2164/jandrol.05144.CrossRefPubMed

16.

Castellano JM, Navarro VM, Fernandez-Fernandez R, Castano JP, Malagon MM, Aguilar E, Dieguez C, Magni P, Pinilla L, Tena-Sempere M: Ontogeny and mechanisms of action for the stimulatory effect of kisspeptin on gonadotropin-releasing hormone system of the rat. Mol Cell Endocrinol. 2006, 257–258: 75-83. 10.1016/j.mce.2006.07.002.CrossRefPubMed

17.

Arreguin-Arevalo JA, Lents CA, Farmerie TA, Nett TM, Clay CM: KiSS-1 peptide induces release of LH by a direct effect on the hypothalamus of ovariectomized ewes. Anim Reprod Sci. 2007, 101 (3–4): 265-75. 10.1016/j.anireprosci.2006.09.021.CrossRefPubMed

18.

Seminara SB: Metastin and its G protein-coupled receptor, GPR54: critical pathway modulating GnRH secretion. Front Neuroendocrinol. 2005, 26: 131-138. 10.1016/j.yfrne.2005.10.001.CrossRefPubMed

19.

Navarro VM, Castellano JM, Fernandez-Fernandez R, Tovar S, Roa J, Mayen A, Barreiro ML, Casanueva FF, Aguilar E, Dieguez C, et al: Effects of KiSS-1 peptide, the natural ligand of GPR54, on follicle-stimulating hormone secretion in the rat. Endocrinology. 2005, 146: 1689-1697. 10.1210/en.2004-1353.CrossRefPubMed

20.

Messager S, Chatzidaki EE, Ma D, Hendrick AG, Zahn D, Dixon J, Thresher RR, Malinge I, Lomet D, Carlton MB, et al: Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci USA. 2005, 102: 1761-1766. 10.1073/pnas.0409330102.CrossRefPubMedPubMedCentral

21.

Dhillo WS, Chaudhri OB, Patterson M, Thompson EL, Murphy KG, Badman MK, McGowan BM, Amber V, Patel S, Ghatei MA, et al: Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab. 2005, 90: 6609-6615. 10.1210/jc.2005-1468.CrossRefPubMed

22.

Thompson EL, Patterson M, Murphy KG, Smith KL, Dhillo WS, Todd JF, Ghatei MA, Bloom SR: Central and peripheral administration of kisspeptin-10 stimulates the hypothalamic-pituitary-gonadal axis. J Neuroendocrinol. 2004, 16: 850-858. 10.1111/j.1365-2826.2004.01240.x.CrossRefPubMed

23.

Navarro VM, Fernandez-Fernandez R, Castellano JM, Roa J, Mayen A, Barreiro ML, Gaytan F, Aguilar E, Pinilla L, Dieguez C, et al: Advanced vaginal opening and precocious activation of the reproductive axis by KiSS-1 peptide, the endogenous ligand of GPR54. J Physiol. 2004, 561: 379-386. 10.1113/jphysiol.2004.072298.CrossRefPubMedPubMedCentral

24.

Matsui H, Takatsu Y, Kumano S, Matsumoto H, Ohtaki T: Peripheral administration of metastin induces marked gonadotropin release and ovulation in the rat. Biochem Biophys Res Commun. 2004, 320: 383-388. 10.1016/j.bbrc.2004.05.185.CrossRefPubMed

25.

Gottsch ML, Cunningham MJ, Smith JT, Popa SM, Acohido BV, Crowley WF, Seminara S, Clifton DK, Steiner RA: A role for kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology. 2004, 145: 4073-4077. 10.1210/en.2004-0431.CrossRefPubMed

26.

Shirasaki F, Takata M, Hatta N, Takehara K: Loss of expression of the metastasis suppressor gene KiSS1 during melanoma progression and its association with LOH of chromosome 6q16.3-q23. Cancer Res. 2001, 61: 7422-7425.PubMed

27.

Sanchez-Carbayo M, Capodieci P, Cordon-Cardo C: Tumor suppressor role of KiSS-1 in bladder cancer: loss of KiSS-1 expression is associated with bladder cancer progression and clinical outcome. Am J Pathol. 2003, 162: 609-617.CrossRefPubMedPubMedCentral

28.

Ringel MD, Hardy E, Bernet VJ, Burch HB, Schuppert F, Burman KD, Saji M: Metastin receptor is overexpressed in papillary thyroid cancer and activates MAP kinase in thyroid cancer cells. J Clin Endocrinol Metab. 2002, 87: 2399-10.1210/jc.87.5.2399.CrossRefPubMed

29.

Nicolle G, Comperat E, Nicolaiew N, Cancel-Tassin G, Cussenot O: Metastin (KISS-1) and metastin-coupled receptor (GPR54) expression in transitional cell carcinoma of the bladder. Ann Oncol. 2007, 18 (3): 605-607. 10.1093/annonc/mdl421.CrossRefPubMed

30.

Martin TA, Watkins G, Jiang WG: KiSS-1 expression in human breast cancer. Clin Exp Metastasis. 2005, 22: 503-511. 10.1007/s10585-005-4180-0.CrossRefPubMed

31.

Ikeguchi M, Yamaguchi K, Kaibara N: Clinical significance of the loss of KiSS-1 and orphan G-protein-coupled receptor (hOT7T175) gene expression in esophageal squamous cell carcinoma. Clin Cancer Res. 2004, 10: 1379-1383. 10.1158/1078-0432.CCR-1519-02.CrossRefPubMed

32.

Ikeguchi M, Hirooka Y, Kaibara N: Quantitative reverse transcriptase polymerase chain reaction analysis for KiSS-1 and orphan G-protein-coupled receptor (hOT7T175) gene expression in hepatocellular carcinoma. J Cancer Res Clin Oncol. 2003, 129: 531-535. 10.1007/s00432-003-0469-z.CrossRefPubMed

33.

Dhar DK, Naora H, Kubota H, Maruyama R, Yoshimura H, Tonomoto Y, Tachibana M, Ono T, Otani H, Nagasue N: Downregulation of KiSS-1 expression is responsible for tumor invasion and worse prognosis in gastric carcinoma. Int J Cancer. 2004, 111: 868-872. 10.1002/ijc.20357.CrossRefPubMed

34.

Zhang SL, Yu Y, Jiang T, Lin B, Gao H: Expression and significance of KiSS-1 and its receptor GPR54 mRNA in epithelial ovarian cancer. Zhonghua Fu Chan Ke Za Zhi. 2005, 40: 689-692.PubMed

35.

Hata K, Dhar DK, Watanabe Y, Nakai H, Hoshiai H: Expression of metastin and a G-protein-coupled receptor (AXOR12) in epithelial ovarian cancer. Eur J Cancer. 2007, 43: 1452-1459. 10.1016/j.ejca.2007.03.004.CrossRefPubMed

36.

Ng TL, Gown AM, Barry TS, Cheang MC, Chan AK, Turbin DA, Hsu FD, West RB, Nielsen TO: Nuclear beta-catenin in mesenchymal tumors. Mod Pathol. 2005, 18: 68-74. 10.1038/modpathol.3800272.CrossRefPubMed

37.

TMA Photomicrographs. [http://www.gpecimage.ubc.ca/tma/web/viewer.php]

38.

Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958, 53: 457-481. 10.2307/2281868.CrossRef

39.

Cox D: Regression models and life tables. J R Stat Soc B. 1972, 34: 187-220.

40.

Cox D: Partial likelihood. Biometrika. 1975, 62: 269-276. 10.1093/biomet/62.2.269.CrossRef

41.

Chernoff H, Lehmann EL: The use of maximum likelihood estimates in chi square tests for goodness-of-fit. Ann Math Stat. 1954, 25: 576-586.

42.

Castellano JM, Gaytan M, Roa J, Vigo E, Navarro VM, Bellido C, Dieguez C, Aguilar E, Sanchez-Criado JE, Pellicer A, et al: Expression of KiSS-1 in rat ovary: putative local regulator of ovulation?. Endocrinology. 2006, 147: 4852-4862. 10.1210/en.2006-0117.CrossRefPubMed

43.

Kendall M: Rank Correlation Methods. 1970, London: Griffin, 4

44.

Pectasides D, Pectasides E, Psyrri A, Economopoulos T: Treatment issues in clear cell carcinoma of the ovary: a different entity?. Oncologist. 2006, 11: 1089-1094. 10.1634/theoncologist.11-10-1089.CrossRefPubMed

45.

Masui T, Doi R, Mori T, Toyoda E, Koizumi M, Kami K, Ito D, Peiper SC, Broach JR, Oishi S, et al: Metastin and its variant forms suppress migration of pancreatic cancer cells. Biochem Biophys Res Commun. 2004, 315: 85-92. 10.1016/j.bbrc.2004.01.021.CrossRefPubMed

46.

Muir AI, Chamberlain L, Elshourbagy NA, Michalovich D, Moore DJ, Calamari A, Szekeres PG, Sarau HM, Chambers JK, Murdock P, et al: AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1. J Biol Chem. 2001, 276: 28969-28975. 10.1074/jbc.M102743200.CrossRefPubMed

47.

Ramaswamy S, Seminara SB, Pohl CR, Dipietro MJ, Crowley WF, Plant TM: Effect of continuous iv administration of human metastin 45–54 on the neuroendocrine activity of the hypothalamic-pituitary-testicular axis in the adult male rhesus monkey (Macaca mulatta). Endocrinology. 2007, 148 (7): 3364-3370. 10.1210/en.2007-0207. doi:10.1210/en.2007-0207.CrossRefPubMed

48.

Plant TM, Ramaswamy S, Dipietro MJ: Repetitive activation of hypothalamic G protein-coupled receptor 54 with intravenous pulses of kisspeptin in the juvenile monkey (Macaca mulatta) elicits a sustained train of gonadotropin-releasing hormone discharges. Endocrinology. 2006, 147: 1007-1013. 10.1210/en.2005-1261.CrossRefPubMed

49.

Navarro VM, Castellano JM, Fernandez-Fernandez R, Tovar S, Roa J, Mayen A, Nogueiras R, Vazquez MJ, Barreiro ML, Magni P, et al: Characterization of the potent luteinizing hormone-releasing activity of KiSS-1 peptide, the natural ligand of GPR54. Endocrinology. 2005, 146: 156-163. 10.1210/en.2004-0836.CrossRefPubMed

50.

Nash KT, Phadke PA, Navenot JM, Hurst DR, Accavitti-Loper MA, Sztul E, Vaidya KS, Frost AR, Kappes JC, Peiper SC, et al: Requirement of KISS1 secretion for multiple organ metastasis suppression and maintenance of tumor dormancy. J Natl Cancer Inst. 2007, 99: 309-321. 10.1093/jnci/djk053.CrossRefPubMedPubMedCentral

51.

Panidis D, Rousso D, Koliakos G, Kourtis A, Katsikis I, Farmakiotis D, Votsi E, Diamanti-Kandarakis E: Plasma metastin levels are negatively correlated with insulin resistance and free androgens in women with polycystic ovary syndrome. Fertil Steril. 2006, 85: 1778-1783. 10.1016/j.fertnstert.2005.11.044.CrossRefPubMed

52.

Horikoshi Y, Matsumoto H, Takatsu Y, Ohtaki T, Kitada C, Usuki S, Fujino M: Dramatic elevation of plasma metastin concentrations in human pregnancy: metastin as a novel placenta-derived hormone in humans. J Clin Endocrinol Metab. 2003, 88: 914-919. 10.1210/jc.2002-021235.CrossRefPubMed

53.

Dhillo WS, Savage P, Murphy KG, Chaudhri OB, Patterson M, Nijher GM, Foggo VM, Dancey GS, Mitchell H, Seckl MJ, et al: Plasma kisspeptin is raised in patients with gestational trophoblastic neoplasia and falls during treatment. Am J Physiol Endocrinol Metab. 2006, 291: E878-884. 10.1152/ajpendo.00555.2005.CrossRefPubMed

The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/5/33/prepub

Title: Kisspeptin and GPR54 immunoreactivity in a cohort of 518 patients defines favourable prognosis and clear cell subtype in ovarian carcinoma
Authors: Leah M Prentice
Christian Klausen
Steve Kalloger
Martin Köbel
Steven McKinney
Jennifer L Santos
Challayne Kenney
Erika Mehl
C Blake Gilks
Peter Leung
Ken Swenerton
David G Huntsman
Samuel AJ Aparicio
Publication date: 01-12-2007
Publisher: BioMed Central
Published in: BMC Medicine / Issue 1/2007
Electronic ISSN: 1741-7015
DOI: https://doi.org/10.1186/1741-7015-5-33

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Kisspeptin and GPR54 immunoreactivity in a cohort of 518 patients defines favourable prognosis and clear cell subtype in ovarian carcinoma

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2007

The effects of dictatorship on health: the case of Turkmenistan

Risk factors and myocardial infarction in patients with obstructive sleep apnea: impact of β2-adrenergic receptor polymorphisms

Are MRI-defined fat infiltrations in the multifidus muscles associated with low back pain?

Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease

Do citizens have minimum medical knowledge? A survey

Migraine aura or transient ischemic attacks? A five-year follow-up case-control study of women with transient central nervous system disorders in pregnancy