Low expression of secreted frizzled-related protein 2 and nuclear accumulation of β-catenin in aggressive nonfunctioning pituitary adenoma

Wu,Youtu; Bai,Jiwei; Hong,Linchuan; Liu,Chunhui; Yu,Shengyuan; Yu,Guoqiang; Zhang,Yazhuo

doi:10.3892/ol.2016.4560

Low expression of secreted frizzled-related protein 2 and nuclear accumulation of β-catenin in aggressive nonfunctioning pituitary adenoma

Authors:
- Youtu Wu
- Jiwei Bai
- Linchuan Hong
- Chunhui Liu
- Shengyuan Yu
- Guoqiang Yu
- Yazhuo Zhang
View Affiliations

Affiliations: Department of Neurosurgery, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, P.R. China, Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, P.R. China
Published online on: May 13, 2016 https://doi.org/10.3892/ol.2016.4560
Pages: 199-206

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

The identification of a specific molecular marker for aggressiveness of nonfunctioning pituitary adenomas (NFPAs) is urgently required in order to guide the clinical diagnosis and treatment of NFPAs. In the present study, low expression of secreted frizzled-related protein 2 (sFRP2) in NFPAs was demonstrated by reverse transcription‑quantitative polymerase chain reaction, western blot and immunohistochemical analyses. The results confirmed an abnormal accumulation of free β-catenin in the nuclei of NFPAs, which is the core step for the activation of the Wnt canonical signaling pathway. Furthermore, cyclin D1 and c‑Myc, the downstream proteins of the Wnt canonical signaling pathway, were overexpressed in aggressive NFPAs. These findings demonstrated the activation of the Wnt canonical signaling pathway in aggressive NFPAs. In addition, sFRP2 expression was observed to be inversely correlated to the aggressiveness of NFPAs. Therefore, sFRP2 may act as a tumor suppressor through modulation of the cellular cytosolic pool of β-catenin in NFPAs. Furthermore, the expression of sFRP2 may serve as a biomarker for NFPAs aggressiveness and prognosis.

View Figures

View References

1	Scheithauer BW, Gaffey TA, Lloyd RV, Sebo TJ, Kovacs KT, Horvath E, Yapicier O, Young WF Jr, Meyer FB, Kuroki T, et al: Pathobiology of pituitary adenomas and carcinomas. Neurosurgery. 59:341–353. 2006. View Article : Google Scholar : PubMed/NCBI
2	Korbonits M and Carlsen E: Recent clinical and pathophysiological advances in non-functioning pituitary adenomas. Horm Res. 71(Suppl 2): 123–130. 2009. View Article : Google Scholar : PubMed/NCBI
3	Saeger W, Lüdecke DK, Buchfelder M, Fahlbusch R, Quabbe HJ and Petersenn S: Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry. Eur J Endocrinol. 156:203–216. 2007. View Article : Google Scholar : PubMed/NCBI
4	Colao A, Pivonello R, Di Somma C, Savastano S, Grasso LF and Lombardi G: Medical therapy of pituitary adenomas: Effects on tumor shrinkage. Rev Endocr Metab Disord. 10:111–123. 2009. View Article : Google Scholar : PubMed/NCBI
5	Chand-Fouché ME, Colin P and Bondiau PY: Pituitary adenomas: Multimodal management and modern irradiation techniques. Cancer Radiother. 16(Suppl): S90–S100. 2012.(In French). View Article : Google Scholar : PubMed/NCBI
6	Grossman AB: The 2004 World Health Organization classification of pituitary tumors: Is it clinically helpful? Acta Neuropathol. 111:76–77. 2006. View Article : Google Scholar : PubMed/NCBI
7	Gürlek A, Karavitaki N, Ansorge O and Wass JA: What are the markers of aggressiveness in prolactinomas? Changes in cell biology, extracellular matrix components, angiogenesis and genetics. Eur J Endocrinol. 156:143–153. 2007. View Article : Google Scholar : PubMed/NCBI
8	Wierinckx A, Auger C, Devauchelle P, Reynaud A, Chevallier P, Jan M, Perrin G, Fèvre-Montange M, Rey C, Figarella-Branger D, et al: A diagnostic marker set for invasion, proliferation, and aggressiveness of prolactin pituitary tumors. Endocr Relat Cancer. 14:887–900. 2007. View Article : Google Scholar : PubMed/NCBI
9	Al-Shraim M and Asa SL: The 2004 World Health Organization classification of pituitary tumors: What is new? Acta Neuropathol. 111:1–7. 2006. View Article : Google Scholar : PubMed/NCBI
10	Clevers H and Nusse R: Wnt/β-catenin signaling and disease. Cell. 149:1192–1205. 2012. View Article : Google Scholar : PubMed/NCBI
11	MacDonald BT, Tamai K and He X: Wnt/beta-catenin signaling: Components, mechanisms, and diseases. Dev Cell. 17:9–26. 2009. View Article : Google Scholar : PubMed/NCBI
12	Herr P, Hausmann G and Basler K: WNT secretion and signalling in human disease. Trends Mol Med. 18:483–493. 2012. View Article : Google Scholar : PubMed/NCBI
13	Saito-Diaz K, Chen TW, Wang X, Thorne CA, Wallace HA, Page-McCaw A and Lee E: The way Wnt works: Components and mechanism. Growth Factors. 31:1–31. 2013. View Article : Google Scholar : PubMed/NCBI
14	Polakis P: The many ways of Wnt in cancer. Curr Opin Genet Dev. 17:45–51. 2007. View Article : Google Scholar : PubMed/NCBI
15	Polakis P: Wnt signaling in cancer. Cold Spring Harb Perspect Biol. 4:pii.a0080522012. View Article : Google Scholar
16	Cruciat CM and Niehrs C: Secreted and transmembrane wnt inhibitors and activators. Cold Spring Harb Perspect Biol. 5:a0150812013. View Article : Google Scholar : PubMed/NCBI
17	Hrzenjak A, Tippl M, Kremser ML, Strohmeier B, Guelly C, Neumeister D, Lax S, Moinfar F, Tabrizi AD, Isadi-Moud N, et al: Inverse correlation of secreted frizzled-related protein 4 and beta-catenin expression in endometrial stromal sarcomas. J Pathol. 204:19–27. 2004. View Article : Google Scholar : PubMed/NCBI
18	O'Hurley G, Perry AS, O'Grady A, Loftus B, Smyth P, O'Leary JJ, Sheils O, Fitzpatrick JM, Hewitt SM, Lawler M and Kay EW: The role of secreted frizzled-related protein 2 expression in prostate cancer. Histopathology. 59:1240–1248. 2011. View Article : Google Scholar : PubMed/NCBI
19	Saran U, Arfuso F, Zeps N and Dharmarajan A: Secreted frizzled-related protein 4 expression is positively associated with responsiveness to cisplatin of ovarian cancer cell lines in vitro and with lower tumour grade in mucinous ovarian cancers. BMC Cell Biol. 13:252012. View Article : Google Scholar : PubMed/NCBI
20	Marsit CJ, Karagas MR, Andrew A, Liu M, Danaee H, Schned AR, Nelson HH and Kelsey KT: Epigenetic inactivation of SFRP genes and TP53 alteration act jointly as markers of invasive bladder cancer. Cancer Res. 65:7081–7085. 2005. View Article : Google Scholar : PubMed/NCBI
21	Qi J, Zhu YQ, Luo J and Tao WH: Hypermethylation and expression regulation of secreted frizzled-related protein genes in colorectal tumor. World J Gastroenterol. 12:7113–7117. 2006. View Article : Google Scholar : PubMed/NCBI
22	Chung MT, Lai HC, Sytwu HK, Yan MD, Shih YL, Chang CC, Yu MH, Liu HS, Chu DW and Lin YW: SFRP1 and SFRP2 suppress the transformation and invasion abilities of cervical cancer cells through Wnt signal pathway. Gynecol Oncol. 112:646–653. 2009. View Article : Google Scholar : PubMed/NCBI
23	Vézina JL, Hardy J and Yamashita M: Microadenomas and hypersecreting pituitary adenomas. Arq Neuropsiquiatr. 33:119–127. 1975.(In Portuguese). PubMed/NCBI
24	Knosp E, Steiner E, Kitz K and Matula C: Pituitary adenomas with invasion of the cavernous sinus space: A magnetic resonance imaging classification compared with surgical findings. Neurosurgery. 33:610–618. 1993. View Article : Google Scholar : PubMed/NCBI
25	Zlobec I, Terracciano L, Jass JR and Lugli A: Value of staining intensity in the interpretation of immunohistochemistry for tumor markers in colorectal cancer. Virchows Arch. 451:763–769. 2007. View Article : Google Scholar : PubMed/NCBI
26	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
27	Zhao P, Wang H, Gao H, Li C and Zhang Y: Reversal of multidrug resistance by magnetic chitosan-Fe3O4 nanoparticle-encapsulated MDR1 siRNA in glioblastoma cell line. Neurol Res. 35:821–828. 2013. View Article : Google Scholar : PubMed/NCBI
28	Yu R, Zhong J, Li M, Guo X, Zhang H and Chen J: PACAP induces the dimerization of PAC1 on the nucleus associated with the cAMP increase in the nucleus. Neurosci Lett. 549:92–96. 2013. View Article : Google Scholar : PubMed/NCBI
29	Kuster DW, Merkus D, Jorna HJ, Dekkers DH, Duncker DJ and Verhoeven AJ: Nuclear protein extraction from frozen porcine myocardium. J Physiol Biochem. 67:165–173. 2011. View Article : Google Scholar : PubMed/NCBI
30	Sano M, Driscoll DR, De Jesus-Monge WE, Klimstra DS and Lewis BC: Activated wnt signaling in stroma contributes to development of pancreatic mucinous cystic neoplasms. Gastroenterology. 146:257–267. 2014. View Article : Google Scholar : PubMed/NCBI
31	Zhang Y, Morris JP IV, Yan W, Schofield HK, Gurney A, Simeone DM, Millar SE, Hoey T, Hebrok M and di Pasca Magliano M: Canonical wnt signaling is required for pancreatic carcinogenesis. Cancer Res. 73:4909–4922. 2013. View Article : Google Scholar : PubMed/NCBI
32	Chambers TJ, Giles A, Brabant G and Davis JR: Wnt signalling in pituitary development and tumorigenesis. Endocr Relat Cancer. 20:R101–R111. 2013. View Article : Google Scholar : PubMed/NCBI
33	Li Q, Shen K, Zhao Y, He X, Ma C, Wang L, Wang B, Liu J and Ma J: MicroRNA-222 promotes tumorigenesis via targeting DKK2 and activating the Wnt/β-catenin signaling pathway. FEBS Lett. 587:1742–1748. 2013. View Article : Google Scholar : PubMed/NCBI
34	Dellinger TH, Planutis K, Tewari KS and Holcombe RF: Role of canonical Wnt signaling in endometrial carcinogenesis. Expert Rev Anticancer Ther. 12:51–62. 2012. View Article : Google Scholar : PubMed/NCBI
35	Howng SL, Wu CH, Cheng TS, Sy WD, Lin PC, Wang C and Hong YR: Differential expression of Wnt genes, beta-catenin and E-cadherin in human brain tumors. Cancer Lett. 183:95–101. 2002. View Article : Google Scholar : PubMed/NCBI
36	Elston MS, Gill AJ, Conaglen JV, Clarkson A, Shaw JM, Law AJ, Cook RJ, Little NS, Clifton-Bligh RJ, Robinson BG and McDonald KL: Wnt pathway inhibitors are strongly down-regulated in pituitary tumors. Endocrinology. 149:1235–1242. 2008. View Article : Google Scholar : PubMed/NCBI
37	Cheng YY, Yu J, Wong YP, Man EP, To KF, Jin VX, Li J, Tao Q, Sung JJ, Chan FK and Leung WK: Frequent epigenetic inactivation of secreted frizzled-related protein 2 (SFRP2) by promoter methylation in human gastric cancer. Br J Cancer. 97:895–901. 2007.PubMed/NCBI
38	Becker G, Kocher M, Kortmann RD, Paulsen F, Jeremic B, Müller RP and Bamberg M: Radiation therapy in the multimodal treatment approach of pituitary adenoma. Strahlenther Onkol. 178:173–186. 2002. View Article : Google Scholar : PubMed/NCBI