Open Access

Expression patterns of Wnt signaling component, secreted frizzled‑related protein 3 in astrocytoma and glioblastoma

  • Authors:
    • Nives Pećina‑Šlaus
    • Anja Kafka
    • Ana Maria Varošanec
    • Leon Marković
    • Željka Krsnik
    • Niko Njirić
    • Goran Mrak
  • View Affiliations

  • Published online on: March 28, 2016     https://doi.org/10.3892/mmr.2016.5061
  • Pages: 4245-4251
  • Copyright: © Pećina‑Šlaus et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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


Abstract

Secreted frizzled-related protein 3 (SFRP3) is a member of the family of soluble proteins, which modulate the Wnt signaling cascade. Novel research has identified aberrant expression of SFRPs in different types of cancer. In the present study the expression intensities and localizations of the SFRP3 protein across different histopathological grades of astrocytic brain tumors were investigated by immunohistochemistry, digital scanning and image analysis. The results demonstrated that the differences between expression levels and malignancy grades were statistically significant. Tumors were classified into four malignancy grades according to the World Health Organization guidelines. Moderate (P=0.014) and strong (P=0.028) nuclear expression levels were significantly different in pilocytic (grade I) and diffuse (grade II) astrocytomas demonstrating higher expression values, as compared with anaplastic astrocytoma (grade III) and glioblastoma (grade IV). When the sample was divided into two groups, the moderate and high cytoplasmic expression levels were observed to be significantly higher in glioblastomas than in the group comprising astrocytoma II and III. Furthermore, the results indicated that high grade tumors were associated with lower values of moderate (P=0.002) and strong (P=0.018) nuclear expression in comparison to low grade tumors. Analysis of cytoplasmic staining demonstrated that strong cytoplasmic expression was significantly higher in the astrocytoma III and IV group than in the astrocytoma I and II group (P=0.048). Furthermore, lower grade astrocytomas exhibited reduced membranous SFRP3 staining when compared with higher grade astrocytomas and this difference was statistically significant (P=0.036). The present results demonstrated that SFRP3 protein expression levels were decreased in the nucleus in higher grade astrocytoma (indicating the expected behavior of an antagonist of Wnt signaling), whereas when the SFRP3 was located in the cytoplasm an increased expression level of SFRP3 was identified in the high grade astrocytomas when compared with those of a low grade. This may suggest that SFRP3 acts as an agonist of Wnt signaling and promotes invasive behavior.

References

1 

Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW and Kleihues P: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 114:97–109. 2007. View Article : Google Scholar : PubMed/NCBI

2 

Rampazzo E, Persano L, Pistollato F, Moro E, Frasson C, Porazzi P, Della Puppa A, Bresolin S, Battilana G, Indraccolo S, et al: Wnt activation promotes neuronal differentiation of glioblastoma. Cell Death Dis. 4:e5002013. View Article : Google Scholar : PubMed/NCBI

3 

Rheinbay E, Suvè ML, Gillespie SM, Wakimoto H, Patel AP, Shahid M, Oksuz O, Rabkin D, Martuza RL, Rivera MN, et al: An aberrant transcription factor network essential for Wnt signaling and stem cell maintenance in glioblastoma. Cell Rep. 3:1567–1579. 2013. View Article : Google Scholar : PubMed/NCBI

4 

Delic S, Lottmann N, Stelzl A, Liesenberg F, Wolter M, Götze S, Zapatka M, Shiio Y, Sabel MC, Felsberg J, et al: MiR-328 promotes glioma cell invasion via SFRP1-dependent Wnt-signaling activation. Neuro Oncol. 16:179–190. 2014. View Article : Google Scholar :

5 

Nikuševa-Martić T, Beroš V, Pećina-Šlaus N, Pećina HI and Bulić-Jakuš F: Genetic changes of CDH1, APC, and CTNNB1 found in human brain tumors. Pathol Res Pract. 203:779–787. 2007. View Article : Google Scholar

6 

Pećina-Šlaus N, Martić TN, Kokotović T, Kusec V, Tomas D and Hrasćan R: AXIN-1 protein expression and localization in glioblastoma. Coll Antropol. 35(Suppl 1): 101–106. 2011.

7 

Pećina-Šlaus N, Kafka A, Tomas D, Marković L, Okštajner PK, Sukser V and Krušlin B: Wnt signaling transcription factors TCF-1 and LEF-1 are upregulated in malignant astrocytic brain tumors. Histol Histopathol. 29:1557–1564. 2014.

8 

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

9 

Polakis P: Wnt signaling in cancer. Genes Dev. 14:1837–1851. 2000.PubMed/NCBI

10 

Fagotto F: Looking beyond the Wnt pathway for the deep nature of β-catenin. EMBO Rep. 14:422–433. 2013. View Article : Google Scholar : PubMed/NCBI

11 

Kafka A, Bašić-Kinda S and Pećina-Šlaus N: The cellular story of dishevelleds. Croat Med J. 55:459–467. 2014. View Article : Google Scholar : PubMed/NCBI

12 

Hoang B, Moos M Jr, Vukicevic S and Luyten FP: Primary structure and tissue distribution of FRZB, a novel protein related to Drosophila frizzled, suggest a role in skeletal morphogenesis. J Biol Chem. 271:26131–26137. 1997.

13 

Shi Y, He B, You L and Jablons DM: Roles of secreted frizzled-related proteins in cancer. Acta Pharmacol Sin. 28:1499–1504. 2007. View Article : Google Scholar : PubMed/NCBI

14 

Bovolenta P, Esteve P, Ruiz JM, Cisneros E and Lopez-Rios J: Beyond Wnt inhibition: New functions of secreted Frizzled-related proteins in development and disease. J Cell Sci. 121:737–746. 2008. View Article : Google Scholar : PubMed/NCBI

15 

Jones SE and Jomary C: Secreted Frizzled-related proteins: Searching for relationships and patterns. Bioessays. 24:811–820. 2002. View Article : Google Scholar : PubMed/NCBI

16 

Kawano Y and Kypta R: Secreted antagonists of the Wnt signalling pathway. J Cell Sci. 116:2627–2634. 2003. View Article : Google Scholar : PubMed/NCBI

17 

Hirata H, Hinoda Y, Ueno K, Majid S, Saini S and Dahiya R: Role of secreted frizzled-related protein 3 in human renal cell carcinoma. Cancer Res. 70:1896–1905. 2010. View Article : Google Scholar : PubMed/NCBI

18 

Surana R, Sikka S, Cai W, Shin EM, Warrier SR, Tan HJ, Arfuso F, Fox SA, Dharmarajan AM and Kumar AP: Secreted frizzled related proteins: Implications in cancer. Biochim Biophys Acta. 1845:53–65. 2014.

19 

Mii Y and Taira M: Secreted Wnt 'inhibitors' are not just inhibitors: Regulation of extracellular Wnt by secreted Frizzled-related proteins. Dev Growth Differ. 53:911–923. 2011. View Article : Google Scholar : PubMed/NCBI

20 

Roth W, Wild-Bode C, Platten M, Grimmel C, Melkonyan HS, Dichgans J and Weller M: Secreted Frizzled-related proteins inhibit motility and promote growth of human malignant glioma cells. Oncogene. 19:4210–4220. 2000. View Article : Google Scholar : PubMed/NCBI

21 

Harrison-Uy SJ and Pleasure SJ: Wnt signaling and forebrain development. Cold Spring Harb Perspect Biol. 4:a0080942012. View Article : Google Scholar : PubMed/NCBI

22 

Zhao X, Huang H, Chen Y, Liu Y, Zhang Z, Ma Q and Qiu M: Dynamic expression of secreted Frizzled-related protein 3 (sFRP3) in the developing mouse spinal cord and dorsal root ganglia. Neuroscience. 248:594–601. 2013. View Article : Google Scholar : PubMed/NCBI

23 

Sun J, Bonaguidi MA, Jun H, Guo JU, Sun GJ, Will B, Yang Z, Jang MH, Song H, Ming GL and Christian KM: A septo-remporal molecular gradient of sfrp3 in the dentate gyrus differentially regulates quiescent adult hippocampal neural stem activation. Mol Brain. 8:522015. View Article : Google Scholar

24 

Pazanin L: Histopatholoy of glial tumors. Medicina fluminensis. 47:157–166. 2011.In Croatian.

25 

Lee JL, Chang CJ, Wu SY, Sargan DR and Lin CT: Secreted frizzled-related protein 2 (SFRP2) is highly expressed in canine mammary gland tumors but not in normal mammary glands. Breast Cancer Res Treat. 84:139–149. 2004. View Article : Google Scholar : PubMed/NCBI

26 

Abu-Jawdeh G, Comella N, Tomita Y, Brown LF, Tognazzi K, Sokol SY and Kocher O: Differential expression of frpHE: A novel human stromal protein of the secreted frizzled gene family, during the endometrial cycle and malignancy. Lab Investig. 79:439–447. 1999.PubMed/NCBI

27 

Drake J, Shearwood AM, White J, Friis R, Zeps N, Charles A and Dharmarajan A: Expression of secreted frizzled-related protein 4 (SFRP4) in primary serous ovarian tumours. Eur J Gynaecol Oncol. 30:133–141. 2009.PubMed/NCBI

28 

Huang D, Yu B, Deng Y, Sheng W, Peng Z, Qin W and Du X: SFRP4 was overexpressed in colorectal carcinoma. J Cancer Res Clin Oncol. 136:395–401. 2010. View Article : Google Scholar

29 

Paw I, Carpenter RC, Watabe K, Debinski W and Lo HW: Mechanisms regulating glioma invasion. Cancer Lett. 362:1–7. 2015. View Article : Google Scholar : PubMed/NCBI

30 

Wang H, Xu T, Jiang Y, Xu H, Yan Y, Fu D and Chen J: The challenges and the promise of molecular targeted therapy in malignant gliomas. Neoplasia. 17:239–255. 2015. View Article : Google Scholar : PubMed/NCBI

31 

Uren A, Reichsman F, Anest V, Taylor WG, Muraiso K, Bottaro DP, Cumberledge S and Rubin JS: Secreted frizzled-related protein-1 binds directly to Wingless and is a biphasic modulator of Wnt signaling. J Biol Chem. 275:4374–4382. 2000. View Article : Google Scholar : PubMed/NCBI

32 

Xaviera CP, Melikovaa M, Chumana Y, Üren A, Baljinnyama B and Rubina JS: Secreted Frizzled-related protein potentiation versus inhibition of Wnt3a/β-catenin signaling. Cell Signal. 26:94–101. 2014. View Article : Google Scholar

33 

Lin K, Wang S, Julius MA, Kitajewski J, Moos M Jr and Luyten FP: The cysteine-rich frizzled domain of Frzb-1 is required and sufficient for modulation of Wnt signaling. Proc Natl Acad Sci USA. 94:11196–11200. 1997. View Article : Google Scholar : PubMed/NCBI

34 

Bafico A, Gazit A, Pramila T, Finch PW, Yaniv A and Aaronson SA: Interaction of frizzled related protein (FRP) with Wnt ligands and the frizzled receptor suggests alternative mechanisms for FRP inhibition of Wnt signaling. J Biol Chem. 274:16180–16187. 1999. View Article : Google Scholar : PubMed/NCBI

35 

Nikuševa Martić T, Pećina-Šlaus N, Kušec V, Kokotović T, Mušinović H, Tomas D and Zeljko M: Changes of AXIN-1 and beta-catenin in neuroepithelial brain tumors. Pathol Oncol Res. 16:75–79. 2010. View Article : Google Scholar

36 

Zhang N, Wei P, Gong A, Chiu WT, Lee HT, Colman H, Huang H, Xue J, Liu M, Wang Y, et al: FoxM1 promotes β-catenin nuclear localization and controls Wnt target-gene expression and glioma tumorigenesis. Cancer Cell. 20:427–442. 2011. View Article : Google Scholar : PubMed/NCBI

37 

Kahlert UD, Maciaczyk D, Doostkam S, Orr BA, Simons B, Bogiel T, Reithmeier T, Prinz M, Schubert J, Niedermann G, et al: Activation of canonical WNT/β-catenin signaling enhances in vitro motility of glioblastoma cells by activation of ZEB1 and other activators of epithelial-to-mesenchymal transition. Cancer Lett. 325:42–53. 2012. View Article : Google Scholar : PubMed/NCBI

38 

Cheng YY, Yu J, Wong JP, Man EP, To KF, Jin VX, Li J, Tao Q, Sung JJ, Chan JK 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

39 

Schiefer L, Visweswaran M, Perumal V, Arfuso F, Groth D, Newsholme P, Warrier S and Dharmarajan A: Epigenetic regulation of the secreted frizzled-related protein family in human glioblastoma multiforme. Cancer Gene Ther. 21:297–303. 2014. View Article : Google Scholar : PubMed/NCBI

40 

Willert K, Brown JD, Danenberg E, Duncan AW, Weissman IL, Reya T, Yates JR III and Nusse R: Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature. 423:448–452. 2003. View Article : Google Scholar : PubMed/NCBI

41 

Reya T and Clevers H: Wnt signaling in stem cells and cancer. Nature. 434:834–850. 2005. View Article : Google Scholar

Related Articles

Journal Cover

May 2016
Volume 13 Issue 5

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Pećina‑Šlaus, N., Kafka, A., Varošanec, A.M., Marković, L., Krsnik, Ž., Njirić, N., & Mrak, G. (2016). Expression patterns of Wnt signaling component, secreted frizzled‑related protein 3 in astrocytoma and glioblastoma. Molecular Medicine Reports, 13, 4245-4251. https://doi.org/10.3892/mmr.2016.5061
MLA
Pećina‑Šlaus, N., Kafka, A., Varošanec, A. M., Marković, L., Krsnik, Ž., Njirić, N., Mrak, G."Expression patterns of Wnt signaling component, secreted frizzled‑related protein 3 in astrocytoma and glioblastoma". Molecular Medicine Reports 13.5 (2016): 4245-4251.
Chicago
Pećina‑Šlaus, N., Kafka, A., Varošanec, A. M., Marković, L., Krsnik, Ž., Njirić, N., Mrak, G."Expression patterns of Wnt signaling component, secreted frizzled‑related protein 3 in astrocytoma and glioblastoma". Molecular Medicine Reports 13, no. 5 (2016): 4245-4251. https://doi.org/10.3892/mmr.2016.5061