Increased SNAIL expression and low syndecan levels are associated with high Gleason grade in prostate cancer

Poblete,Cristian E.; Fulla,Juan; Gallardo,Marcela; Muñoz,Valentina; Castellón,Enrique A.; Gallegos,Ivan; Contreras,Hector R.

doi:10.3892/ijo.2014.2254

Increased SNAIL expression and low syndecan levels are associated with high Gleason grade in prostate cancer

Authors:
- Cristian E. Poblete
- Juan Fulla
- Marcela Gallardo
- Valentina Muñoz
- Enrique A. Castellón
- Ivan Gallegos
- Hector R. Contreras
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Affiliations: Physiology and Biophysics Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile, Pathological Anatomy Service, Clinic Hospital, University of Chile, Santiago, Chile
Published online on: January 10, 2014 https://doi.org/10.3892/ijo.2014.2254
Pages: 647-654
Copyright: © Poblete et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Prostate cancer (PC) is a leading male oncologic malignancy wideworld. During malignant transformation, normal epithelial cells undergo genetic and morphological changes known as epithelial-mesenchymal transition (EMT). Several regulatory genes and specific marker proteins are involved in PC EMT. Recently, syndecans have been associated with malignancy grade and Gleason score in PC. Considering that SNAIL is mainly a gene repressor increased in PC and that syndecan promoters have putative binding sites for this repressor, we propose that SNAIL might regulate syndecan expression during PC EMT. The aim of this study was to analyze immunochemically the expression of SNAIL, syndecans 1 and 2 and other EMT markers in a tissue microarray (TMA) of PC samples and PC cell lines. The TMAs included PC samples of different Gleason grade and benign prostatic hyperplasia (BPH) samples, as non‑malignant controls. PC3 and LNCaP cell lines were used as models of PC representing different tumorigenic capacities. Semi-quantitative immunohistochemistry was performed on TMAs and fluorescence immunocytochemistry and western blot analysis were conducted on cell cultures. Results show that SNAIL exhibits increased expression in high Gleason specimens compared to low histological grade and BPH samples. Accordingly, PC3 cells show higher SNAIL expression levels compared to LNCaP cells. Conversely, syndecan 1, similarly to E-cadherin (a known marker of EMT), shows a decreased expression in high Gleason grades samples and PC3 cells. Interestingly, syndecan 2 shows no changes associated to histological grade. It is concluded that increased SNAIL levels in advanced PC are associated with low expression of syndecan 1. The mechanism by which SNAIL regulates the expression of syndecan 1 remains to be investigated.

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1.	Jemal A, Bray F, Center MM, et al: Global Cancer Statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
2.	Kufe DW, Pollock RE, Weichselbaum RR, Bast RC Jr, Gansler TS, Holland JF and Frei E III: Neoplasms of the prostate. Cancer Medicine. Decker BC: ISBN: ISBN 1-55009-113-12003
3.	Long RM, Morrissey C, Fitzpatrick JM and Watson WG: Prostate epithelial cell differentiation and its relevance to the understanding of prostate cancer therapies. Clin Sci (Lond). 108:1–11. 2005. View Article : Google Scholar : PubMed/NCBI
4.	De Marzo AM, Platz EA, Sutcliffe S, et al: Inflammation in prostate carcinogenesis. Nat Rev Cancer. 7:256–269. 2007.
5.	Thiery JP: Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2:442–454. 2002. View Article : Google Scholar : PubMed/NCBI
6.	Gos M, Miloszewska J and Przybyszewska M: Epithelial-mesenchymal transition in cancer progression. Postepy Biochem. 55:121–128. 2009.PubMed/NCBI
7.	Delahunt B, Miller RJ, Srigley JR, et al: Gleason grading: past, present and future. Histopathology. 60:75–86. 2012. View Article : Google Scholar : PubMed/NCBI
8.	Micalizzi DS, Farabaugh SM and Ford HL: Epithelial-mesenchymal transition in cancer: Parallels between normal development and tumor progression. J Mammary Gland Biol Neoplasia. 15:117–134. 2010. View Article : Google Scholar : PubMed/NCBI
9.	Pecina-Slaus N: Tumor suppressor gene E-cadherin and its role in normal and malignant cells. Cancer Cell Int. 3:17–18. 2003. View Article : Google Scholar : PubMed/NCBI
10.	Chan AO, Lam SK, Chu KM, et al: Soluble E-cadherin is a valid prognostic marker in gastric carcinoma. Gut. 48:808–811. 2001. View Article : Google Scholar : PubMed/NCBI
11.	Mell LK, Meyer JJ, Tretiakova M, et al: Prognostic significance of E-cadherin protein expression in pathological stage I–III endometrial cancer. Clin Cancer Res. 10:5546–5553. 2004.PubMed/NCBI
12.	Gould Rothberg B and Bracken M: E-cadherin immunohistochemical expression as a prognostic factor in infiltrating ductal carcinoma of the breast: a systematic review and meta-analysis. Breast Cancer Res Treat. 100:139–148. 2006.PubMed/NCBI
13.	Musial J, Sporny S and Nowicki A: Prognostic significance of E-cadherin and ezrin immunohistochemical expression in prostate cancer. Pol J Pathol. 58:235–243. 2007.PubMed/NCBI
14.	Zhou Q, Yan B, Hu X, et al: Luteolin inhibits invasion of prostate cancer PC3 cells through E-cadherin. Mol Cancer Ther. 8:1684–1691. 2009. View Article : Google Scholar : PubMed/NCBI
15.	Heebøll S, Borre M, Ottosen PD, et al: Snail1 is over-expressed in prostate cancer. APMIS. 117:196–204. 2009.
16.	Smith B and Odero-Marah V: The role of Snail in prostate cancer. Cell Adh Migr. 6:433–441. 2012. View Article : Google Scholar : PubMed/NCBI
17.	Edwards IJ: Proteoglycans in prostate cancer. Nat Rev Urol. 21:196–206. 2012. View Article : Google Scholar
18.	Contreras HR, Ledezma RA, Vergara J, et al: The expression of syndecan-1 and -2 is associated with Gleason score and epithelial-mesenchymal transition markers E-cadherin and beta-catenin, in prostate cancer. Urol Oncol. 28:534–540. 2010. View Article : Google Scholar : PubMed/NCBI
19.	Shimada K, Nakamura M, De Velasco MA, et al: Syndecan-1, a new target molecule involved in progression of androgen-independent prostate cancer. Cancer Sci. 100:1248–1254. 2009. View Article : Google Scholar : PubMed/NCBI
20.	Popović A, Demirović A, Spajić B, et al: Expression and prognostic role of syndecan-2 in prostate cancer. Prostate Cancer Prostatic Dis. 13:78–82. 2010.PubMed/NCBI
21.	Ledezma R, Cifuentes F, Gallegos I, et al: Altered expression patterns of syndecan-1 and -2 predict biochemical recurrence in prostate cancer. Asian J Androl. 13:476–480. 2011. View Article : Google Scholar : PubMed/NCBI
22.	Vihinen T, Määttä A, Jaakkola P, et al: Functional characterization of mouse syndecan-1 promoter. J Biol Chem. 271:12532–12541. 1996. View Article : Google Scholar : PubMed/NCBI
23.	Nackaerts K, Verbeken E, Deneffe G, et al: Heparan sulfate proteoglycan expression in human lung-cancer cells. Int J Cancer. 74:335–345. 1997. View Article : Google Scholar : PubMed/NCBI
24.	Contreras HR, Fabre M, Granés F, et al: Syndecan-2 expression in colorectal cancer-derived HT-29 M6 epithelial cells induces a migratory phenotype. Biochem Biophys Res Commun. 286:742–751. 2001. View Article : Google Scholar : PubMed/NCBI
25.	Behnsawy HM, Miyake H, Harada K and Fujisawa M: Expression patterns of epithelial-mesenchymal transition markers in localized prostate cancer: significance in clinicopathological outcomes following radical prostatectomy. BJU Int. 111:30–37. 2013. View Article : Google Scholar
26.	Kiviniemi J, Kallajoki M, Kujala I, et al: Altered expression of syndecan-1 in prostate cancer. APMIS. 112:89–97. 2004. View Article : Google Scholar : PubMed/NCBI
27.	Mennerich D, Vogel A, Klaman I, et al: Shift of syndecan-1 expression from epithelial to stromal cells during progression of solid tumours. Eur J Cancer. 40:1373–1382. 2004. View Article : Google Scholar : PubMed/NCBI
28.	Shariat SF, Svatek RS, Kabbani W, et al: Prognostic value of syndecan-1 expression in patients treated with radical prostatectomy. BJU Int. 101:232–237. 2008.PubMed/NCBI
29.	Brimo F, Vollmer RT, Friszt M, et al: Syndecan-1 expression in prostate cancer and its value as biomarker for disease progression. BJU Int. 106:418–423. 2010. View Article : Google Scholar : PubMed/NCBI
30.	Zong F, Fthenou E, Mundt F, et al: Syndecan-1 domains regulate mesenchymal tumor cell adhesion, motility and migration. PLoS One. 6:e148162011. View Article : Google Scholar : PubMed/NCBI
31.	Manon-Jensen T, Itoh Y and Couchman JR: Proteoglycans in health and disease: the multiple roles of syndecan shedding. FEBS J. 277:3876–3889. 2010. View Article : Google Scholar : PubMed/NCBI
32.	Choi S, Lee H, Choi JR and Oh ES: Shedding; towards a new paradigm of syndecan function in cancer. BMB Rep. 43:305–310. 2010. View Article : Google Scholar : PubMed/NCBI
33.	Fears C, Gladson C and Woods A: Syndecan-2 is expressed in the microvasculature of gliomas and regulates angiogenic processes in microvascular endothelial cells. J Biol Chem. 281:14533–14536. 2006. View Article : Google Scholar : PubMed/NCBI
34.	Talbot L, Bhattacharya S and Kuo P: Epithelial-mesenchymal transition, the tumor microenvironment, and metastatic behavior of epithelial malignancies. Int J Biochem Mol Biol. 3:117–136. 2012.PubMed/NCBI
35.	Cano A, Pérez-Moreno MA, Rodrigo I, et al: The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2:76–83. 2000. View Article : Google Scholar : PubMed/NCBI
36.	Nieto M and Cano A: The epithelial-mesenchymal transition under control: Global programs to regulate epithelial plasticity. Semin Cancer Biol. 22:361–368. 2012. View Article : Google Scholar : PubMed/NCBI
37.	Emadi Baygi M, Soheili ZS, Schmitz I, et al: Snail regulates cell survival and inhibits cellular senescence in human metastatic prostate cancer cell lines. Cell Biol Toxicol. 26:553–567. 2010.PubMed/NCBI
38.	Baritaki S, Chapman A, Yeung K, et al: Inhibition of epithelial to mesenchymal transition in metastatic prostate cancer cells by the novel proteasome inhibitor, NPI-0052: pivotal roles of Snail repression and RKIP induction. Oncogene. 28:3573–3585. 2009. View Article : Google Scholar
39.	Wang H, Fang R, Wang XF, et al: Stabilization of Snail through AKT/GSK-3β signaling pathway is required for TNF-α-induced epithelial-mesenchymal transition in prostate cancer PC3 cells. Eur J Pharmacol. 714:48–55. 2013.PubMed/NCBI