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

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.

The Role of the IGF Axis in Epithelial-to-Mesenchymal Transition during the Progression of Prostate Cancer

“…In prostate cancer, immunohistochemical studies using tissue microarray assessing the gene expression profiles of Snail, have discovered that the expression of Snail is positively correlated with Gleason grade, with the highest expression seen in metastatic prostate cancer [75,76]. This is also supported by a recent in vitro study showing higher Snail expression in PC3 cells which exhibit advanced cancer properties compared to androgen-dependent LNCaP cells which exhibit more epithelial properties [77]. The importance of Snail in EMT-associated cell migration has further been revealed by overexpression of Snail in LNCaP cells which resulted in relocalization of E-cadherin from the cell membrane to the cytosol and increases in vimentin [78].…”

Transición epitelial-mesenquimal en la progresión del adenocarcinoma prostático

“…Este además participa en la inducción de la EMT en respuesta a la hipoxia (48,49). También se ha encontrado sobreexpresión de Snail en el CaP, con aumento progresivo desde el tejido benigno hasta las metástasis, asociado con índice alto de Gleason y mal pronóstico (29,32,50).…”

“…La mayoría de las proteasas involucradas pertenecen a la familia de las metaloproteinasas de matriz (MMP), de las cuales MMP9 y MMP2 juegan un papel fundamental en la invasión tumoral (5). En el CaP se encontró correlación positiva entre la expresión aumentada de Snail y la expresión o activación de MMP, y se plantea que estas enzimas pueden ser responsables de la pérdida de Ecadherina y el aumento de expresión de N-cadherina mediados por Snail (50). La liberación de citocinas inflamatorias por las células inmunes, los fibroblastos tumorales y el endotelio también induce la EMT (64).…”

Reduced serum levels of syndecan‐1 in patients with tongue squamous cell carcinoma

“…The downregulation of syndecan‐1 is shown to be associated with the higher risk of metastasis and unfavorable outcome in head and neck SCC . The decrease of syndecan‐1 expression on tumor cells is shown to be associated with the release of the molecule from the cell surface as well as cytoplasmic or nuclear sequestration . In head and neck SCC, the decrease in the expression of the syndecan‐1 molecule is reported to be concomitant with the induction of its expression in the stromal cells of the tumor, which correlates with the recurrence and tumor‐specific death in 2 years follow‐up …”