Oncotarget

Research Papers:

SNAI2/Slug gene is silenced in prostate cancer and regulates neuroendocrine differentiation, metastasis-suppressor and pluripotency gene expression

Silvia Esposito _, Marco V. Russo, Irma Airoldi, Maria Grazia Tupone, Carlo Sorrentino, Giulia Barbarito, Serena Di Meo and Emma Di Carlo

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Oncotarget. 2015; 6:17121-17134. https://doi.org/10.18632/oncotarget.2736

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Abstract

Silvia Esposito1,2,*, Marco V. Russo1,2,*, Irma Airoldi4, Maria Grazia Tupone1,2, Carlo Sorrentino1,2,3, Giulia Barbarito4, Serena Di Meo1,2, Emma Di Carlo1,2

1Department of Medicine and Sciences of Aging, Section of Anatomic Pathology and Molecular Medicine, “G. d'Annunzio” University, Chieti, Italy

2Ce.S.I. Aging Research Center, “G. d'Annunzio” University Foundation, Chieti, Italy

3Specialisation School in Clinical Biochemistry, “G. d'Annunzio” University, Chieti, Italy

4Laboratory of Oncology, Istituto Giannina Gaslini, Genova, Italy

*These authors have contributed equally to this work

Correspondence to:

Emma Di Carlo, e-mail: edicarlo@unich.it

Keywords: Prostate Cancer, Neuroendocrine Differentiation, Laser Capture Microdissection, SNAI2/Slug

Received: August 25, 2014     Accepted: November 11, 2014     Published: February 05, 2015

ABSTRACT

Prostate Cancer (PCa)-related deaths are mostly due to metastasization of poorly differentiated adenocarcinomas often endowed with neuroendocrine differentiation (NED) areas.

The SNAI2/Slug gene is a major regulator of cell migration and tumor metastasization. We here assessed its biological significance in NED, and metastatic potential of PCa.

SNAI2 expression was down-regulated in most PCa epithelia, in association with gene promoter methylation, except for cell clusters forming: a. the expansion/invasion front of high-grade PCa, b. NED areas, or c. lymph node metastasis.

Knockdown of SNAI2 in PC3 cells down-regulated the expression of neural-tissue-associated adhesion molecules, Neural-Cadherin, Neural-Cadherin-2, Neuronal-Cell-Adhesion-Molecule, and of the NED marker Neuron-Specific Enolase, whereas it abolished Chromogranin-A expression. The metastasis-suppressor genes, Nm23-H1 and KISS1, were up-regulated, while the pluripotency genes SOX2, NOTCH1, CD44v6, WWTR1/TAZ and YAP1 were dramatically down-regulated. Over-expression of SNAI2 in DU145 cells substantiated its ability to regulate metastasis-suppressor, NED and pluripotency genes. In PCa and lymph node metastasis, expression of SOX2 and NOTCH1 was highly related to that of SNAI2.

In conclusion, I. SNAI2 silencing in PCa may turn-off the expression of NED markers and pluripotency genes, while turning-on that of specific metastasis-suppressors, II. SNAI2 expression in selected PCa cells, by regulating their self-renewal, NED and metastatic potential, endows them with highly malignant properties. SNAI2 may thus constitute a key target for modern approaches to PCa progression.


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