title: SNAI2/Slug gene is silenced in prostate cancer and regulates neuroendocrine differentiation, metastasis-suppressor and pluripotency gene expression.
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.
authors: Department of Medicine and Sciences of Aging, Section of Anatomic Pathology and Molecular Medicine, "G. d'Annunzio" University, Chieti, Italy.|Ce.S.I. Aging Research Center, "G. d'Annunzio" University Foundation, Chieti, Italy.
authors: Silvia
authors: S
authors: Esposito
authors: Department of Medicine and Sciences of Aging, Section of Anatomic Pathology and Molecular Medicine, "G. d'Annunzio" University, Chieti, Italy.|Ce.S.I. Aging Research Center, "G. d'Annunzio" University Foundation, Chieti, Italy.
authors: Marco V
authors: MV
authors: Russo
authors: Laboratory of Oncology, Istituto Giannina Gaslini, Genova, Italy.
authors: Irma
authors: I
authors: Airoldi
authors: Department of Medicine and Sciences of Aging, Section of Anatomic Pathology and Molecular Medicine, "G. d'Annunzio" University, Chieti, Italy.|Ce.S.I. Aging Research Center, "G. d'Annunzio" University Foundation, Chieti, Italy.
authors: Maria Grazia
authors: MG
authors: Tupone
authors: Department of Medicine and Sciences of Aging, Section of Anatomic Pathology and Molecular Medicine, "G. d'Annunzio" University, Chieti, Italy.|Ce.S.I. Aging Research Center, "G. d'Annunzio" University Foundation, Chieti, Italy.|Specialisation School in Clinical Biochemistry, "G. d'Annunzio" University, Chieti, Italy.
authors: Carlo
authors: C
authors: Sorrentino
authors: Laboratory of Oncology, Istituto Giannina Gaslini, Genova, Italy.
authors: Giulia
authors: G
authors: Barbarito
authors: Department of Medicine and Sciences of Aging, Section of Anatomic Pathology and Molecular Medicine, "G. d'Annunzio" University, Chieti, Italy.|Ce.S.I. Aging Research Center, "G. d'Annunzio" University Foundation, Chieti, Italy.
authors: Serena
authors: S
authors: Di Meo
authors: Department of Medicine and Sciences of Aging, Section of Anatomic Pathology and Molecular Medicine, "G. d'Annunzio" University, Chieti, Italy.|Ce.S.I. Aging Research Center, "G. d'Annunzio" University Foundation, Chieti, Italy.
authors: Emma
authors: E
authors: Di Carlo
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology* / Q000556:secondary; D000368:Aged; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D061346:Laser Capture Microdissection; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C000604407:SNAI1 protein, human; C000604408:SNAI2 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors
keywords: SNAI2/Slug; laser capture microdissection; neuroendocrine differentiation; prostate cancer