title: SOX2 boosts major tumor progression genes in prostate cancer and is a functional biomarker of lymph node metastasis.
abstract: Critical issues in prostate cancer (PC) are a. identification of molecular drivers of the highly aggressive neuroendocrine differentiation (NED) in adenocarcinoma, and b. early assessment of disease progression. The SRY (sex determining region Y)-box 2 gene, SOX2, is an essential embryonic stem cell gene involved in prostate tumorigenesis. Here we assessed its implications in NED and progression of PC and its diagnostic and prognostic value. Laser microdissection, qRT-PCR, quantitative Methylation-Specific PCR and immunohistochemistry were used to analyze SOX2 gene expression and regulation in 206 PC samples. Results were examined according to the patient's clinical pathological profile and follow-ups. Functional studies were performed using PC cells transfected to overexpress or silence SOX2. SOX2 was consistently downregulated in PC, except in cell clusters lying within lymph node (LN)-positive PC. Multivariate analysis revealed that SOX2 mRNA expression in the primary tumor was significantly associated with LN metastasis. When SOX2 mRNA levels were ≥1.00, relative to (XpressRef) Universal Total RNA, adjusted Odds Ratio was 24.4 (95% CI: 7.54-79.0), sensitivity 0.81 (95% CI: 0.61-0.93) and specificity 0.87 (95% CI: 0.81-0.91). Patients experiencing biochemical recurrence had high median levels of SOX2 mRNA. In both PC and LN metastasis, SOX2 and NED marker, Chromogranin-A, were primarily co-expressed. In PC cells, NED genes were upregulated by SOX2 overexpression and downregulated by its silencing, which also abolished SNAI2/Slug dependent NED. Moreover, SOX2 upregulated neural CAMs, neurotrophins/neurotrophin receptors, pluripotency and epithelial-mesenchymal transition transcription factors, growth, angiogenic and lymphangiogenic factors, and promoted PC cell invasiveness and motility. This study discloses novel SOX2 target genes driving NED and spread of PC and proposes SOX2 as a functional biomarker of LN metastasization for PC.
authors.affiliation: Department of Medicine and Sciences of Aging, "G. d'Annunzio" University, Chieti, Italy.|Ce.S.I. Biotech, Aging Research Center, "G. d'Annunzio" University Foundation, Chieti, Italy.
authors.forename: Marco Vincenzo
authors.initials: MV
authors.lastname: Russo
authors.affiliation: Department of Medicine and Sciences of Aging, "G. d'Annunzio" University, Chieti, Italy.|Ce.S.I. Biotech, Aging Research Center, "G. d'Annunzio" University Foundation, Chieti, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Esposito
authors.affiliation: Department of Medicine and Sciences of Aging, "G. d'Annunzio" University, Chieti, Italy.|Ce.S.I. Biotech, Aging Research Center, "G. d'Annunzio" University Foundation, Chieti, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Tupone
authors.affiliation: Department of Medicine and Sciences of Aging, "G. d'Annunzio" University, Chieti, Italy.
authors.forename: Lamberto
authors.initials: L
authors.lastname: Manzoli
authors.affiliation: Laboratory of Oncology, Istituto "Giannina Gaslini", Genova, Italy.
authors.forename: Irma
authors.initials: I
authors.lastname: Airoldi
authors.affiliation: Operative Unit of Urology, "Santo Spirito" Hospital, Pescara, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Pompa
authors.affiliation: Department of Urology, "San Pio da Pietrelcina" Hospital, Vasto, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Cindolo
authors.affiliation: Department of Urology, "San Pio da Pietrelcina" Hospital, Vasto, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Schips
authors.affiliation: Department of Medicine and Sciences of Aging, "G. d'Annunzio" University, Chieti, Italy.|Ce.S.I. Biotech, Aging Research Center, "G. d'Annunzio" University Foundation, Chieti, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Sorrentino
authors.affiliation: Department of Medicine and Sciences of Aging, "G. d'Annunzio" University, Chieti, Italy.|Ce.S.I. Biotech, Aging Research Center, "G. d'Annunzio" University Foundation, Chieti, Italy.
authors.forename: Emma
authors.initials: E
authors.lastname: Di Carlo
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D045744:Cell Line, Tumor; D018450:Disease Progression; D015536:Down-Regulation; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D055748:SOXB1 Transcription Factors / Q000235:genetics*; D014162:Transfection
chemical_list: D014408:Biomarkers, Tumor; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors
keywords: SOX2; laser capture microdissection; metastasization; neuroendocrine differentiation; prostate cancer