Research Papers:
SOX2 boosts major tumor progression genes in prostate cancer and is a functional biomarker of lymph node metastasis
PDF | HTML | Supplementary Files | How to cite
Metrics: PDF 1716 views | HTML 2511 views | ?
Abstract
Marco Vincenzo Russo1,2, Silvia Esposito1,2, Maria Grazia Tupone1,2, Lamberto Manzoli1, Irma Airoldi3, Paolo Pompa4, Luca Cindolo5, Luigi Schips5, Carlo Sorrentino1,2, Emma Di Carlo1,2
1Department of Medicine and Sciences of Aging, “G. d'Annunzio” University, Chieti, Italy
2Ce.S.I. Biotech, Aging Research Center, “G. d'Annunzio” University Foundation, Chieti, Italy
3Laboratory of Oncology, Istituto “Giannina Gaslini”, Genova, Italy
4Operative Unit of Urology, “Santo Spirito” Hospital, Pescara, Italy
5Department of Urology, “San Pio da Pietrelcina” Hospital, Vasto, Italy
Correspondence to:
Emma Di Carlo, e-mail: [email protected]
Keywords: prostate cancer, laser capture microdissection, neuroendocrine differentiation, SOX2, metastasization
Received: July 21, 2015 Accepted: October 06, 2015 Published: October 19, 2015
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 6029