Prognostic value of SOX2 expression in neuroblastoma

Neuroblastoma (NB) is the most common extracranial solid neoplasm in children. Arising from neural-derived crest cells, this tumor is remarkable for its biological heterogeneity, with a broad spectrum of clinical behavior, ranging from spontaneous regression or maturation into a benign form, ganglioneuroma, to rapid tumor progression and death, despite intensive multimodality treatment (Cohn et al., 2009). Complex patterns of genetic abnormalities interact to determine the clinical phenotype. The molecular biology of NB is characterized by somatically acquired genetic events. Amplification of the MYCN gene occurs in 20–25% of NBs and is an independent marker of poor prognosis. Aberrant copy number or mutation in the ALK gene had been related to poor prognosis of the disease (De Brouwer S et al., 2010; Subramaniam et al., 2009). Moreover, there are unbalanced translocations resulting in gain or loss of genetic material from a number of chromosomes, such as 17q23qter, 1p36, and 11q23, genetic aberrations that have prognostic information (Cohn et al., 2009; Maris, 2010). This diversity in genetics and behavior also correlate with a great number of features, like age at diagnosis, stage of disease, histopathology, tumor markers (ferritin, LDH and NSE), DNA index, neurotrophines, and vascularity. Combinations of some of these prognostic variables are used for risk-group assignment and treatment stratification (Cohn et al., 2009). The heterogeneity, characteristic of NBs throughout their differential disease progression, is related to many factors, including the embryology, and makes this disease a logical candidate for a malignancy arising from cancer stem cells (CSCs) of the neural crest. The putative existence of stem-like cells in NB might be supported by the analysis of genes involved in the regulation of stem cell properties (Pietras et al., 2008), and their dysregulation in NBs might be associated with cancer onset and/or progression of the disease (Melone et al., 2009). Transcriptional profiling of stem cells allowed a preliminary identification of ‘‘stemness’’ genes participating in the control of stem cell properties, such as self-renewal ability and retention of an uncommitted state. These genes have been identified in pluripotent embryonic stem cells and also in stem cells in multiple adult tissues (Lu et al., 2010). One of these genes is SOX2, a transcription factor that regulates embryonic stem cell pluripotency. SOX2 is a member of the SOX (SRYrelated high mobility group box) family, located in chromosome 3q26.3 (Sinclair et al., 1990). Many members of the SOX gene family have been identified to play essential roles in stem cell biology, regulation of organ development, and cell type specification (Boer et al., 2007). Reduction of SOX2 expression has been associated with loss of the pluripotent state and a propensity for differentiation in mouse embryonic stem cells (Chew et al., 2005). Several recent studies have demonstrated that transcription factor SOX2 is overexpressed in small cell lung cancers (Gure et al., 2000), basal cell-like breast carcinomas (Rodriguez-Pinilla et al., 2007) and cervical carcinomas (Ji and Zheng, 2010) and is reduced in a few carcinomas such as gastric cancer and choriocarcinoma (Sanada et al., 2006; Otsubo et al., 2008). SOX2 could also be involved in the process of invasion and metastasis (Sanada et al., 2006). In pulmonary non small cell and neuroendocrine carcinoma, as well as in medulloblastomas, the immunohistochemical expression of SOX2 has been associated with a ‘‘stemness’’ phenotype that predicts poor outcome (Sholl et al., 2010; Sutter et al., 2010). Furthermore, it was reported in this journal that a subgroup of oral squamous cell carcinomas has a gain in SOX2 gene copy number and high SOX2 protein expression. These findings indicate that SOX2 may participate in oral carcinogenesis (Freier et al. 2010). Based on these findings, we decided to explore the expression and clinical significance of the