6657

SOX2

SRY (sex determining region Y)-box 2;SOX2;SRY (sex determining region Y)-box 2

SRY-related HMG-box gene 2|transcription factor SOX-2|transcription factor SOX2

3q26.3-q27

protein-coding

The dynamic nature of cancer stem cells that underlie metastasis or their ability to switch between different cellular identities, as in EMT and MET, has profound implications for cancer therapy. The functional relationship between molecules involved in cancer cell stemness and metastasis is not clear. In this regard, our studies on hGBM tissue grade IV specimens showed significant expression of Twist1 and Sox2, known mesenchymal and stemness related markers, respectively, indicating their association with glial tumor genesis and metastasis. The glioma stem cells obtained from CD133+ cells demonstrated increased expression of Twist1 and Sox2 accompanied by significant increase in the mesenchymal markers such as N-cadherin, vimentin and beta-catenin. Our studies on glioma stem cells treatment with human umbilical cord blood derived- mesenchymal stem cells, showed down regulation of Twist1 and Sox2 proteins, apart from other mesenchymal stem cell markers. Based on the in vitro experiments and in vivo intracranial xenograft mouse model studies, we elucidated the potential therapeutic role of hUCBSC in suppressing glioma cancer stemness by the induction of MET.

BACKGROUND: The SRY-related HMG-box family of transcription factors member SOX2 has been mainly studied in embryonic stem cells as well as early foregut and neural development. More recently, SOX2 was shown to participate in reprogramming of adult somatic cells to a pluripotent stem cell state and implicated in tumorigenesis in various organs. In breast cancer, SOX2 expression was reported as a feature of basal-like tumors. In this study, we assessed SOX2 expression in 95 primary tumors of postmenopausal breast cancer patients. METHODS: Samples from 95 patients diagnosed and treated at the University of Tuebingen Institute of Pathology and Women's Hospital were analyzed by immunohistochemistry for SOX2 expression in the primary tumor samples and in corresponding lymph node metastasis, where present. Furthermore, SOX2 amplification status was assessed by FISH in representative samples. In addition, eighteen fresh frozen samples were analyzed for SOX2, NANOG and OCT4 gene expression by real-time PCR. RESULTS: SOX2 expression was detected in 28% of invasive breast carcinoma as well as in 44% of ductal carcinoma in situ (DCIS) lesions. A score of SOX2 expression (score 0 to 3) was defined in order to distinguish SOX2 negative (score 0) from SOX2 positive samples (score 1-3) and among latter the subgroup of SOX2 high expressors (score 3 > 50% positive cells). Overall, the incidence of SOX2 expression (score 1-3) was higher than previously reported in a cohort of lymph node negative patients (28% versus 16.7%). SOX2 expression was detected across different breast cancer subtypes and did not correlate with tumor grading. However, high SOX2 expression (score 3) was associated with larger tumor size (p = 0.047) and positive lymph node status (0.018). Corresponding metastatic lymph nodes showed higher SOX2 expression and were significantly more often SOX2 positive than primary tumors (p = 0.0432). CONCLUSIONS: In this report, we show that the embryonic stem cell factor SOX2 is expressed in a variety of early stage postmenopausal breast carcinomas and metastatic lymph nodes. Our data suggest that SOX2 plays an early role in breast carcinogenesis and high expression may promote metastatic potential. Further studies are needed to explore whether SOX2 can predict metastatic potential at an early tumor stage.

BACKGROUND: We previously determined that cancer stem-like cells may influence the susceptibility of colorectal cancer (CRC) cells to chemotherapeutic agents. Although Takahashi and Park identified a set of induced pluripotent stem cell (iPS)-related genes required for normal stem cell maintenance, the precise role of iPS-related gene expression in CRC pathogenesis remains to be determined. The purpose of this study was to clarify the clinical relevance of "stemness"-regulating gene expression in CRC cases. MATERIALS AND METHODS: cancer cells were excised from tissues of 79 CRC cases by laser microdissection (LMD), and quantitative RT-PCR was used to evaluate expression levels of the iPS-related genes c-MYC, SOX2, OCT3/4, LIN28, KLF4, and NANOG, and to identify any associations between their expression and clinicopathological CRC progression. RESULTS: We found that LIN28 expression is significantly associated with lymph node metastasis (p = 0.018) and Dukes stage (p = 0.0319). SOX2expression is also correlated with lymph node metastasis. Furthermore, the ten cases with Dukes D disease expressed significantly higher levels of SOX2transcript than the other 69 cases (p = 0.0136). In contrast, KLF4 expression was inversely related to Dukes stage. expression of c-MYC, OCT3/4, and NANOG did not appear to have clinical relevance in CRC cases. CONCLUSION: The present analysis strongly suggests that altered expression of several iPS-related genes plays a role in CRC pathogenesis.

cancer stem cells, as a subgroup of tumor cells, resemble critical properties of embryonic stem cells (ESCs) such as self-renewal and maintenance of stemness state. SALL4 and SOX2 are two main transcription factors involving in maintenance of pluripotency, self-renewal and cell fate decision in ESCs. In this study, we aimed to elucidate the expression levels of these important transcription factors in esophageal squamous cell carcinoma (ESCC) and to reveal their probable roles in maintenance and progression of the disease. The expression level of SALL4 and SOX2 was analyzed in fresh tumoral tissues in comparison with distant tumor-free tissues of 50 ESCC patients by relative comparative real-time PCR. SALL4 and SOX2 were overexpressed in 64 and 32% of tumor samples, respectively, in significant correlation with each other (p = 0.028). There was a significantly inverse correlation between low level of SALL4 expression and metastasis of tumor cells into the lymph nodes (p = 0.035). Furthermore, co-overexpression of the genes was significantly correlated with the depth of tumor invasion (p = 0.045) and metastasis to the lymph nodes (p = 0.049). SALL4 and SOX2 are co-overexpressed in ESCC and have a significant correlation with invasion and metastasis of the disease. To the best of our knowledge, this is the first report of SALL4 clinical relevance in ESCC to date. The clinical consequences of SALL4-SOX2 association suggest a possible functional interaction between these factors in regulation of ESCC maintenance and aggressiveness and introduce these regulators of stemness state as potentially interesting therapeutic targets to bring new opportunities for onco-therapeutic modalities.

Sox2 is a major transcription factor essential to the stemness characteristics and is associated with various types of cancers. In this study, we investigated the expressions and functional roles of Sox2 in hepatocellular carcinoma (HCC). Our data show that high level of Sox2 expression correlates with metastasis and low survival rate in HCC. HCC cells overexpressing Sox2 are characterized by active epithelial-mesenchymal transition and exhibit increased ability of transwell invasion, soft agar colonization, and sphere formation. We also found Sox2 expression was correlated with the transcription activity of SLUG promoter region. These results present novel mechanistic insight into an important role of Sox2 in HCC and suggest a potential application of Sox2 in HCC prognosis and treatment.

Sentinel lymph node evaluation is a critical component of melanoma staging, and lymph node status provides one of the most powerful predictors of melanoma recurrence and survival. One of the well-known diagnostic pitfalls in melanoma sentinel lymph node evaluation is the presence of nodal melanocytic nevi, which has been demonstrated in up to 26% of lymphadenectomy specimens and specifically in melanoma patients. Melanocytic markers enhance the sensitivity of melanoma detection in sentinel lymph nodes. However, established markers such as anti-melan-A/MART1, S100 protein and SOX10 antibodies cannot discriminate melanoma metastasis from nodal nevi. Recent studies have demonstrated strong expression of neural stem/progenitor cell markers nestin and SOX2 in melanoma. In this study, we tested the diagnostic utility of nestin and SOX2 in differentiating metastatic melanomas from nodal nevi. Twenty-three lymph nodes with metastatic melanomas and 17 with nodal nevi were examined. Of the 23 metastatic melanomas, 18 showed diffuse and strong (3+) nestin, 4 showed rare cells with strong (3+) nestin, and one showed diffuse but faint (1+) nestin staining. Nuclear SOX2 was positive in 13 metastatic melanomas. In contrast, 15 nodal nevi showed no nestin, and 2 showed rare cells with very faint (<1+) nestin staining. SOX2 was negative in 13 nodal nevi. Overall, nestin was strongly expressed in metastatic melanomas (n=22/23; 96%), but not in nodal melanocytic nevi (n=15/17; 88%; P<0.0001). SOX2 was also expressed in metastatic melanomas (n=13/23; 57%) but not in the majority of nodal melanocytic nevi (n=13/16; 81%; P=0.02). In one lymph node harboring metastatic melan-A-negative desmoplastic melanoma, nestin and SOX2 strongly highlighted the infiltrating tumor cells, suggesting the potential clinical value of these two markers in desmoplastic melanoma lymph node biopsies. This study provides evidence that nestin and SOX2 can effectively differentiate nodal melanocytic nevi from metastatic melanomas and serve as powerful diagnostic adjuncts in melanoma staging.

The significance of SOX2 in nasopharyngeal carcinoma (NPC), a tumor associated with Epstein-Barr virus (EBV), remains unclear. Here, we reported that, in the univariate analysis, SOX2 expression was correlated with a poorer distant metastasis-free survival (DMFS). The EBV-VCA/IgA titers in patients with NPC were also associated with a poorer overall survival (OS). Patients with NPC, who had both strong staining of SOX2 and high titers of EBV-VCA/IgA, had the poorest prognoses. Therefore, SOX2 or the combination of the SOX2 expression level and EBV-VCA/IgA titers could be valuable to predict distant metastasis or the prognosis of NPC.

One of the major factors involved in the prognosis of oral squamous cell carcinoma (OSCC) patients is metastasis. Recent progress in cancer stem-like cell/cancer-initiating cell (CSC/CIC) research indicates that CSCs are related to metastasis. Aldehyde dehydrogenase 1 - (ALDH1) and SRY-related HMG-box gene 2 (SOX2) have recently been shown to be putative CSC markers for several human malignancies. The aim of this study was to determine the association of ALDH1 and SOX2 expression in oral squamous cell carcinoma (OSCC) with lymph node metastasis. Immunohistochemical staining of ALDH1, SOX2 and Ki67 was performed in 80 OSCC tissues. High expression rates of ALDH1 (2%-40%) were found to be related to lymph node metastasis (P = 0.0017). Interestingly, we found that SOX2 staining could be classified into two patterns: (i) peripheral staining pattern; and (ii) diffuse staining pattern. The diffuse staining pattern showed a significant correlation with lymph node metastasis (P < 0.001). No correlation was found between Ki67 staining and lymph node metastasis (P = 0.4724). The ALDH1 positive staining rates in metastatic lymph nodes were higher than that in corresponding primary OSCC tissues. These results indicate that high expression rates of ALDH1 and SOX2 diffuse staining patterns might be novel prediction markers for OSCC lymph node metastasis.

BACKGROUND: The transcription factor sex determining region Y (SRY)-box 2 (SOX2) (3q26.3-q27) has been recently identified as a recurrently activated major oncogene in squamous cell carcinoma of various sites. Its prognostic value in head and neck squamous cell carcinoma (HNSCC) is currently unclear. AIM: To correlate SOX2 protein expression with the occurrence of occult lymph node metastasis and relapse free survival in early oral SCC. METHODS: SOX2 expression in 120 T1/T2 oral SCC patients was evaluated using a tissue microarray technique. Intensity of SOX2 expression was quantified by assessing the Intensity/Reactivity Scores (IRSs). These scores were correlated with the lymph node status of biopsied sentinel lymph nodes and recurrence. Log rank univariate and Cox regression multivariate analysis was used to determine statistical significance. RESULTS: Twenty-six of 120 primary tumours (21.7%) showed high SOX2 expression. High expression levels of SOX2 significantly correlated with negative lymph node status in univariate (p=0.001) and multivariate analysis (p=0.003). Sensitivity was found to be 95.6% with a negative predictive value of 92.3%. Specificity was 32% with a positive predictive value of 45.7%. CONCLUSION: SOX2 up-regulation is frequent in early SCC of the oral cavity and associated with decreased risk of lymphatic metastasis. SOX2 immunohistochemistry may be used as a predictor for lymph node metastasis in squamous cell carcinoma of the oral cavity.

The purpose of this study was to examine the expression pattern of MUC5AC and SOX2 in ampulla of vater adenocarcinoma and evaluate the association between expression of these gastric epithelial markers and the histologic phenotype of ampulla of vater carcinoma. Six surgically resected samples of ampulla of vater adenocarcinoma, including four intestinal type carcinomas and two pancreatobiliary type carcinomas, were studied. We performed immunohistochemistry with a monoclonal antibody against MUC5AC and a polyclonal anti-SOX2 antibody. In two of the four intestinal type carcinomas, MUC5AC and SOX2 were focally expressed in the superficial neoplastic mucosa. However, in the centre of the tumour and in other invasive lesions, including vascular invasive lesions and metastatic lymph nodes, neither MUC5AC nor SOX2 was expressed. In contrast, in both pancreatobiliary type carcinomas, expression of MUC5AC and SOX2 was maintained or increased in invasive lesions. Our immunohistochemistry data suggest that MUC5AC and SOX2 are associated with the pancreatobiliary phenotype of ampulla of vater carcinoma and involved in later events in carcinogenesis, such as invasion and metastasis.