Abstract
The SRY-related HMG-box family of transcription factors member SOX2 regulates stemness and pluripotency in embryonic stem cells and plays important roles during early embryogenesis. More recently, SOX2 expression was documented in several tumor types including ovarian carcinoma, suggesting an involvement of SOX2 in regulation of cancer stem cells (CSC). Intriguingly, however, studies exploring the predictive value of SOX2 protein expression with respect to histopathologic and clinical parameters report contradictory results in individual tumors, indicating that SOX2 may play tumor-specific roles. In this report, we analyze the functional relevance of SOX2 expression in human ovarian carcinoma. We report that in human serous ovarian carcinoma (SOC) cells, SOX2 expression increases the expression of CSC markers, the potential to form tumor spheres, and the in vivo tumor-initiating capacity, while leaving cellular proliferation unaltered. Moreover, SOX2-expressing cells display enhanced apoptosis resistance in response to conventional chemotherapies and TRAIL. Hence, our data show that SOX2 associates with stem cell state in ovarian carcinoma and induction of SOX2 imposes CSC properties on SOC cells. We propose the existence of SOX2-expressing ovarian CSCs as a mechanism of tumor aggressiveness and therapy resistance in human SOC.
Highlights
Pluripotency-associated stem cell factors such as OCT4 and SOX2 regulate cellular identity in embryonic stem cells and facilitate the reprogramming of terminally differentiated somatic cells back to a pluripotent stem cell state [1]
SOX2 modulates cancer stem cells (CSC) properties in human serous ovarian carcinoma (SOC) cells To explore the functional role of SOX2 in ovarian carcinoma, we stably suppressed SOX2 expression in OVCAR-3, the SOC line with the highest basal SOX2 expression, using two different lentiviruses containing SOX2-inhibitory short hairpin RNA (shRNA) (Fig. 2A and Supplementary Fig. S2A)
SOX2 is a key regulator for maintaining the pluripotency and self-renewal of embryonic stem cells and contributes to the reprogramming of differentiated somatic cells back to a pluripotent stem cell state
Summary
Pluripotency-associated stem cell factors such as OCT4 and SOX2 regulate cellular identity in embryonic stem cells and facilitate the reprogramming of terminally differentiated somatic cells back to a pluripotent stem cell state [1]. SOX proteins are important regulators of early development in different tissues, such as the foregut and lung, where for example SOX2 expression controls bronchogenesis by inhibiting airway branching [2, 3]. SOX2 is expressed in different epithelial compartments marking cells with selfrenewal properties [4], and targeted ablation lethally disrupts epithelial tissue homeostasis [4]. Authors' Affiliations: Departments of 1Internal Medicine II and 2Preclinical Imaging and Radiopharmacy, Laboratory for Preclinical Imaging and Imaging Technology of the Werner Siemens-Foundation; 3Institute of Pathology; 4Interfaculty Institute for Biochemistry; 5Women's Hospital, University of Tuebingen, Tuebingen; 6Institute of Pathology, University of Bonn, Bonn; and 7German Cancer Consortium (DKTK) and German Cancer Research Center, Heidelberg, Germany. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Paczulla contributed to this work and share first authorship
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