6657

SOX2

SOX2 is a high-mobility group box containing transcription factor essential for the maintenance of embryonic stem cells. Recent evidence indicates that SOX2 overexpression correlates with metastasis and poor prognosis in patients with laryngeal squamous cell cancer. To investigate how SOX2 contributes to this aggressive phenotype, we introduced the human SOX2 gene into a low SOX2-expressing human laryngeal cancer cell line Hep-2. Cell migration and invasion were determined by the Transwell assay with or without Matrigel coating. The epithelial-mesenchymal transition (EMT)-related markers were assayed by Western blot analysis or immunofluorescence. Our results showed that exogenous expression of SOX2 in Hep-2 cells substantially promoted their migratory and invasive capabilities in culture. Moreover, Hep-2 cells stably overexpressing SOX2 underwent EMT phenotype, as evidenced by mesenchymal morphology, decreased expression of epithelial marker (E-cadherin), and increased expression of mesenchymal markers (N-cadherin, vimentin, fibronectin, and alpha-smooth muscle actin). Strikingly, Western blot analysis and immunofluorescence also showed that overexpression of SOX2 resulted in substantial increase and nuclear accumulation of beta-catenin in Hep-2 cells. However, small interfering RNA targeting beta-catenin significantly attenuated the reduced expression of E-cadherin and increased cell migration and invasion abilities in SOX2-overexpressing cells, suggesting that SOX2-induced EMT process, migration, and invasion are dependent on beta-catenin activation. Taken together, our findings underscore a novel role for SOX2 in laryngeal cancer migration and invasion.

OBJECTIVES: Sox2, a high-mobility-group DNA binding protein, is part of the key set of transcription factors that are involved in the maintenance of pluripotency and self-renewal in undifferentiated stem cells. A recent study has further suggested cancer stem cells (CSCs) are key contributors to radiochemoresistance and are responsible for oral squamous cell carcinoma (OSCC) progression. The aim of this study was to determine the emerging role of Sox2 in radiochemosensitivity of oral CSCs. METHODS: We determined the function of Sox2 on oncogenicity and radiochemosensitivity of OSCC by overexpression or silencing Sox2 in vitro and in vivo. RESULTS: Initially, Sox2 expression was increased in OSCC cell lines and OSCC specimens. Upregulated Sox2 is correlated with poor survival outcome of OSCC patients. Overexpression of Sox2 was demonstrated to enhance invasiveness, anchorage-independent growth, xenotransplantation tumourigenicity in OSCC cells. Targeting Sox2 to spheroid cells (SC) and ALDH1+CD44+ cells from OSCC significantly inhibited their CSCs and tumorigenic abilities. Down regulation of SOX2 in OSCC-SC was found to repress invasiveness and diminish epithelail-mesenchymal transition (EMT) traits. Furthermore, silencing Sox2 effectively suppressed the expression of drug-resistance and anti-apoptotic genes and increased the sensitivity of the cells to radiation combined cisplatin treatment. Finally, the in vivo therapeutic efficacy of targeting Sox2 synergistically suppressed tumorigenesis and improved the survival rate when used in combination with radiotherapy and cisplatin in OSCC-SC-transplanted immunocompromised mice. CONCLUSION: Sox2-mediated CSCs property is associated with the regulation of EMT and Sox2 s as therapeutic target in OSCC.CI - Copyright (c) 2014 Elsevier Ltd. All rights reserved.

TIF1gamma is a novel regulator of transforming growth factor (TGF)-beta/Smad signaling. Our previous studies show that dysregulated expression of transcriptional intermediary factor 1 gamma (TIF1gamma) and abnormal TGF-beta/Smad signaling are implicated in non-small-cell lung cancer (NSCLC) separately. However, how TIF1gamma contributes to NSCLC by controlling TGF-beta/Smad signaling is poorly understood. Here, we investigated the mechanistic role of TIF1gamma in TGF-beta-induced epithelial-mesenchymal transition (EMT), as well as a link between TIF1gamma and SOX2 in NSCLC. We show that TIF1gamma is a downstream target of SOX2 in NSCLC cells. SOX2 overexpression negatively regulated TIF1gamma promoter activity and thereby attenuated TIF1gamma mRNA and protein expression levels; SOX2 knockdown significantly enhanced TIF1gamma promoter activity and augmented TIF1gamma expression. Moreover, TIF1gamma mRNA expression was downregulated in human NSCLC tissues and negatively correlated with SOX2 protein, which was upregulated in NSCLC tissues. Importantly, knockdown of TIF1gamma or SOX2 overexpression augmented SMAD4 (human Mad (mothers against decapentaplegic)-related homologous protein 4)-dependent transcriptional responses, and enhanced TGF-beta-induced EMT and human NSCLC cell invasion; knockdown of SOX2 impaired TGF-beta-induced EMT and NSCLC cell invasion. In an in vivo model of metastasis, knockdown of TIF1gamma promotes NSCLC cell metastasis. In addition, our data suggested that TIF1gamma inhibited TGF-beta-induced EMT through competing with SMAD4 in NSCLC cells. Taken together, our findings reveal a new mechanism by which SOX2-mediated transcription repression of TIF1gamma promotes TGF-beta-induced EMT in NSCLC.

UNLABELLED: The transcription factor sex determining region (Y SRY)-box 2 (SOX2) is known to play a crucial role in the maintenance of self renewal or pluripotency of undifferentiated embryonic and neuronal stem cells. An elevated expression of SOX2 has been correlated with poor prognosis of esophageal squamous cell carcinoma (ESCC). We sought to investigate the mechanism(s) by which SOX2 modulates the ESCC metastasis. The SOX2 coding DNA sequence was inserted into pCMV vector and stably transfected in ESCC cells (Eca-109). The effect of SOX2 over expression was evaluated on cell migration, invasion and epithelial to mesenchymal transition (EMT). We also measured the expression of Slug to explore if this transcription factor is involved in SOX2-mediated regulation of cell migration/invasion and EMT. In addition, we determined the role of STAT3/HIF-1alpha to further probe the mechanism of SOX2-mediated metastasis via Slug. Our results demonstrated that SOX2 over expressing Eca-109 cells showed an enhanced cell migration/invasion. Moreover, these cells exhibited the EMT characteristics, that is, a significantly suppressed expression of the epithelial cells marker with a concomitant enhancement of those of the mesenchymal markers. An increased expression of Slug in SOX2 over expressing cells suggested the involvement of this transcription factor in SOX2-regulated metastasis. Whereas the expressions of STAT3/HIF-1alpha were found to be up-regulated in SOX2 expressing cells, blockade of these transcription factors resulted in the inhibition of Slug expression at both protein and mRNA levels. CONCLUSION: These results suggest that SOX2 promoted the metastasis of ESCC, at least in part, by modulating Slug expression through the activation of STAT3/HIF-1alpha signaling.

Although the Oct4/Sox2 complex is crucial for maintaining the pluripotency of stem cells, the molecular basis underlying its regulation during lineage-specific differentiation remains unknown. Here, we revealed that the highly conserved Oct4/Lys-156 is important for maintaining the stability of the Oct4 protein and the intermolecular salt bridge between Oct4/Lys-151 and Sox2/Asp-107 that contributes to the Oct4/Sox2 interaction. Post-translational modifications at Lys-156 and K156N, a somatic mutation detected in bladder cancer patients, both impaired the Lys-151-Asp-107 salt bridge and the Oct4/Sox2 interaction. When produced as a recombinant protein or overexpressed in pluripotent stem cells, Oct4/K156N, with reduced binding to Sox2, significantly down-regulated the stemness genes that are cooperatively controlled by the Oct4/Sox2 complex and specifically up-regulated the mesendodermal genes and the SNAIL family genes that promote the epithelial-mesenchymal transition. Thus, we conclude that Oct4/Lys-156-modulated Oct4/Sox2 interaction coordinately controls the epithelial-mesenchymal transition and mesendoderm specification induced by specific differentiation signals.CI - (c) 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

The anterior pituitary gland is comprised of specialized cell-types that produce and secrete polypeptide hormones in response to hypothalamic input and feedback from target organs. These specialized cells arise from stem cells that express SOX2 and the pituitary transcription factor PROP1, which is necessary to establish the stem cell pool and promote an epithelial to mesenchymal-like transition, releasing progenitors from the niche. The adult anterior pituitary responds to physiological challenge by mobilizing the SOX2-expressing progenitor pool and producing additional hormone-producing cells. Knowledge of the role of signaling pathways and extracellular matrix components in these processes may lead to improvements in the efficiency of differentiation of embryonic stem cells or induced pluripotent stem cells into hormone producing cells in vitro. Advances in our basic understanding of pituitary stem cell regulation and differentiation may lead to improved diagnosis and treatment for patients with hypopituitarism.CI - Copyright (c) 2016. Published by Elsevier B.V.

Aberrant expression of microRNAs has been identified as regulators of biological processes of hepatocellular carcinoma (HCC) by negatively regulating protein-coding mRNAs. Several studies have demonstrated that miR-638 expression was dysregulated in various human cancers. However, the clinical significance and underlying mechanisms of miR-638 involved in HCC remain to be elucidated. Herein, we confirmed that a reduced miR-638 expression was present in HCC tissues and cell lines. Our clinical analysis revealed that the downregulated miR-638 expression was significantly correlated with poor prognostic features including high Edmondson-Steiner grade, venous infiltration and advanced tumor-node-metastasis (TNM) stage. Moreover, we demonstrated that miR-638 was a novel independent prognostic marker for predicting 5-year survival of HCC patients. Functionally, overexpressed miR-638 expression inhibited cell migration and invasion, while downregulated miR-638 reversed the effect. In addition, miR-638 could regulate SOX2 by directly binding to its 3'-UTR. Alternation of SOX2 expression at least partially abolished the migration and invasion effects of miR-638 on HCC cells. Aberrant miR-638 expression could regulate the expression level of epithelial-to-mesenchymal transition markers in vitro and in vivo by modulating SOX2 expression. In conclusion, our data indicated that miR-638 functioned as a tumor suppressor gene and play a critical role in the development of HCC.