OBJECTIVETo investigate the expression of Sox17 and β-catenin proteins in oligodendroglioma, and its clinical significance.

METHODSOne hundred cases of oligodendroglioma of different grades and 10 cases of surrounding benign tissue from First Affiliated Hospital of Xinjiang Medical University from 2003 to 2013 were assessed by immunohistochemistry for Sox17 and β-catenin protein expression. The clinicopathologic characteristics and outcome of patients with oligodendroglioma were evaluated by Kaplan-Meien and Cox regression analyses.

RESULTSSox17 was expressed in 10/10, 82% (41/50) and 62% (31/50) of normal control, oligodendroglioma and anaplastic oligodendroglioma, respectively. β-catenin was expressed in 2/10, 22% (11/50), and 52% (26/50) of normal control, oligodendroglioma and anaplastic oligodendroglioma, respectively. The differences of Sox17 and β-catenin expression between normal control and different types of oligodendroglioma were statistically significant. Univariate analysis showed that the expression of Sox17 protein (P = 0.000), β-catenin protein (P = 0.033), tumor position (P = 0.001), radiotherapy (P = 0.077), and chemotherapy (P = 0.000) were significant prognostic factors.

CONCLUSIONSOligodendrogliomas with expression of Sox17 protein, but not β-catenin, have better prognosis. Evaluation of Sox17 and β-catenin protein expression is important for accurate pathological diagnosis, prognostication and guiding treatment.

Brain Neoplasms ; metabolism ; Humans ; Neoplasm Proteins ; metabolism ; Oligodendroglioma ; metabolism ; Regression Analysis ; SOXF Transcription Factors ; metabolism ; beta Catenin ; metabolism

The sex-determining region Y-box 7 (Sox7) is a important member of SOX family containing high mobi- lity group (HMG), mapped to human chromosome 8p23.1. Wnt/β-catenin signaling pathway plays an important role in cell survival, differentiation, self-renewal, proliferation and apoptosis, and is closely related with carcinogenesis. SOX7 gene is likely to be a tumor suppressor gene in MDS and other hematological malignancies. As a negative regulator of the WNT/β-catenin signaling pathway, the function loss of this gene can lead to carcinogenesis. The methylation of SOX7 gene leads to the silence of this gene, resulting in tumorigenesis. The decision of hematopoietic stem cells to self-renew or differentiate is a stochastic process, but SOX7 can promote the differentiation into all blood cell types. This review focuses on the role of SOX7 in hematopoietic system development and hematological malignancies.
DNA Methylation ; Gene Silencing ; Hematologic Neoplasms ; genetics ; metabolism ; Hematopoietic System ; physiopathology ; Humans ; SOXF Transcription Factors ; genetics ; metabolism ; Wnt Signaling Pathway

Sex-determining region Y box 18 (Sox18/SOX18) gene is an important regulator of vascular development playing a role in endothelial cell specification or differentiation, angiogenesis and atherogenesis. The aim of this study was to perform comprehensive functional characterization of the human SOX18 promoter, including determination of transcription start point (tsp) and identification of control elements involved in the regulation of SOX18 gene expression, with an emphasis on angiogenesis-related transcription factors. Analyses were performed in HeLa cells, representing a tumor cell line, and in EA.hy926 cells used as an endothelial model system. We have determined unique tsp of SOX18 gene, located 172 nucleotides upstream from ATG codon. Further, we have shown that SOX18 promoter region, -726 to -89 bp relative to tsp, contains positive cis-regulatory element(s) that stimulates SOX18 promoter activity, while region -89 to + 166 represents the minimal promoter. Within this region we have recognized the presence of essential element(s), positioned from -89 to +29, which harbors cluster of three putative early growth response 1 (EGR1) binding sites. By in vitro binding assays and functional analyses we have shown that these three putative binding sites are functionally relevant and sufficient for EGR1-induced SOX18 transcription. Mutations of these binding sites significantly impaired activity of the SOX18 promoter, particularly in EA.hy926 cells, indicating the importance of these regulatory elements for SOX18 promoter activity in endothelial setting. By data presented in this study, we have established SOX18 as a novel target gene regulated by EGR1 transcription factor, thus providing the first functional link between two transcription factors previously shown to be involved in the control of angiogenesis.
Early Growth Response Protein 1/genetics/*metabolism ; Electrophoretic Mobility Shift Assay ; Endothelium/*metabolism/pathology ; Gene Expression Regulation ; Hela Cells ; Humans ; Mutagenesis, Site-Directed ; Neovascularization, Physiologic/genetics ; Promoter Regions, Genetic ; Protein Binding/genetics ; SOXF Transcription Factors/genetics/*metabolism ; Transcription Initiation Site ; Transcriptional Activation

BACKGROUNDSRY-related HMG-box 17 (SOX17) encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and in the determination of the cell fate. Recently, it was considered as a tumor suppressor gene to inhibit canonical Wnt/β-catenin signaling pathway in several malignancies. However, the function of SOX17 in thyroid cancer was unknown. Therefore, we investigated the epigenetic changes and the function of SOX17 in thyroid cancer.

METHODSThe methylation status of the promoter region of SOX17 was detected using methylation-specific PCR in 63 papillary thyroid carcinoma (PTC) tissue, 10 normal thyroid tissue, and two thyroid cancer cell lines. Semi-quantitative RT-PCR was used to assess mRNA expression of SOX17 before and after 5-aza-2'-deoxycytidine treatment in thyroid cancer cell lines. Expression of SOX17 and β-catenin were detected by immunohistochemistry in PTC and adjacent tissue. Luciferase reporter assay, colony formation, transfection, and Western blotting were employed to analyze the effect of SOX17 on thyroid cancer cell proliferation and the function of SOX17 in the Wnt signal pathway.

RESULTSLoss of SOX17 expression was correlated to the promoter region hypermethylation in thyroid cancer cell lines. Re-expression of SOX17 was found in TPC-1 cell line after 5-aza-2'-deoxycytidine treatment. In primary thyroid cancer, 60.3% (38/63) were methylated and 39.7% (25/63) unmethylated. But no methylation was found in noncancerous thyroid tissues. Methylation of SOX17 was associated reversely with β-catenin expression in the cytoplasm or nucleus significantly in the PTC (P < 0.05). Colony formation was inhibited by re-expression of SOX17 in TPC-1 cells. SOX17 suppressed the Wnt signaling pathway and the HMG domain was essential for this effect.

CONCLUSIONSSOX17 was frequently methylated in human PTC. Loss of SOX17 expression was induced by promoter region hypermethylation. SOX17 inhibited thyroid cancer proliferation. Methylation of SOX17 activated the Wnt signaling pathway in human thyroid cancer.

Blotting, Western ; Carcinoma ; genetics ; metabolism ; Carcinoma, Papillary ; Cell Line, Tumor ; DNA Methylation ; genetics ; Epigenesis, Genetic ; genetics ; physiology ; Humans ; Immunohistochemistry ; Polymerase Chain Reaction ; Promoter Regions, Genetic ; genetics ; SOXF Transcription Factors ; genetics ; metabolism ; Thyroid Neoplasms ; genetics ; metabolism ; Tumor Cells, Cultured ; Wnt Signaling Pathway ; genetics ; physiology ; beta Catenin ; genetics ; metabolism

Recent evidence has suggested that human skin fibroblasts may represent a novel source of therapeutic stem cells. In this study, we report a 3-stage method to induce the differentiation of skin fibroblasts into insulin-producing cells (IPCs). In stage 1, we establish the isolation, expansion and characterization of mesenchymal stem cells from human labia minora dermis-derived fibroblasts (hLMDFs) (stage 1: MSC expansion). hLMDFs express the typical mesenchymal stem cell marker proteins and can differentiate into adipocytes, osteoblasts, chondrocytes or muscle cells. In stage 2, DMEM/F12 serum-free medium with ITS mix (insulin, transferrin, and selenite) is used to induce differentiation of hLMDFs into endoderm-like cells, as determined by the expression of the endoderm markers Sox17, Foxa2, and PDX1 (stage 2: mesenchymal-endoderm transition). In stage 3, cells in the mesenchymal-endoderm transition stage are treated with nicotinamide in order to further differentiate into self-assembled, 3-dimensional islet cell-like clusters that express multiple genes related to pancreatic beta-cell development and function (stage 3: IPC). We also found that the transplantation of IPCs can normalize blood glucose levels and rescue glucose homeostasis in streptozotocin-induced diabetic mice. These results indicate that hLMDFs have the capacity to differentiate into functionally competent IPCs and represent a potential cell-based treatment for diabetes mellitus.
Animals ; Biological Markers/metabolism ; *Cell Culture Techniques ; *Cell Differentiation ; Cell Proliferation/drug effects ; Cell Separation ; Cells, Cultured ; Dermis/*cytology/drug effects ; Diabetes Mellitus, Experimental/*surgery ; Female ; Fibroblasts/*cytology/drug effects ; Genitalia, Female/*cytology ; Glucose/metabolism ; Hepatocyte Nuclear Factor 3-beta/metabolism ; Homeodomain Proteins/metabolism ; Humans ; Insulin/pharmacology/secretion ; Insulin-Secreting Cells/*cytology/metabolism ; *Islets of Langerhans Transplantation ; Mesenchymal Stem Cells/*cytology/drug effects/metabolism ; Mice ; Mice, Nude ; Niacinamide/pharmacology ; Recovery of Function ; SOXF Transcription Factors/metabolism ; Sodium Selenite/pharmacology ; Trans-Activators/metabolism ; Transferrin/pharmacology