SOX17

Gene Summary

Gene:SOX17; SRY (sex determining region Y)-box 17
Aliases: VUR3
Location:8q11.23
Summary:This gene 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. The encoded protein may act as a transcriptional regulator after forming a protein complex with other proteins. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:transcription factor SOX-17
HPRD
Source:NCBIAccessed: 08 August, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 08 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Esophageal Cancer
  • Gene Expression Profiling
  • Base Sequence
  • Tumor Suppressor Proteins
  • Octamer Transcription Factor-3
  • Xenopus Proteins
  • Young Adult
  • Precancerous Conditions
  • Wnt Proteins
  • Immunohistochemistry
  • RTPCR
  • Polymerase Chain Reaction
  • Xenograft Models
  • Western Blotting
  • Chromosome 8
  • CpG Islands
  • Survival Rate
  • Up-Regulation
  • Promoter Regions
  • SOXF Transcription Factors
  • DNA-Binding Proteins
  • Messenger RNA
  • Neoplasm Proteins
  • Breast Cancer
  • Testicular Cancer
  • Disease Progression
  • Epigenetics
  • Wnt Signaling Pathway
  • Vascular Endothelial Growth Factor Receptor-2
  • Transcription Factors
  • DNA Methylation
  • Membrane Proteins
  • Cancer Gene Expression Regulation
  • Sensitivity and Specificity
  • Cell Proliferation
  • Down-Regulation
  • Signal Transduction
  • MicroRNAs
  • beta Catenin
  • RT-PCR
Tag cloud generated 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: SOX17 (cancer-related)

Oudijk L, Neuhofer CM, Lichtenauer UD, et al.
Immunohistochemical expression of stem cell markers in pheochromocytomas/paragangliomas is associated with SDHx mutations.
Eur J Endocrinol. 2015; 173(1):43-52 [PubMed] Related Publications
OBJECTIVE: Pheochromocytomas (PCCs) are neuroendocrine tumors that occur in the adrenal medulla, whereas paragangliomas (PGLs) arise from paraganglia in the head, neck, thorax, or abdomen. In a variety of tumors, cancer cells with stem cell-like properties seem to form the basis of tumor initiation because of their ability to self-renew and proliferate. Specifically targeting this small cell population may lay the foundation for more effective therapeutic approaches. In the present study, we intended to identify stem cells in PCCs/PGLs.
DESIGN: We examined the immunohistochemical expression of 11 stem cell markers (SOX2, LIN28, NGFR, THY1, PREF1, SOX17, NESTIN, CD117, OCT3/4, NANOG, and CD133) on tissue microarrays containing 208 PCCs/PGLs with different genetic backgrounds from five European centers.
RESULTS: SOX2, LIN28, NGFR, and THY1 were expressed in more than 10% of tumors, and PREF1, SOX17, NESTIN, and CD117 were expressed in <10% of the samples. OCT3/4, NANOG, and CD133 were not detectable at all. Double staining for chromogranin A/SOX2 and S100/SOX2 demonstrated SOX2 immunopositivity in both tumor and adjacent sustentacular cells. The expression of SOX2, SOX17, NGFR, LIN28, PREF1, and THY1 was significantly associated with mutations in one of the succinate dehydrogenase (SDH) genes. In addition, NGFR expression was significantly correlated with metastatic disease.
CONCLUSION: Immunohistochemical expression of stem cell markers was found in a subset of PCCs/PGLs. Further studies are required to validate whether some stem cell-associated markers, such as SOX2, could serve as targets for therapeutic approaches and whether NGFR expression could be utilized as a predictor of malignancy.

Fu D, Ren C, Tan H, et al.
Sox17 promoter methylation in plasma DNA is associated with poor survival and can be used as a prognostic factor in breast cancer.
Medicine (Baltimore). 2015; 94(11):e637 [PubMed] Related Publications
Aberrant DNA methylation that leads to the inactivation of tumor suppressor genes is known to play an important role in the development and progression of breast cancer. Methylation status of cancer-related genes is considered to be a promising biomarker for the early diagnosis and prognosis of tumors. This study investigated the methylation status of the Sox17 gene in breast cancer tissue and its corresponding plasma DNA to evaluate the association of methylation levels with clinicopathological parameters and prognosis.The methylation status of the Sox17 gene promoter was evaluated with methylation-specific polymerase chain reaction (MSP) in 155 paired breast cancer tissue and plasma samples and in 60 paired normal breast tissue and plasma samples. Association of Sox17 methylation status with clinicopathological parameters was analyzed by χ tests. Overall and disease-free survival (DFS) curves were calculated using Kaplan-Meier analysis, and the differences between curves were analyzed by log-rank tests.The frequency of Sox17 gene methylation was 72.9% (113/155) in breast cancer tissues and 58.1% (90/155) in plasma DNA. Sox17 gene methylation was not found in normal breast tissues or in their paired plasma DNA. There was a significant correlation of Sox17 methylation between corresponding tumor tissues and paired plasma DNA (r = 0.688, P < 0.001). Aberrant Sox17 methylation in cancer tissues and in plasma DNA was significantly associated with the tumor node metastasis stage (P = 0.035 and P = 0.001, respectively) and with lymph node metastasis (P < 0.001 and P = 0.001, respectively). Kaplan-Meier survival curves showed that aberrant Sox17 promoter methylation in cancer tissues and plasma DNA was associated with poor DFS (P < 0.005) and overall survival (OS) (P < 0.005). Multivariate analysis showed that Sox17 methylation in plasma DNA was an independent prognostic factor in breast cancer for both DFS (P = 0.020; hazard ratio [HR] = 2.142; 95% confidence interval [CI]: 1.128-4.067) and for OS (P = 0.001; HR = 4.737; 95% CI: 2.088-10.747).Sox17 gene promoter methylation may play an important role in breast cancer progression and could be used as a prognostic biomarker to identify patients at risk of developing metastasis or recurrence after mastectomy.

Weissferdt A, Rodriguez-Canales J, Liu H, et al.
Primary mediastinal seminomas: a comprehensive immunohistochemical study with a focus on novel markers.
Hum Pathol. 2015; 46(3):376-83 [PubMed] Related Publications
Primary mediastinal seminomas are unusual tumors that can present in a pure form or as part of a mixed germ cell tumor. Contrary to testicular seminomas, little is known about the expression of novel immunohistochemical markers in mediastinal seminomas. This study investigates the immunohistochemical features of these tumors with a focus on novel markers. Thirty-two cases of primary mediastinal seminomas were reviewed; and representative whole-tissue sections were selected for immunohistochemical studies using antibodies directed against high molecular weight cytokeratin 5/6 (CK5/6), low molecular weight cytokeratin (CAM5.2), octamer-binding transcription factor 3/4 (OCT3/4), spalt-like transcription factor 4 (SALL4), GATA binding protein 3 (GATA-3), sry-related HMG box 2 (SOX2), SOX17, human T cell leukemia/lymphoma 1 (TCL1), glypican 3, melanoma associated antigen C2 (MAGEC2), and paired box gene 8 (Pax8). The percentage of positive tumor cells as well as the intensity of staining was evaluated and scored. Thirty-one cases (97%) expressed SOX17, whereas 29 cases (91%) were positive for OCT3/4 and SALL4, respectively. Twenty-eight cases (88%) expressed MAGEC2 and CAM5.2, respectively. Two cases (6%) were positive for Pax8, and a single case (3%) was positive for TCL1. None of the cases stained with CK5/6, GATA-3, SOX2, or glypican 3. Similar to testicular seminomas, mediastinal seminomas show consistent expression of OCT3/4, SALL4, SOX17, and MAGEC2 and are negative for SOX2, glypican 3, GATA-3, and CK5/6. Pax8 positivity is only inconsistently identified in mediastinal seminomas. Contrary to their testicular counterparts, mediastinal tumors show diffuse expression of low-molecular-weight cytokeratin in up to 90% of cases and are commonly negative for TCL1. Although there is some immunohistochemical overlap between testicular and mediastinal seminomas, considerable differences also exist and should be acknowledged when dealing with these tumors.

Irie N, Weinberger L, Tang WW, et al.
SOX17 is a critical specifier of human primordial germ cell fate.
Cell. 2015; 160(1-2):253-68 [PubMed] Free Access to Full Article Related Publications
Specification of primordial germ cells (PGCs) marks the beginning of the totipotent state. However, without a tractable experimental model, the mechanism of human PGC (hPGC) specification remains unclear. Here, we demonstrate specification of hPGC-like cells (hPGCLCs) from germline competent pluripotent stem cells. The characteristics of hPGCLCs are consistent with the embryonic hPGCs and a germline seminoma that share a CD38 cell-surface marker, which collectively defines likely progression of the early human germline. Remarkably, SOX17 is the key regulator of hPGC-like fate, whereas BLIMP1 represses endodermal and other somatic genes during specification of hPGCLCs. Notable mechanistic differences between mouse and human PGC specification could be attributed to their divergent embryonic development and pluripotent states, which might affect other early cell-fate decisions. We have established a foundation for future studies on resetting of the epigenome in hPGCLCs and hPGCs for totipotency and the transmission of genetic and epigenetic information.

Lu J, Zhang G, Cheng Y, et al.
Reduced expression of SRY-box containing gene 17 correlates with an unfavorable melanoma patient survival.
Oncol Rep. 2014; 32(6):2571-9 [PubMed] Related Publications
SRY-box containing gene 17 (Sox17), a transcription factor, is considered as an antagonist to canonical Wnt/β‑catenin signaling in several types of malignant tumors. As the influence of Sox17 in the pathogenesis of human melanoma is still unknown, the investigation of Sox17 expression in melanoma is warranted and its prognostic value is of great interest. In the present study, Sox17 expression was examined in 525 cases of melanocytic lesions (33 common acquired nevi, 59 dysplastic nevi, 291 primary melanomas and 142 metastatic melanomas) at different stages by tissue microarray. The correlation of Sox17 expression with melanoma progression and its prognostic value in melanoma patients were examined. We also analyzed the correlation between Sox17 and cyclin-dependent kinase inhibitor p27 expression in 374 melanoma samples. The results showed that Sox17 expression was significantly decreased in primary and metastatic melanoma compared to common acquired nevi and dysplastic nevi (P=2.4x10-17). Furthermore, Sox17 expression was inversely correlated with American Joint Committee on Cancer stage (P=4.6x10-15), thickness (P=0.00004) and ulceration (P=0.03). Notably, reduced Sox17 expression was correlated with a poorer overall and disease-specific 5- and 10-year survival of the patients. Multivariate Cox regression analyses indicated that Sox17 is an independent prognostic marker for melanoma patients. Moreover, we found a significant positive correlation between Sox17 and p27 expression in melanoma biopsies; their concomitant expression was closely correlated with the survival of melanoma patients. Taken together, decreased Sox17 expression is correlated with melanoma progression, an unfavorable survival of melanoma patients and is an independent molecular prognostic factor for melanoma.

Conway K, Edmiston SN, May R, et al.
DNA methylation profiling in the Carolina Breast Cancer Study defines cancer subclasses differing in clinicopathologic characteristics and survival.
Breast Cancer Res. 2014; 16(5):450 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Breast cancer is a heterogeneous disease, with several intrinsic subtypes differing by hormone receptor (HR) status, molecular profiles, and prognosis. However, the role of DNA methylation in breast cancer development and progression and its relationship with the intrinsic tumor subtypes are not fully understood.
METHODS: A microarray targeting promoters of cancer-related genes was used to evaluate DNA methylation at 935 CpG sites in 517 breast tumors from the Carolina Breast Cancer Study, a population-based study of invasive breast cancer.
RESULTS: Consensus clustering using methylation (β) values for the 167 most variant CpG loci defined four clusters differing most distinctly in HR status, intrinsic subtype (luminal versus basal-like), and p53 mutation status. Supervised analyses for HR status, subtype, and p53 status identified 266 differentially methylated CpG loci with considerable overlap. Genes relatively hypermethylated in HR+, luminal A, or p53 wild-type breast cancers included FABP3, FGF2, FZD9, GAS7, HDAC9, HOXA11, MME, PAX6, POMC, PTGS2, RASSF1, RBP1, and SCGB3A1, whereas those more highly methylated in HR-, basal-like, or p53 mutant tumors included BCR, C4B, DAB2IP, MEST, RARA, SEPT5, TFF1, THY1, and SERPINA5. Clustering also defined a hypermethylated luminal-enriched tumor cluster 3 that gene ontology analysis revealed to be enriched for homeobox and other developmental genes (ASCL2, DLK1, EYA4, GAS7, HOXA5, HOXA9, HOXB13, IHH, IPF1, ISL1, PAX6, TBX1, SOX1, and SOX17). Although basal-enriched cluster 2 showed worse short-term survival, the luminal-enriched cluster 3 showed worse long-term survival but was not independently prognostic in multivariate Cox proportional hazard analysis, likely due to the mostly early stage cases in this dataset.
CONCLUSIONS: This study demonstrates that epigenetic patterns are strongly associated with HR status, subtype, and p53 mutation status and may show heterogeneity within tumor subclass. Among HR+ breast tumors, a subset exhibiting a gene signature characterized by hypermethylation of developmental genes and poorer clinicopathologic features may have prognostic value and requires further study. Genes differentially methylated between clinically important tumor subsets have roles in differentiation, development, and tumor growth and may be critical to establishing and maintaining tumor phenotypes and clinical outcomes.

Yang T, Li XN, Li L, et al.
Sox17 inhibits hepatocellular carcinoma progression by downregulation of KIF14 expression.
Tumour Biol. 2014; 35(11):11199-207 [PubMed] Related Publications
Sox17, an antagonist of canonical Wnt/β-catenin signaling, inhibits several malignant carcinogenesis and progression. However, little is known about Sox17 in hepatocellular carcinoma (HCC). Here, we found that Sox17 is downregulated in HCC tissue. Furthermore, Sox17 inhibits cell proliferation and migration in HCC. KIF14, a member of kinesin superfamily protein (KIFs), is an oncogene in a variety of malignant tumors including HCC. We demonstrated that Sox17 is negatively related to KIF14 expression in HCC tissue and Sox17 inhibits HCC cell proliferation and migration by transcriptional downregulation of KIF14 expression. Our results may provide a strategy for blocking HCC carcinogenesis and progression.

Tang CY, Lin J, Qian W, et al.
Low SOX17 expression: prognostic significance in de novo acute myeloid leukemia with normal cytogenetics.
Clin Chem Lab Med. 2014; 52(12):1843-50 [PubMed] Related Publications
BACKGROUND: Aberrant expression of SRY-box containing gene 17 (SOX17) has been observed in several solid tumors. However, little is known about SOX17 expression in acute myeloid leukemia (AML). The purpose of this study was to investigate the alteration of SOX17 expression and to explore its clinical significance in AML.
METHODS: Real-time quantitative PCR (RQ-PCR) was performed to analyze the status of SO1X17 expression in 103 patients with de novo AML and 26 normal controls. The clinical relevance of SOX17 expression was analyzed in AML.
RESULTS: SOX17 level in AML was significantly down-regulated compared to controls (p<0.001). Receiver operating characteristic curve (ROC) curve analysis revealed that an area under the ROC curve (AUC) of 0.834 (95% CI 0.765-0.903; p<0.0001) or 0.789 (95% CI 0.690-0.888, p<0.001) in discriminating all patients or cytogenetically normal patients from controls, respectively. The cohort of AML patients was divided into two groups according to the cut-off value of 0.017 (60% sensitivity and 100% specificity, respectively). Cytogenetically normal patients with low SOX17 expression had significantly shorter OS than those with high SOX17 expression (median 4 vs. 25 months, respectively, p=0.035). Multivariate analysis confirmed low SOX17 expression as an independent risk factor.
CONCLUSIONS: Our findings indicated that low SOX17 level may define an important risk factor in AML with normal cyotgenetics.

Kuo IY, Chang JM, Jiang SS, et al.
Prognostic CpG methylation biomarkers identified by methylation array in esophageal squamous cell carcinoma patients.
Int J Med Sci. 2014; 11(8):779-87 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is an aggressive cancer with poor prognosis. We aimed to identify a panel of CpG methylation biomarkers for prognosis prediction of ESCC patients.
METHODS: Illumina's GoldenGate methylation array, supervised principal components, Kaplan-Meier survival analyses and Cox regression model were conducted on dissected tumor tissues from a training cohort of 40 ESCC patients to identify potential CpG methylation biomarkers. Pyrosequencing quantitative methylation assay were performed to validate prognostic CpG methylation biomarkers in 61 ESCC patients. The correlation between DNA methylation and RNA expression of a validated marker, SOX17, was examined in a validation cohort of 61 ESCC patients.
RESULTS: We identified a panel of nine CpG methylation probes located at promoter or exon1 region of eight genes including DDIT3, FES, FLT3, NTRK3, SEPT5, SEPT9, SOX1, and SOX17, for prognosis prediction in ESCC patients. Risk score calculated using the eight-gene panel statistically predicted poor outcome for patients with high risk score. These eight-gene also showed a significantly higher methylation level in tumor tissues than their corresponding normal samples in all patients analyzed. In addition, we also detected an inverse correlation between CpG hypermethylation and the mRNA expression level of SOX17 gene in ESCC patients, indicating that DNA hypermethylation was responsible for decreased expression of SOX17.
CONCLUSIONS: This study established a proof-of-concept CpG methylation biomarker panel for ESCC prognosis that can be further validated by multiple cohort studies. Functional characterization of the eight prognostic methylation genes in our biomarker panel could help to dissect the mechanism of ESCC tumorigenesis.

Lee SH, Lee S, Yang H, et al.
Notch pathway targets proangiogenic regulator Sox17 to restrict angiogenesis.
Circ Res. 2014; 115(2):215-26 [PubMed] Related Publications
RATIONALE: The Notch pathway stabilizes sprouting angiogenesis by favoring stalk cells over tip cells at the vascular front. Because tip and stalk cells have different properties in morphology and function, their transcriptional regulation remains to be distinguished. Transcription factor Sox17 is specifically expressed in endothelial cells, but its expression and role at the vascular front remain largely unknown.
OBJECTIVE: To specify the role of Sox17 and its relationship with the Notch pathway in sprouting angiogenesis.
METHODS AND RESULTS: Endothelial-specific Sox17 deletion reduces sprouting angiogenesis in mouse embryonic and postnatal vascular development, whereas Sox17 overexpression increases it. Sox17 promotes endothelial migration by destabilizing endothelial junctions and rearranging cytoskeletal structure and upregulates expression of several genes preferentially expressed in tip cells. Interestingly, Sox17 expression is suppressed in stalk cells in which Notch signaling is relatively high. Notch activation by overexpressing Notch intracellular domain reduces Sox17 expression both in primary endothelial cells and in retinal angiogenesis, whereas Notch inhibition by delta-like ligand 4 (Dll4) blockade increases it. The Notch pathway regulates Sox17 expression mainly at the post-transcriptional level. Furthermore, endothelial Sox17 ablation rescues vascular network from excessive tip cell formation and hyperbranching under Notch inhibition in developmental and tumor angiogenesis.
CONCLUSIONS: Our findings demonstrate that the Notch pathway restricts sprouting angiogenesis by reducing the expression of proangiogenic regulator Sox17.

Looijenga LH, Stoop H, Biermann K
Testicular cancer: biology and biomarkers.
Virchows Arch. 2014; 464(3):301-13 [PubMed] Related Publications
The term "human germ cell tumors" (GCTs) refers to a heterogeneous group of neoplasms, all with a defined histological appearance. They have specific epidemiological characteristics, clinical behavior, and pathogenesis. Histologically, GCTs contain various tissue elements, which are homologs of normal embryogenesis. We have proposed a subclassification of GCTs in five subtypes, three of which preferentially occur in the testis. These include teratomas and yolk sac tumors of neonates and infants (type I), seminomas and nonseminomas of (predominantly) adolescents and adults (type II), and spermatocytic seminomas of the elderly (type III). Both spontaneous and induced animal models have been reported, of which the relevance for human GCTs is still to be clarified. Multidisciplinary studies have recently shed new light on the (earliest steps in the) pathogenesis of GCTs, mainly in regard of malignant type II GCTs (germ cell cancer (GCC)). This review discusses novel understanding of the pathogenesis of (mainly) GCC, focusing on identification of informative diagnostic markers suitable for application in a clinical setting. These include OCT3/4, SOX9/FOXL2, SOX17/SOX2, as well as embryonic microRNAs. These markers have been identified through studies on normal embryogenesis, specifically related to the gonads, including the germ cell lineage. Their strengths and limitations are discussed as well as the expected future approach to identify the group of individuals at highest risk for development of a GCC. The latter would allow screening of defined populations, early diagnosis, optimal follow-up, and potentially early treatment, preventing long-term side effects of systemic treatment.

Kuo IY, Wu CC, Chang JM, et al.
Low SOX17 expression is a prognostic factor and drives transcriptional dysregulation and esophageal cancer progression.
Int J Cancer. 2014; 135(3):563-73 [PubMed] Related Publications
The transcriptional network of the SRY (sex determining region Y)-box 17 (SOX17) and the prognostic impact of SOX17 protein expression in human cancers remain largely unclear. In this study, we evaluated the prognostic effect of low SOX17 protein expression and its dysregulation of transcriptional network in esophageal squamous cell carcinoma (ESCC). Low SOX17 protein expression was found in 47.4% (73 of 154) of ESCC patients with predicted poor prognosis. Re-expression of SOX17 in ESCC cells caused reduced foci formation, cell motility, decreased ESCC xenograft growth and metastasis in animals. Knockdown of SOX17 increased foci formation in ESCC and normal esophageal cells. Notably, 489 significantly differential genes involved in cell growth and motility controls were identified by expression array upon SOX17 overexpression and 47 genes contained putative SRY element in their promoters. Using quantitative chromatin immunoprecipitation-PCR and promoter activity assays, we confirmed that MACC1, MALAT1, NBN, NFAT5, CSNK1A1, FN1 and SERBP1 genes were suppressed by SOX17 via the SRY binding-mediated transcriptional regulation. Overexpression of FN1 and MACC1 abolished SOX17-mediated migration and invasion suppression. The inverse correlation between SOX17 and FN1 protein expression in ESCC clinical samples further strengthened our conclusion that FN1 is a transcriptional repression target gene of SOX17. This study provides compelling clinical evidence that low SOX17 protein expression is a prognostic biomarker and novel cell and animal data of SOX17-mediated suppression of ESCC metastasis. We establish the first transcriptional network and identify new suppressive downstream genes of SOX17 which can be potential therapeutic targets for ESCC.

Voorham QJ, Janssen J, Tijssen M, et al.
Promoter methylation of Wnt-antagonists in polypoid and nonpolypoid colorectal adenomas.
BMC Cancer. 2013; 13:603 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Nonpolypoid adenomas are a subgroup of colorectal adenomas that have been associated with a more aggressive clinical behaviour compared to their polypoid counterparts. A substantial proportion of nonpolypoid and polypoid adenomas lack APC mutations, APC methylation or chromosomal loss of the APC locus on chromosome 5q, suggesting the involvement of other Wnt-pathway genes. The present study investigated promoter methylation of several Wnt-pathway antagonists in both nonpolypoid and polypoid adenomas.
METHODS: Quantitative methylation-specific PCR (qMSP) was used to evaluate methylation of four Wnt-antagonists, SFRP2, WIF-1, DKK3 and SOX17 in 18 normal colorectal mucosa samples, 9 colorectal cancer cell lines, 18 carcinomas, 44 nonpolypoid and 44 polypoid adenomas. Results were integrated with previously obtained data on APC mutation, methylation and chromosome 5q status from the same samples.
RESULTS: Increased methylation of all genes was found in the majority of cell lines, adenomas and carcinomas compared to normal controls. WIF-1 and DKK3 showed a significantly lower level of methylation in nonpolypoid compared to polypoid adenomas (p < 0.01). Combining both adenoma types, a positive trend between APC mutation and both WIF-1 and DKK3 methylation was observed (p < 0.05).
CONCLUSIONS: Methylation of Wnt-pathway antagonists represents an additional mechanism of constitutive Wnt-pathway activation in colorectal adenomas. Current results further substantiate the existence of partially alternative Wnt-pathway disruption mechanisms in nonpolypoid compared to polypoid adenomas, in line with previous observations.

Chen YC, Huang RL, Huang YK, et al.
Methylomics analysis identifies epigenetically silenced genes and implies an activation of β-catenin signaling in cervical cancer.
Int J Cancer. 2014; 135(1):117-27 [PubMed] Related Publications
Using DNA methylation biomarkers in cancer detection is a potential direction in clinical testing. Some methylated genes have been proposed for cervical cancer detection; however, more reliable methylation markers are needed. To identify new hypermethylated genes in the discovery phase, we compared the methylome between a pool of DNA from normal cervical epithelium (n = 19) and a pool of DNA from cervical cancer tissues (n = 38) using a methylation bead array. We integrated the differentially methylated genes with public gene expression databases, which resulted in 91 candidate genes. Based on gene expression after demethylation treatment in cell lines, we confirmed 61 genes for further validation. In the validation phase, quantitative MSP and bisulfite pyrosequencing were used to examine their methylation level in an independent set of clinical samples. Fourteen genes, including ADRA1D, AJAP1, COL6A2, EDN3, EPO, HS3ST2, MAGI2, POU4F3, PTGDR, SOX8, SOX17, ST6GAL2, SYT9, and ZNF614, were significantly hypermethylated in CIN3+ lesions. The sensitivity, specificity, and accuracy of POU4F3 for detecting CIN3+ lesions were 0.88, 0.82, and 0.85, respectively. A bioinformatics function analysis revealed that AJAP1, EDN3, EPO, MAGI2, and SOX17 were potentially implicated in β-catenin signaling, suggesting the epigenetic dysregulation of this signaling pathway during cervical cancer development. The concurrent methylation of multiple genes in cancers and in subsets of precancerous lesions suggests the presence of a driver of methylation phenotype in cervical carcinogenesis. Further validation of these new genes as biomarkers for cervical cancer screening in a larger population-based study is warranted.

Wang LS, Kuo CT, Huang TH, et al.
Black raspberries protectively regulate methylation of Wnt pathway genes in precancerous colon tissue.
Cancer Prev Res (Phila). 2013; 6(12):1317-27 [PubMed] Free Access to Full Article Related Publications
Ulcerative colitis is frequently an intermediate step to colon cancer. The interleukin-10 knockout mouse is a genetic model of this progression. We report that knockout mice fed 5% black raspberries (BRB) had significantly less colonic ulceration as compared with knockout mice that consumed the control diet. Dysfunction of the Wnt signaling pathway is a key event in ulcerative colitis-associated colon carcinogenesis. Therefore, we investigated the effects of BRBs on the Wnt pathway and found that the BRB-fed knockout mice exhibited a significantly lower level of β-catenin nuclear translocation. We followed-up this observation by evaluating the effect of BRBs on selected Wnt pathway antagonists. The mRNA expression levels of wif1, sox17, and qki were diminished in the knockout mice, whereas they were expressed at normal levels in knockout mice that were fed BRBs. The lower mRNA expression of these genes in the colon from the knockout mice correlated with hypermethylation of their promoter regions; BRBs decreased their promoter methylation and increased mRNA expression of these genes. This hypomethylation was associated with elevated protein expression of key proteins/enzymes that augment methylation, for example, dnmt3b, hdac1, hdac2, and mbd2 in the knockout mice; in addition, BRBs decreased the protein expression of these proteins/enzymes. The knockout mouse model recapitulates what occurs in human ulcerative colitis. Promoter methylation of CDH1 and SFRP1 was significantly higher in human ulcerative colitis tissues compared with their adjacent normal tissues. In conclusion, our results suggest that BRBs inhibit colonic ulceration and, ultimately, colon cancer partly through inhibiting aberrant epigenetic events that dysregulate Wnt signaling.

Pula B, Olbromski M, Wojnar A, et al.
Impact of SOX18 expression in cancer cells and vessels on the outcome of invasive ductal breast carcinoma.
Cell Oncol (Dordr). 2013; 36(6):469-83 [PubMed] Related Publications
PURPOSE: SOX18 is a transcription factor known to be involved in hair follicle, blood and lymphatic vessel development, as well as wound healing processes (together with SOX7 and SOX17). In addition, it has been reported that SOX18 may affect the growth of cancer cells in vitro. Until now, the exact role of SOX18 expression in invasive ductal breast carcinoma (IDC) has remained unknown.
METHODS: In this study, we have investigated SOX18 expression in cancer cells and endothelial cells in 122 IDC samples using immunohistochemistry (IHC). SOX18 expression was also determined using real-time PCR and Western blotting in a series of breast cancer-derived cell lines (i.e., MCF-7, BT-474, SK-BR-3, MDA-MB-231, BO2).
RESULTS: Using IHC, we observed SOX18 nuclear expression in cancer cells, as well as in blood and lymphatic vessels of the IDC samples tested. SOX18 expression in the IDC samples correlated with a higher malignancy grade (Grade 2 and Grade 3 versus Grade 1; p = 0.02 and p = 0.009, respectively) and VEGF-D expression (r = 0.27, p = 0.007). SOX18 expression was also associated with HER2 positivity (p = 0.02). A significantly higher SOX18 expression was found in the HER2-positive cell line BT-474, and a significantly lower expression in the triple negative cell lines MDA-MB-231 and BO2. Laser capture microdissection of IDC samples revealed significantly higher mRNA SOX7, SOX17 and SOX18 expression levels in the vessels as compared to the cancer cells (p = 0.02 and p = 0.0002, p < 0.0001, respectively). SOX18 positive intratumoral and peritumoral microvessel counts (MVC) were associated with higher malignancy grades (p = 0.04 and p = 0.02, respectively). Moreover, peritumoral SOX18 positive MVC were found to act as an independent marker for a poor prognosis (p = 0.04).
CONCLUSION: SOX18 expression may serve as a marker for a poor prognosis in IDC.

Babic AM, Jang S, Nicolov E, et al.
Culture of mouse amniotic fluid-derived cells on irradiated STO feeders results in the generation of primitive endoderm cell lines capable of self-renewal in vitro.
Cells Tissues Organs. 2013; 198(2):111-26 [PubMed] Free Access to Full Article Related Publications
The cells present in amniotic fluid (AF) are currently used for prenatal diagnosis of fetal anomalies but are also a potential source of cells for cell therapy. To better characterize putative progenitor cell populations present in AF, we used culture conditions that support self-renewal to determine if these promoted the generation of stable cell lines from AF-derived cells (AFC). Cells isolated from E11.5 mouse were cultured on irradiated STO fibroblast feeder layers in human embryonic germ cell derivation conditions. The cultures grew multicellular epithelial colonies that could be repropagated from single cells. Reverse transcription semiquantitative polymerase chain reaction of established cell lines revealed that they belonged to the extraembryonic endoderm (ExEn) expressing high levels of Gata6, Gata4, Sox17, Foxa2 and Sox7 mRNA. Hierarchical clustering based on the whole transcriptome expression profile of the AFC lines (AFCL) shows significant correlation between transcription profiles of AFCL and blastocyst-derived XEN, an ExEn cell line. In vitro differentiation of AFCL results in the generation of cells expressing albumin and α-fetoprotein (AFP), while intramuscular injection of AFCL into immunodeficient mice produced AFP-positive tumors with primitive endodermal appearance. Hence, E11.5 mouse AF contains cells that efficiently produce XEN lines. These AF-derived XEN lines do not spontaneously differentiate into embryonic-type cells but are phenotypically stable and have the capacity for extensive expansion. The lack of requirement for reprogramming factors to turn AF-derived progenitor cells into stable cell lines capable of massive expansion together with the known ability of ExEn to contribute to embryonic tissue suggests that this cell type may be a candidate for banking for cell therapies.

Goeppert B, Konermann C, Schmidt CR, et al.
Global alterations of DNA methylation in cholangiocarcinoma target the Wnt signaling pathway.
Hepatology. 2014; 59(2):544-54 [PubMed] Related Publications
UNLABELLED: The molecular mechanisms underlying the genesis of cholangiocarcinomas (CCs) are poorly understood. Epigenetic changes such as aberrant hypermethylation and subsequent atypical gene expression are characteristic features of most human cancers. In CC, data regarding global methylation changes are lacking so far. We performed a genome-wide analysis for aberrant promoter methylation in human CCs. We profiled 10 intrahepatic and 8 extrahepatic CCs in comparison to non-neoplastic biliary tissue specimens, using methyl-CpG immunoprecipitation (MCIp) combined with whole-genome CpG island arrays. DNA methylation was confirmed by quantitative mass spectrometric analysis and functional relevance of promoter hypermethylation was shown in demethylation experiments of two CC cell lines using 5-aza-2'deoxycytidine (DAC) treatment. Immunohistochemical staining of tissue microarrays (TMAs) from 223 biliary tract cancers (BTCs) was used to analyze candidate gene expression at the protein level. Differentially methylated, promoter-associated regions were nonrandomly distributed and enriched for genes involved in cancer-related pathways including Wnt, transforming growth factor beta (TGF-β), and PI3K signaling pathways. In CC cell lines, silencing of genes involved in Wnt signaling, such as SOX17, WNT3A, DKK2, SFRP1, SFRP2, and SFRP4 was reversed after DAC administration. Candidate protein SFRP2 was substantially down-regulated in neoplastic tissues of all BTC subtypes as compared to normal tissues. A significant inverse correlation of SFRP2 protein expression and pT status was found in BTC patients.
CONCLUSION: We provide a comprehensive analysis to define the genome-wide methylation landscape of human CC. Several candidate genes of cancer-relevant signaling pathways were identified, and closer analysis of selected Wnt pathway genes confirmed the relevance of this pathway in CC. The presented global methylation data are the basis for future studies on epigenetic changes in cholangiocarcinogenesis.

Van Der Zwan YG, Stoop H, Rossello F, et al.
Role of epigenetics in the etiology of germ cell cancer.
Int J Dev Biol. 2013; 57(2-4):299-308 [PubMed] Related Publications
Embryonic development is strictly controlled by functionality of genes in which the existing networks can act both on transcription and translation regulation. Germ cell cancers (GCC) are unique because of a number of characteristics. In spite of their clinical presentation, i.e., predominantly after puberty, they arise from primordial germ cells/gonocytes that have failed appropriate maturation to either pre-spermatogonia or oogonia. GCC mimic embryonal development to a certain extent, including capacity for totipotency. This knowledge has allowed the identification of informative diagnostic markers, including OCT3/4 (POU5F1), SOX2 and SOX17. An additional marker is the overall demethylated status of the genome. Genetic mutations in GCC are rare, which is exceptional for solid cancers. Our hypothesis is that a disturbed epigenetic regulation (through combined interaction of genetic or environmental parameters; referred to as genvironment) affect embryonic germ cell development, resulting in delayed or blocked maturation, and potentially progression to GCC. In this respect, studies of patients with Disorders of Sex Development (DSD) have increased our knowledge significantly. Genvironmental influences can lead to retention of existence of embryonic germ cells, the first step in the pathogenesis of GCC, resulting into the precursor lesions gonadoblastoma or carcinoma in situ. Identification of epigenetic alterations could lead to better understanding these processes and development of specific markers for early detection, eventually leading to development of targeted treatment. This review describes an interactive model related to the role of epigenetics in GCC pathogenesis, focusing on DNA methylation, histone modifications, epigenetic memory and inheritance, as well as environmental factors.

Balgkouranidou I, Karayiannakis A, Matthaios D, et al.
Assessment of SOX17 DNA methylation in cell free DNA from patients with operable gastric cancer. Association with prognostic variables and survival.
Clin Chem Lab Med. 2013; 51(7):1505-10 [PubMed] Related Publications
BACKGROUND: DNA methylation represents one of the most common epigenetic changes in human cancer providing important information regarding carcinogenesis. A possible role as a prognostic indicator has also been proposed. The aim of our study was to evaluate the prognostic significance of SOX17 promoter methylation status in patients with operable gastric cancer.
METHODS: Using methylation-specific PCR (MSP) we examined the incidence and prognostic significance of SOX17 methylation status in cell free circulating DNA in the serum of 73 patients with operable gastric cancer. Fifty-one patients were male (69.9%), their median age was 65 years, 43 patients (58.9%) had regional lymph node involvement and all had a Performance Status (WHO) of 0-1.
RESULTS: SOX17 promoter was found to be methylated in 43 out of 73 gastric cancer serum samples examined (58.9%). All 20 control serum samples from healthy individuals were negative. Overall survival (OS) was found to be significantly associated with SOX17 methylation (p=0.049). A significant correlation between methylation status and differentiation (p=0.031) was also observed. No other significant associations between different tumor parameters examined and SOX17 methylation status were observed.
CONCLUSIONS: SOX17 promoter methylation in cell free DNA of patients with operable gastric cancer is a frequent event and may provide important information regarding prognosis in this group of patients.

Russell SM, Lechner MG, Mokashi A, et al.
Establishment and characterization of a new human extragonadal germ cell line, SEM-1, and its comparison with TCam-2 and JKT-1.
Urology. 2013; 81(2):464.e1-9 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: To describe the establishment and characterization of a human cell line, SEM-1, from a patient diagnosed with a mediastinal seminoma.
METHODS: A small percentage of germ cell tumors develop as primary lesions in extragonadal sites, and the etiology of these tumors is poorly understood. Currently, only 2 cell lines from seminoma patients have been reported, JKT-1 and TCam-2, both derived from the testis. The cell line was characterized by heterotransplantation in Nude mice, cytogenetic studies, immunohistochemical and flow cytometry staining for germ cell tumor biomarkers, quantitative reverse-transcription polymerase chain reaction for cancer testis antigen expression, and BRAF mutation screening with quantitative polymerase chain reaction.
RESULTS: Characterization studies confirmed the human extragonadal seminoma origin of SEM-1 and demonstrated that it had more features in common with TCam-2 than JKT-1. Specifically, SEM-1 was positive for Sal-like protein 4 (SALL-4), activator protein-2γ (AP-2γ), and cytokeratin CAM5.2, and demonstrated heterogeneous expression of stem cell markers octamer-binding transcription factor 3/4, NANOG, c-KIT, SOX17, and SOX2. Cytogenetic analysis revealed a hypotriploid chromosome number, with multiple copies of 12p, but isochromosome 12p and the BRAF mutation V600E were not identified. The cell lines also did not contain the BRD4/NUT gene rearrangement [t(15,19)] seen in midline carcinomas nor did they contain overexpressed nuclear protein in testis (NUT) genes.
CONCLUSION: SEM-1 is the first cell line derived from an extragonadal germ cell tumor showing intermediate characteristics between seminoma and nonseminoma, and as such, is an important model to study the molecular pathogenesis of this malignancy.

Yang H, Lee S, Lee S, et al.
Sox17 promotes tumor angiogenesis and destabilizes tumor vessels in mice.
J Clin Invest. 2013; 123(1):418-31 [PubMed] Free Access to Full Article Related Publications
Little is known about the transcriptional regulation of tumor angiogenesis, and tumor ECs (tECs) remain poorly characterized. Here, we studied the expression pattern of the transcription factor Sox17 in the vasculature of murine and human tumors and investigated the function of Sox17 during tumor angiogenesis using Sox17 genetic mouse models. Sox17 was specifically expressed in tECs in a heterogeneous pattern; in particular, strong Sox17 expression distinguished tECs with high VEGFR2 expression. Whereas overexpression of Sox17 in tECs promoted tumor angiogenesis and vascular abnormalities, Sox17 deletion in tECs reduced tumor angiogenesis and normalized tumor vessels, inhibiting tumor growth. Tumor vessel normalization by Sox17 deletion was long lasting, improved anticancer drug delivery into tumors, and inhibited tumor metastasis. Sox17 promoted endothelial sprouting behavior and upregulated VEGFR2 expression in a cell-intrinsic manner. Moreover, Sox17 increased the percentage of tumor-associated CD11b+Gr-1+ myeloid cells within tumors. The vascular effects of Sox17 persisted throughout tumor growth. Interestingly, Sox17 expression specific to tECs was also observed in highly vascularized human glioblastoma samples. Our findings establish Sox17 as a key regulator of tumor angiogenesis and tumor progression.

Chimonidou M, Strati A, Malamos N, et al.
SOX17 promoter methylation in circulating tumor cells and matched cell-free DNA isolated from plasma of patients with breast cancer.
Clin Chem. 2013; 59(1):270-9 [PubMed] Related Publications
INTRODUCTION: Detection of circulating tumor cells (CTCs) and cell-free DNA (cfDNA) in the peripheral blood of patients with solid tumors has been widely studied for the early detection of metastatic spread. We evaluated whether there was an association between the origin of cfDNA and CTCs. We investigated whether SRY (sex determining region Y)-box 17 (SOX17) promoter methylation in CTCs was associated with the methylation pattern of this gene in matched cfDNA isolated from plasma of patients with breast cancer.
METHODS: We examined SOX17 methylation in 79 primary breast tumors, in 114 paired samples of DNA isolated from CTCs and cfDNA, and in 60 healthy individuals. Isolated DNA was modified by sodium bisulfite and subjected to methylation specific PCR.
RESULTS: The SOX17 promoter was methylated in 68 (86.0%) of 79 of primary breast tumors. In CTCs, SOX17 was methylated in 19 (34.5%) of 55 patients with early breast cancer, 27 (45.8%) of 59 patients with metastatic cancer, and 1 (4.3%) of 23 healthy individuals, whereas in matched cfDNA SOX17 was methylated in 19 (34.5%) of 55, 24 (40.7%) of 59, and 1 (2.0%) of 49 of these same groups, respectively. There was a significant correlation between SOX17 methylation in cfDNA and CTCs in patients with early breast cancer (P = 0.008), but not in patients with verified metastasis (P = 0.283).
CONCLUSIONS: The SOX17 promoter is highly methylated in primary breast tumors, in CTCs isolated from patients with breast cancer, and in corresponding cfDNA samples. Our findings indicate a direct connection between the presence of CTCs and cfDNA in patients with operable breast cancer, after surgical removal of the primary tumor.

Li JY, Han C, Zheng LL, Guo MZ
Epigenetic regulation of Wnt signaling pathway gene SRY-related HMG-box 17 in papillary thyroid carcinoma.
Chin Med J (Engl). 2012; 125(19):3526-31 [PubMed] Related Publications
BACKGROUND: SRY-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.
METHODS: The 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.
RESULTS: Loss 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.
CONCLUSIONS: SOX17 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.

Chiyomaru T, Yamamura S, Zaman MS, et al.
Genistein suppresses prostate cancer growth through inhibition of oncogenic microRNA-151.
PLoS One. 2012; 7(8):e43812 [PubMed] Free Access to Full Article Related Publications
Genistein has been shown to suppress the growth of several cancers through modulation of various pathways. However, the effects of genistein on the regulation of oncogenic microRNA-151 (miR-151) have not been reported. In this study, we investigated whether genistein could alter the expression of oncogenic miR-151 and its target genes that are involved in the progression and metastasis of prostate cancer (PCa). Real-time RT-PCR showed that the expression of miR-151 was higher in PC3 and DU145 cells compared with RWPE-1 cells. Treatment of PC3 and DU145 cells with 25 µM genistein down-regulated the expression of miR-151 compared with vehicle control. Inhibition of miR-151 in PCa cells by genistein significantly inhibited cell migration and invasion. In-silico analysis showed that several genes (CASZ1, IL1RAPL1, SOX17, N4BP1 and ARHGDIA) suggested to have tumor suppressive functions were target genes of miR-151. Luciferase reporter assays indicated that miR-151 directly binds to specific sites on the 3'UTR of target genes. Quantitative real-time PCR analysis showed that the mRNA expression levels of the five target genes in PC3 and DU145 were markedly changed with miR-151 mimics and inhibitor. Kaplan-Meier curves and log-rank tests revealed that high expression levels of miR-151 had an adverse effect on survival rate. This study suggests that genistein mediated suppression of oncogenic miRNAs can be an important dietary therapeutic strategy for the treatment of PCa.

Jia Y, Yang Y, Zhan Q, et al.
Inhibition of SOX17 by microRNA 141 and methylation activates the WNT signaling pathway in esophageal cancer.
J Mol Diagn. 2012; 14(6):577-85 [PubMed] Related Publications
In this study, we explored the possibility of SOX17 promoter region methylation as an esophageal cancer detection marker, the regulation of SOX17 expression, and the function of SOX17 in the WNT signaling pathway in esophageal cancer. Eight esophageal cancer cell lines, 9 normal esophageal mucosa samples, 60 cases of dysplasia, and 169 cancer tissue samples were included. Methylation-specific PCR, semiquantitative reverse transcription-PCR, immunohistochemistry, luciferase reporter assay, colony formation, and Western blot analysis were used to analyze methylation and function of SOX17 in esophageal cancer. MicroRNA-related detection methods were performed to evaluate microRNA regulation of SOX17. SOX17 methylation was found in progression tendency with 0% of normal mucosa, 39% of grade 1 dysplasia, 48% of grades 2 and 3 dysplasia, and 65% of primary cancer. SOX17 methylation is related to esophageal cancer patients' history of alcohol use and may induce β-catenin expression and redistribution. Loss of SOX17 expression is correlated to promoter region hypermethylation, and re-expression was activated by 5-aza-2'-deoxycytidine treatment in esophageal cancer cell lines. Restoration of SOX17 expression suppresses TCF/β-catenin-dependent transcription and colony formation. MicroRNA 141 was also found to down-regulate SOX17 expression and activate the WNT signal pathway. SOX17 is frequently methylated in esophageal cancer and in a progression tendency during esophageal carcinogenesis. Loss of SOX17 removes the normal inhibition of WNT signaling and promotes esophageal tumorigenesis.

Yin D, Jia Y, Yu Y, et al.
SOX17 methylation inhibits its antagonism of Wnt signaling pathway in lung cancer.
Discov Med. 2012; 14(74):33-40 [PubMed] Free Access to Full Article Related Publications
The purpose of this study was to explore epigenetic changes and functions of SOX17 in human lung cancer. Five lung cancer cell lines and 88 primary lung cancer samples were examined in this study. Methylation-specific polymerase chain reaction (MSP), semi-quantitative reverse-transcription PCR, immunohistochemistry, luciferase reporter assays, colony-formation assays, and western blotting were used to analyze methylation changes and functions of SOX17 in lung cancer. SOX17 methylation was found in 60.2% of primary human lung cancer samples, and promoter region methylation of SOX17 silenced its expression. SOX17 methylation was associated with female patients and lung cancer differentiation. Colony-formation assays revealed that SOX17 suppressed lung cancer cell proliferation. Re-expression of SOX17 inhibited Wnt signaling in H23 lung cancer cell line. SOX17 acts as a Wnt signaling inhibitor.

Fischedick G, Klein DC, Wu G, et al.
Zfp296 is a novel, pluripotent-specific reprogramming factor.
PLoS One. 2012; 7(4):e34645 [PubMed] Free Access to Full Article Related Publications
Expression of the four transcription factors Oct4, Sox2, Klf4, and c-Myc (OSKM) is sufficient to reprogram somatic cells into induced pluripotent stem (iPSCs). However, this process is slow and inefficient compared with the fusion of somatic cells with embryonic stem cells (ESCs), indicating that ESCs express additional factors that can enhance the efficiency of reprogramming. We had previously developed a method to detect and isolate early neural induction intermediates during the differentiation of mouse ESCs. Using the gene expression profiles of these intermediates, we identified 23 ESC-specific transcripts and tested each for the ability to enhance iPSC formation. Of the tested factors, zinc finger protein 296 (Zfp296) led to the largest increase in mouse iPSC formation. We confirmed that Zfp296 was specifically expressed in pluripotent stem cells and germ cells. Zfp296 in combination with OSKM induced iPSC formation earlier and more efficiently than OSKM alone. Through mouse chimera and teratoma formation, we demonstrated that the resultant iPSCs were pluripotent. We showed that Zfp296 activates transcription of the Oct4 gene via the germ cell-specific conserved region 4 (CR4), and when overexpressed in mouse ESCs leads to upregulation of Nanog expression and downregulation of the expression of differentiation markers, including Sox17, Eomes, and T, which is consistent with the observation that Zfp296 enhances the efficiency of reprogramming. In contrast, knockdown of Zfp296 in ESCs leads to the expression of differentiation markers. Finally, we demonstrated that expression of Zfp296 in ESCs inhibits, but does not block, differentiation into neural cells.

Hong SM, Omura N, Vincent A, et al.
Genome-wide CpG island profiling of intraductal papillary mucinous neoplasms of the pancreas.
Clin Cancer Res. 2012; 18(3):700-12 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Intraductal papillary mucinous neoplasms (IPMN) are precursors to infiltrating pancreatic ductal adenocarcinomas. Widespread epigenetic alterations are characteristic of many cancers, yet few studies have systematically analyzed epigenetic alterations of neoplastic precursors. Our goal was to conduct genome-wide CpG island methylation profiling to identify aberrantly methylated loci in IPMNs.
EXPERIMENTAL DESIGN: We compared the CpG island methylation profiles of six IPMNs to normal primary pancreatic duct samples using methylation CpG island amplification (MCA) and Agilent CpG island microarray (MCAM) analysis. When selected 13 genes identified as differentially methylated by MCAM for methylation-specific PCR (MSP) analysis in an independent set of IPMNs and normal pancreas samples and conducted expression analysis of selected genes.
RESULTS: We identified 2,259 loci as differentially methylated in at least one of six IPMNs including 245 genes hypermethylated in IPMNs with high-grade dysplasia compared with normal pancreatic duct samples. Eleven of 13 genes evaluated by MSP were more commonly methylated in 61 IPMNs than in 43 normal pancreas samples. Several genes (BNIP3, PTCHD2, SOX17, NXPH1, EBF3) were significantly more likely to be methylated in IPMNs with high-grade than with low-grade dysplasia. One gene, SOX17, showed loss of protein expression by immunohistochemistry in 22% (19 of 88) of IPMNs. The most specific marker, BNIP3, was not methylated in any IPMNs with low-grade dysplasia or in normal pancreas samples.
CONCLUSIONS: IPMNs undergo extensive aberrant CpG island hypermethylation. The detection of genes selectively methylated in high-grade IPMNs such as BNIP3 may have use in the clinical evaluation of IPMNs.

Oishi Y, Watanabe Y, Yoshida Y, et al.
Hypermethylation of Sox17 gene is useful as a molecular diagnostic application in early gastric cancer.
Tumour Biol. 2012; 33(2):383-93 [PubMed] Related Publications
Although minimal invasive treatment is widely accepted in the early stages of gastric cancer (GCa), we still do not have any appropriate risk markers to detect residual neoplasia and the potential for recurrence. We previously reported that aberrant DNA methylation is an early and frequent process in gastric carcinogenesis and could be useful for the detection of gastric neoplasia. Our goal is to find and identify some candidate genes, using genome-wide DNA methylation analysis, as a treatment marker for early gastric cancer (EGC). We performed methylated CpG island amplification microarray analysis using 12 gastric washes (six each of pre- and post-endoscopic treatment in each of the same patients). We finally focused on Sox17 gene. We examined the DNA methylation status of Sox17 in a validation set consisting of 128 wash samples (pre, 64; post, 64) at EGC. We next carried out functional studies to identify Sox17. Sox17 showed significant differential methylation between pre- and post-treatments in EGC patients (Sox17, p < 0.0001). Moreover, treating GCa cells that lacked Sox17 expression with a methyltransferase inhibitor, 5-aza-2'-deoxycytidine, restored the gene's expression. Additionally, the introduction of exogenous Sox17 into silenced cells suppressed colony formation. Gastric wash-based DNA methylation analysis could be useful for early detection of recurrence following endoscopic resection in EGC patients. Our data suggest that the silencing of Sox17 occurs frequently in EGC and may play a key role in the development and progression of the disease.

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