SOX17

Gene Summary

Gene:SOX17; SRY-box transcription factor 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, HGNC, Ensembl, GeneCard, Gene
Protein:transcription factor SOX-17
Source:NCBIAccessed: 31 August, 2019

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 (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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)

Kuo IY, Huang YL, Lin CY, et al.
SOX17 overexpression sensitizes chemoradiation response in esophageal cancer by transcriptional down-regulation of DNA repair and damage response genes.
J Biomed Sci. 2019; 26(1):20 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Prognosis of esophageal squamous cell carcinoma (ESCC) patients is poor and the concurrent chemoradiation therapy (CCRT) provided to ESCC patients often failed due to resistance. Therefore, development of biomarkers for predicting CCRT response is immensely important. In this study, we evaluated the predicting value of SRY (sex determining region Y)-box 17 (SOX17) protein during CCRT and its dysregulation of transcriptional targets in CCRT resistance in ESCC.
METHODS: Pyrosequencing methylation, RT-qPCR and immunohistochemistry assays were performed to examine the DNA methylation, mRNA expression and protein expression levels of SOX17 in endoscopic biopsy from a total of 70 ESCC patients received CCRT. Cell proliferation, clonogenic survival and xenograft growth were used to confirm the sensitization of ESCC cell line KYSE510 in response to cisplatin, radiation or CCRT treatment by SOX17 overexpression in vitro and in vivo. Luciferase activity, RT-qPCR and ChIP-qPCR assays were conducted to examine transcription regulation of SOX17 in KYSE510 parental, KYSE510 radio-resistant cells and their derived xenografts.
RESULTS: High DNA methylation coincided with low mRNA and protein expression levels of SOX17 in pre-treatment endoscopic biopsy from ESCC patients with poor CCRT response. SOX17 protein expression exhibited a good prediction performance in discriminating poor CCRT responders from good responder. Overexpression of SOX17 sensitized KYSE510 radio-resistant cells to cisplatin, radiation or CCRT treatment in cell and xenograft models. Importantly, SOX17 transcriptionally down-regulated DNA repair and damage response-related genes including BRCA1, BRCA2, RAD51, KU80 DNAPK, p21, SIRT1, NFAT5 and REV3L in KYSE510 radio-resistant cells to achieve the sensitization effect to anti-cancer treatment. Low expression of BRCA1, DNAPK, p21, RAD51 and SIRT1 was confirmed in SOX17 sensitized xenograft tissues derived from radio-resistant ESCC cells.
CONCLUSIONS: Our study reveals a novel mechanism by which SOX17 transcriptionally inactivates DNA repair and damage response-related genes to sensitize ESCC cell or xenograft to CCRT treatment. In addition, we establish a proof-of-concept CCRT prediction biomarker using SOX17 immunohistochemical staining in pre-treatment endoscopic biopsies to identify ESCC patients who are at high risk of CCRT failure and need intensive care.

Panagopoulou M, Karaglani M, Balgkouranidou I, et al.
Circulating cell-free DNA in breast cancer: size profiling, levels, and methylation patterns lead to prognostic and predictive classifiers.
Oncogene. 2019; 38(18):3387-3401 [PubMed] Related Publications
Blood circulating cell-free DNA (ccfDNA) is a suggested biosource of valuable clinical information for cancer, meeting the need for a minimally-invasive advancement in the route of precision medicine. In this paper, we evaluated the prognostic and predictive potential of ccfDNA parameters in early and advanced breast cancer. Groups consisted of 150 and 16 breast cancer patients under adjuvant and neoadjuvant therapy respectively, 34 patients with metastatic disease and 35 healthy volunteers. Direct quantification of ccfDNA in plasma revealed elevated concentrations correlated to the incidence of death, shorter PFS, and non-response to pharmacotherapy in the metastatic but not in the other groups. The methylation status of a panel of cancer-related genes chosen based on previous expression and epigenetic data (KLK10, SOX17, WNT5A, MSH2, GATA3) was assessed by quantitative methylation-specific PCR. All but the GATA3 gene was more frequently methylated in all the patient groups than in healthy individuals (all p < 0.05). The methylation of WNT5A was statistically significantly correlated to greater tumor size and poor prognosis characteristics and in advanced stage disease with shorter OS. In the metastatic group, also SOX17 methylation was significantly correlated to the incidence of death, shorter PFS, and OS. KLK10 methylation was significantly correlated to unfavorable clinicopathological characteristics and relapse, whereas in the adjuvant group to shorter DFI. Methylation of at least 3 or 4 genes was significantly correlated to shorter OS and no pharmacotherapy response, respectively. Classification analysis by a fully automated, machine learning software produced a single-parametric linear model using ccfDNA plasma concentration values, with great discriminating power to predict response to chemotherapy (AUC 0.803, 95% CI [0.606, 1.000]) in the metastatic group. Two more multi-parametric signatures were produced for the metastatic group, predicting survival and disease outcome. Finally, a multiple logistic regression model was constructed, discriminating between patient groups and healthy individuals. Overall, ccfDNA emerged as a highly potent predictive classifier in metastatic breast cancer. Upon prospective clinical evaluation, all the signatures produced could aid accurate prognosis.

Yang F, Xiao Z, Zhang S
Knockdown of miR-194-5p inhibits cell proliferation, migration and invasion in breast cancer by regulating the Wnt/β-catenin signaling pathway.
Int J Mol Med. 2018; 42(6):3355-3363 [PubMed] Free Access to Full Article Related Publications
Breast cancer is a major public health concern, due to its increasing incidence and limited effective treatment. The present study aimed to investigate the expression of microRNA (miR)‑194‑5p and its roles in breast cancer. The expression levels of miR‑194‑5p and SRY‑box 17 (SOX17) mRNA were detected in breast cancer tissues and cell lines by reverse transcription‑quantitative polymerase chain reaction. The protein expression levels were determined by western blotting. In addition, MTT, colony formation, scratch and Transwell assays were use to evaluate the characteristics of MCF‑7 cells with miR‑194‑5p knockdown. The target verification of miR‑194‑5p was determined by luciferase reporter assay. Furthermore, tumor‑bearing nude mice with miR‑194‑5p knockdown were used to assess the effects of miR‑194‑5p on tumor activity. In breast cancer tissues, miR‑194‑5p was upregulated, whereas SOX17 was downregulated. In addition, the expression levels of SOX17 and phosphorylated (p)‑β‑catenin in the cytosol and nucleus were increased in the miR‑194‑5p inhibitor group. In addition, cell proliferation, migration and invasion were inhibited in response to miR‑194‑5p knockdown. The luciferase reporter assay confirmed that SOX17 was a target gene of miR‑194‑5p. In the mouse studies, knockdown of miR‑194‑5p suppressed tumor growth and promoted SOX17 expression in nude mice with breast cancer. These findings suggested that knockdown of miR‑194‑5p may increase the expression of SOX17 and regulate the Wnt/β‑catenin signaling pathway in breast cancer cells; therefore, miR‑194‑5p may be considered a potential target for breast cancer prevention.

Kim IK, Kim K, Lee E, et al.
Sox7 promotes high-grade glioma by increasing VEGFR2-mediated vascular abnormality.
J Exp Med. 2018; 215(3):963-983 [PubMed] Free Access to Full Article Related Publications
High-grade glioma (HGG) is highly angiogenic, but antiangiogenic therapy has transient clinical benefit in only a fraction of patients. Vascular regulators of these heterogeneous responses remain undetermined. We found up-regulation of Sox7 and down-regulation of Sox17 in tumor endothelial cells (tECs) in mouse HGG.

Um SW, Kim HK, Kim Y, et al.
Bronchial biopsy specimen as a surrogate for DNA methylation analysis in inoperable lung cancer.
Clin Epigenetics. 2017; 9:131 [PubMed] Free Access to Full Article Related Publications
Background: This study was aimed at understanding whether bronchial biopsy specimen can be used as a surrogate for DNA methylation analysis in surgically resected lung cancer.
Methods: A genome-wide methylation was analyzed in 42 surgically resected tumor tissues, 136 bronchial washing, 12 sputum, and 8 bronchial biopsy specimens using the Infinium HumanMethylation450 BeadChip, and models for prediction of lung cancer were evaluated using TCGA lung cancer data.
Results: Four thousand seven hundred and twenty-six CpGs (
Conclusions: The present study suggests that bronchial biopsy specimen may be used as a surrogate for DNA methylation analysis in patient with inoperable lung cancer.

Liu D, Peng H, Sun Q, et al.
The Indirect Efficacy Comparison of DNA Methylation in Sputum for Early Screening and Auxiliary Detection of Lung Cancer: A Meta-Analysis.
Int J Environ Res Public Health. 2017; 14(7) [PubMed] Free Access to Full Article Related Publications
BACKGROUND: DNA methylation in sputum has been an attractive candidate biomarker for the non-invasive screening and detection of lung cancer.
MATERIALS AND METHODS: Databases including PubMed, Ovid, Cochrane library, Web of Science databases, Chinese Biological Medicine (CBM), Chinese National Knowledge Infrastructure (CNKI), Wanfang, Vip Databases and Google Scholar were searched to collect the diagnostic trials on aberrant DNA methylation in the screening and detection of lung cancer published until 1 December 2016. Indirect comparison meta-analysis was used to evaluate the diagnostic value of the included candidate genes.
RESULTS: The systematic literature search yielded a total of 33 studies including a total of 4801 subjects (2238 patients with lung cancer and 2563 controls) and covering 32 genes. We identified that methylated genes in sputum samples for the early screening and auxiliary detection of lung cancer yielded an overall sensitivity of 0.46 (0.41-0.50) and specificity of 0.83 (0.80-0.86). Combined indirect comparisons identified the superior gene of
CONCLUSIONS: The present meta-analysis demonstrates that methylated

Clarke MA, Luhn P, Gage JC, et al.
Discovery and validation of candidate host DNA methylation markers for detection of cervical precancer and cancer.
Int J Cancer. 2017; 141(4):701-710 [PubMed] Related Publications
Human papillomavirus (HPV) testing has been recently introduced as an alternative to cytology for cervical cancer screening. However, since most HPV infections clear without causing clinically relevant lesions, additional triage tests are required to identify women who are at high risk of developing cancer. We performed DNA methylation profiling on formalin-fixed, paraffin-embedded tissue specimens from women with benign HPV16 infection and histologically confirmed cervical intraepithelial neoplasia grade 3, and cancer using a bead-based microarray covering 1,500 CpG sites in over 800 genes. Methylation levels in individual CpG sites were compared using a t-test, and results were summarized by computing p-values. A total of 12 candidate genes (ADCYAP1, ASCL1, ATP10, CADM1, DCC, DBC1, HS3ST2, MOS, MYOD1, SOX1, SOX17 and TMEFF2) identified by DNA methylation profiling, plus an additional three genes identified from the literature (EPB41L3, MAL and miR-124) were chosen for validation in an independent set of 167 liquid-based cytology specimens using pyrosequencing and targeted, next-generation bisulfite sequencing. Of the 15 candidate gene markers, 10 had an area under the curve (AUC) of ≥ 0.75 for discrimination of high grade squamous intraepithelial lesions or worse (HSIL+) from

Kang SJ, Park YI, Hwang SR, et al.
Hepatic population derived from human pluripotent stem cells is effectively increased by selective removal of undifferentiated stem cells using YM155.
Stem Cell Res Ther. 2017; 8(1):78 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Pluripotent stem cells (PSCs) such as embryonic stem cells and induced pluripotent stem cells are promising target cells for cell regenerative medicine together with recently advanced technology of in-vitro differentiation. However, residual undifferentiated stem cells (USCs) during in-vitro differentiation are considered a potential risk for development of cancer cells and nonspecific lineage cell types. In this study we observed that USCs still exist during hepatic differentiation, consequently resulting in poor quality of the hepatic population and forming teratoma in vivo. Therefore, we hypothesized that effectively removing USCs from in-vitro differentiation could improve the quality of the hepatic population and guarantee safety from risk of teratoma formation.
METHODS: Human PSCs were differentiated to hepatocytes via four steps. YM155, a known BIRC5 inhibitor, was applied for removing the residual USCs on the hepatic differentiation. After YM155 treatment, hepatocyte development was evaluated by measuring gene expression, immunostaining and hepatic functions at each stage of differentiation, and forming teratomas were confirmed by cell transplantation with or without YM155.
RESULTS: The selected concentrations of YM155 removed USCs (NANOG
CONCLUSIONS: We suggest that the removal of USCs using YM155 could improve the quantity and quality of induced hepatocytes and eliminate the potential risk of teratoma formation.

Merino-Azpitarte M, Lozano E, Perugorria MJ, et al.
SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma.
J Hepatol. 2017; 67(1):72-83 [PubMed] Free Access to Full Article Related Publications
BACKGROUND & AIMS: Cholangiocarcinoma (CCA) is a biliary malignancy linked to genetic and epigenetic abnormalities, such as hypermethylation of SOX17 promoter. Here, the role of SOX17 in cholangiocyte differentiation and cholangiocarcinogenesis was studied.
METHODS: SOX17 expression/function was evaluated along the differentiation of human induced pluripotent stem cells (iPSC) into cholangiocytes, in the dedifferentiation process of normal human cholangiocytes (NHC) in culture and in cholangiocarcinogenesis. Lentiviruses for SOX17 overexpression or knockdown were used. Gene expression and DNA methylation profiling were performed.
RESULTS: SOX17 expression is induced in the last stage of cholangiocyte differentiation from iPSC and regulates the acquisition of biliary markers. SOX17 becomes downregulated in NHC undergoing dedifferentiation; experimental SOX17 knockdown in differentiated NHC downregulated biliary markers and promoted baseline and Wnt-dependent proliferation. SOX17 expression is lower in human CCA than in healthy tissue, which correlates with worse survival after tumor resection. In CCA cells, SOX17 overexpression decreased their tumorigenic capacity in murine xenograft models, which was related to increased oxidative stress and apoptosis. In contrast, SOX17 overexpression in NHC did not affect their survival but inhibited their baseline proliferation. In CCA cells, SOX17 inhibited migration, anchorage-independent growth and Wnt/β-catenin-dependent proliferation, and restored the expression of biliary markers and primary cilium length. In human CCA, SOX17 promoter was found hypermethylated and its expression inversely correlates with the methylation grade. In NHC, Wnt3a decreased SOX17 expression in a DNMT-dependent manner, whereas in CCA, DNMT1 inhibition or silencing upregulated SOX17.
CONCLUSIONS: SOX17 regulates the differentiation and maintenance of the biliary phenotype and functions as a tumor suppressor for CCA, being a potential prognostic marker and a promising therapeutic target.
LAY SUMMARY: Understanding the molecular mechanisms involved in the pathogenesis of CCA is key in finding new valuable diagnostic and prognostic biomarkers, as well as therapeutic targets. This study provides evidence that SOX17 regulates the differentiation and maintenance of the biliary phenotype, and its downregulation promotes their tumorigenic transformation. SOX17 acts as a tumor suppressor in CCA and its genetic, molecular and/or pharmacological restoration may represent a new promising therapeutic strategy. Moreover, SOX17 expression correlates with the outcome of patients after tumor resection, being a potential prognostic biomarker.

Hata T, Dal Molin M, Hong SM, et al.
Predicting the Grade of Dysplasia of Pancreatic Cystic Neoplasms Using Cyst Fluid DNA Methylation Markers.
Clin Cancer Res. 2017; 23(14):3935-3944 [PubMed] Free Access to Full Article Related Publications

Zhang Y, Bao W, Wang K, et al.
SOX17 is a tumor suppressor in endometrial cancer.
Oncotarget. 2016; 7(46):76036-76046 [PubMed] Free Access to Full Article Related Publications
β-catenin is a key regulatory factor for the Wnt signaling pathway. SOX17 is an important β-catenin inhibitor, while MAML3 is a co-activator of β-catenin-mediated transcription. Out of 120 endometrial cancer (EC) patients, we found that those with tumors expressing higher SOX17 (n=68) had longer recurrence-free survival (P=0.024), while higher MAML3 expression (n=76) was associated with shorter recurrence-free survival (P=0.022). Immunohistochemical and immunoprecipitation analyses revealed that SOX17 and MAML3 co-localized in EC cell nuclei, and the MAML3 C-terminal region was necessary for SOX17 binding. SOX17 regulated MAML3 transcription via binding to the MAML3 promoter, decreasing Wnt pathway protein expression and suppressing EC cell growth and colony formation in vitro. In nude mice, SOX17 over-expression inhibited tumor growth, and co-inhibition or co-overexpression of SOX17 and MAML3 rescued this response. Our results suggest that decreasing SOX17 levels may promote EC development and progression, and that by downregulating MAML3 expression and Wnt signaling, SOX17 acts as a tumor suppressor that may improve outcome in patients with EC.

Hulbert A, Jusue-Torres I, Stark A, et al.
Early Detection of Lung Cancer Using DNA Promoter Hypermethylation in Plasma and Sputum.
Clin Cancer Res. 2017; 23(8):1998-2005 [PubMed] Free Access to Full Article Related Publications

Li Z, Heng J, Yan J, et al.
Integrated analysis of gene expression and methylation profiles of 48 candidate genes in breast cancer patients.
Breast Cancer Res Treat. 2016; 160(2):371-383 [PubMed] Related Publications
PURPOSE: Gene-specific methylation and expression have shown biological and clinical importance for breast cancer diagnosis and prognosis. Integrated analysis of gene methylation and gene expression may identify genes associated with biology mechanism and clinical outcome of breast cancer and aid in clinical management.
METHODS: Using high-throughput microfluidic quantitative PCR, we analyzed the expression profiles of 48 candidate genes in 96 Chinese breast cancer patients and investigated their correlation with gene methylation and associations with breast cancer clinical parameters.
RESULTS: Breast cancer-specific gene expression alternation was found in 25 genes with significant expression difference between paired tumor and normal tissues. A total of 9 genes (CCND2, EGFR, GSTP1, PGR, PTGS2, RECK, SOX17, TNFRSF10D, and WIF1) showed significant negative correlation between methylation and gene expression, which were validated in the TCGA database. Total 23 genes (ACADL, APC, BRCA2, CADM1, CAV1, CCND2, CST6, EGFR, ESR2, GSTP1, ICAM5, NPY, PGR, PTGS2, RECK, RUNX3, SFRP1, SOX17, SYK, TGFBR2, TNFRSF10D, WIF1, and WRN) annotated with potential TFBSs in the promoter regions showed negative correlation between methylation and expression. In logistics regression analysis, 31 of the 48 genes showed improved performance in disease prediction with combination of methylation and expression coefficient.
CONCLUSIONS: Our results demonstrated the complex correlation and the possible regulatory mechanisms between DNA methylation and gene expression. Integration analysis of methylation and expression of candidate genes could improve performance in breast cancer prediction. These findings would contribute to molecular characterization and identification of biomarkers for potential clinical applications.

Chang WL, Lai WW, Kuo IY, et al.
A six-CpG panel with DNA methylation biomarkers predicting treatment response of chemoradiation in esophageal squamous cell carcinoma.
J Gastroenterol. 2017; 52(6):705-714 [PubMed] Related Publications
BACKGROUND: Prognosis of esophageal squamous cell carcinoma (ESCC) patients remains poor, and the chemoradiotherapy (CRT) applied to ESCC patients often failed. Therefore, development of biomarkers to predict CRT response is immensely important for choosing the best treatment strategy of an individual patient.
METHODS: The methylation array and pyrosequencing methylation assay were performed in pre-treatment endoscopic biopsies to identify probes with differential CpG methylation levels between good and poor CRT responders in a cohort of 12 ESCC patients. Receiver operating characteristic curves and multivariate logistic regressions were conducted to build the risk score equation of selected CpG probes in another cohort of 91 ESCC patients to predict CRT response. Kaplan-Meier analysis was used to estimate progression-free survival or time-to-progression of patients predicted with good and poor CRT responses.
RESULTS: Nine differentially methylated CpG probes were identified to be associated with CRT response. A risk score equation comprising six CpG probes located in IFNGR2, KCNK4, NOTCH4, NPY, PAX6, and SOX17 genes were built. The risk score was derived from the sum of each probe multiplied by its corresponding coefficient. Such a risk score has a good prediction performance in discriminating poor CRT responders from good responders (AUC: 0.930). Moreover, poor CRT responders predicted by risk score significantly had poorer prognosis in terms of shorter progression-free survival and time-to-progression (p = 0.004-0.008).
CONCLUSION: We established a proof-of-concept CRT response prediction panel consisting of six-CpG methylation biomarkers in identifying ESCC patients who are at high risk of CRT failure and need intensive care.

Li W, Wu D, Niu Z, et al.
5-Azacytidine suppresses EC9706 cell proliferation and metastasis by upregulating the expression of SOX17 and CDH1.
Int J Mol Med. 2016; 38(4):1047-54 [PubMed] Free Access to Full Article Related Publications
5-Azacytidine is a well-known anticancer drug that is clinically used in the treatment of breast cancer, melanoma and colon cancer. It has been reported that 5-azacytidine suppresses the biological behavior of esophageal cancer cells. However, corresponding mechanisms remain unclear. In this study, using Transwell invasion and cell proliferation assays, we demonstrated that 5-azacytidine significantly inhibited the metastasis and proliferation of EC9706 cells, and upregulated the expression of cadherin 1 (CDH1) and SRY-box containing gene 17 (SOX17). Moreover, the inhibition of the metastasis of the 5-azacytidine-treated EC9706 cells was impaired following transfection with siRNA targeting CDH1 (CDH1 siRNA), and the inhibition of cell proliferation was attenuated following the downregulation of SOX17 by siRNA targeting SOX17 (SOX17 siRNA). Furthermore, 5-azacytidine remarkably reduced the CDH1 and SOX17 promoter methylation levels, suggesting that 5-azacytidine upregulates the expression of SOX17 and CDH1 by inhibiting the methylation of the SOX17 and CDH1 promoter. The findings of our study confirm that 5-azacytidine suppresses the proliferation and metastasis of EC9706 esophageal cancer cells by upregulating the expression of CDH1 and SOX17. The expression levels of CDH1 and SOX17 negatively correlate with the promoter methylation levels. CDH1 and SOX17 are potential indicators of the clinical application of 5-azacytidine.

Parisi C, Mastoraki S, Markou A, et al.
Development and validation of a multiplex methylation specific PCR-coupled liquid bead array for liquid biopsy analysis.
Clin Chim Acta. 2016; 461:156-64 [PubMed] Related Publications
BACKGROUND: Liquid biopsy is based on minimally invasive blood tests and has the potential to characterize the evolution of a solid tumor in real time, by extracting molecular information from circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA). Epigenetic silencing of tumor and metastasis suppressor genes plays a key role in survival and metastatic potential of cancer cells. Our group was the first to show the presence of epigenetic alterations in CTCs.
METHODS: We present the development and analytical validation of a highly specific and sensitive Multiplex Methylation Specific PCR-coupled liquid bead array (MMSPA) for the simultaneous detection of the methylation status of three tumor and metastasis suppressor genes (CST6, SOX17 and BRMS1) in liquid biopsy material (CTCs, corresponding ctDNA) and paired primary breast tumors.
RESULTS: In the EpCAM-positive CTCs fraction we observed methylation of: a) CST6, in 11/30(37%) and 11/30(37%), b) BRMS1 in 8/30(27%) and 11/30(37%) c) SOX17 in 8/30(27%) and 13/30(43%) early breast cancer patients and patients with verified metastasis respectively. In ctDNA we observed methylation of: a) CST6, in 5/30(17%) and 10/31(32%), b) BRMS1 in 8/30 (27%) and 8/31 (26%) c) SOX17 in 5/30(17%) and 13/31(42%) early breast cancer patients and patients with verified metastasis respectively.
CONCLUSIONS: Our results indicate a high cancerous load at the epigenetic level in EpCAM-positive CTCs fractions and corresponding ctDNA in breast cancer. The main principle of the developed methodology has the potential to be extended in a large number of gene-targets and be applied in many types of cancer.

Li Z, Guo X, Tang L, et al.
Methylation analysis of plasma cell-free DNA for breast cancer early detection using bisulfite next-generation sequencing.
Tumour Biol. 2016; 37(10):13111-13119 [PubMed] Related Publications
Circulating cell-free DNA (cfDNA) has been considered as a potential biomarker for non-invasive cancer detection. To evaluate the methylation levels of six candidate genes (EGFR, GREM1, PDGFRB, PPM1E, SOX17, and WRN) in plasma cfDNA as biomarkers for breast cancer early detection, quantitative analysis of the promoter methylation of these genes from 86 breast cancer patients and 67 healthy controls was performed by using microfluidic-PCR-based target enrichment and next-generation bisulfite sequencing technology. The predictive performance of different logistic models based on methylation status of candidate genes was investigated by means of the area under the ROC curve (AUC) and odds ratio (OR) analysis. Results revealed that EGFR, PPM1E, and 8 gene-specific CpG sites showed significantly hypermethylation in cancer patients' plasma and significantly associated with breast cancer (OR ranging from 2.51 to 9.88). The AUC values for these biomarkers were ranging from 0.66 to 0.75. Combinations of multiple hypermethylated genes or CpG sites substantially improved the predictive performance for breast cancer detection. Our study demonstrated the feasibility of quantitative measurement of candidate gene methylation in cfDNA by using microfluidic-PCR-based target enrichment and bisulfite next-generation sequencing, which is worthy of further validation and potentially benefits a broad range of applications in clinical oncology practice. Quantitative analysis of methylation pattern of plasma cfDNA by next-generation sequencing might be a valuable non-invasive tool for early detection of breast cancer.

Nettersheim D, Arndt I, Sharma R, et al.
The cancer/testis-antigen PRAME supports the pluripotency network and represses somatic and germ cell differentiation programs in seminomas.
Br J Cancer. 2016; 115(4):454-64 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cancer/testis-antigens (CTAs) are specifically expressed in human malignancies and testis tissue, but their molecular functions are poorly understood. CTAs serve as regulators of gene expression, cell cycle and spermatogenesis, as well as targets for immune-based therapies. The CTA PRAME is expressed in various cancers, antagonises retinoic acid signalling and is regulated by DNA methylation and histone acetylation.
METHODS: We analysed the molecular function of the CTA PRAME in primordial germ cells (PGC) and testicular germ cell cancers (GCC). GCCs arise from a common precursor lesion termed germ cell neoplasia in situ (GCNIS), which itself is thought to originate from a defective PGC. GCNIS cells eventually develop into unipotent seminomas or totipotent embryonal carcinomas (ECs), which are capable of differentiation into teratomas, yolk-sac tumours and choriocarcinomas.
RESULTS: PRAME is, like the master regulator of PGCs SOX17 expressed in human PGCs, GCNIS and seminomas but absent in ECs. shRNA-mediated knockdown of PRAME in seminomatous TCam-2 cells left SOX17 levels unchanged, but resulted in downregulation of pluripotency- and PGC-related genes (LIN28, PRDM14, ZSCAN10), whereas somatic and germ cell differentiation markers were upregulated. So, PRAME seems to act downstream of SOX17 by mediating the regulation of the germ cell differentiation and pluripotency programme. Endoderm differentiation is triggered in somatic cells by SOX17, suggesting that in PGCs, PRAME represses this programme and modulates SOX17 to function as a PGC-master regulator. Surprisingly, knockdown of PRAME in TCam-2 cells did not render the cells sensitive towards retinoic acid, despite the fact that PRAME has been described to antagonise retinoic acid signalling. Finally, we demonstrate that in non-seminomas PRAME expression is silenced by DNA methylation, which can be activated by formation of euchromatin via histone-deacetylase-inhibitors.
CONCLUSIONS: We identified the CTA PRAME as a downstream factor of SOX17 and LIN28 in regulating pluripotency and suppressing somatic/germ cell differentiation in PGC, GCNIS and seminomas.

Nettersheim D, Heimsoeth A, Jostes S, et al.
SOX2 is essential for in vivo reprogramming of seminoma-like TCam-2 cells to an embryonal carcinoma-like fate.
Oncotarget. 2016; 7(30):47095-47110 [PubMed] Free Access to Full Article Related Publications
Type II germ cell cancers (GCC) are divided into seminomas, which are highly similar to primordial germ cells and embryonal carcinomas (EC), often described as malignant counterparts to embryonic stem cells.Previously, we demonstrated that the development of GCCs is a highly plastic process and strongly influenced by the microenvironment. While orthotopic transplantation into the testis promotes seminomatous growth of the seminoma-like cell line TCam-2, ectopic xenotransplantation into the flank initiates reprogramming into an EC-like fate.During this reprogramming, BMP signaling is inhibited, leading to induction of NODAL signaling, upregulation of pluripotency factors and downregulation of seminoma markers, like SOX17. The pluripotency factor and EC-marker SOX2 is strongly induced.Here, we adressed the molecular role of SOX2 in this reprogramming. Using CRISPR/Cas9-mediated genome-editing, we established SOX2-deficient TCam-2 cells. Xenografting of SOX2-deficient cells into the flank of nude mice resulted in maintenance of a seminoma-like fate, indicated by the histology and expression of OCT3/4, SOX17, TFAP2C, PRDM1 and PRAME. In SOX2-deficient cells, BMP signaling is inhibited, but NODAL signaling is not activated. Thus, SOX2 appears to be downstream of BMP signaling but upstream of NODAL activation. So, SOX2 is an essential factor in acquiring an EC-like cell fate from seminomas.A small population of differentiated cells was identified resembling a mixed non-seminoma. Analyses of these cells revealed downregulation of the pluripotency and seminoma markers OCT3/4, SOX17, PRDM1 and TFAP2C. In contrast, the pioneer factor FOXA2 and its target genes were upregulated, suggesting that FOXA2 might play an important role in induction of non-seminomatous differentiation.

Galamb O, Kalmár A, Péterfia B, et al.
Aberrant DNA methylation of WNT pathway genes in the development and progression of CIMP-negative colorectal cancer.
Epigenetics. 2016; 11(8):588-602 [PubMed] Free Access to Full Article Related Publications
The WNT signaling pathway has an essential role in colorectal carcinogenesis and progression, which involves a cascade of genetic and epigenetic changes. We aimed to analyze DNA methylation affecting the WNT pathway genes in colorectal carcinogenesis in promoter and gene body regions using whole methylome analysis in 9 colorectal cancer, 15 adenoma, and 6 normal tumor adjacent tissue (NAT) samples by methyl capture sequencing. Functional methylation was confirmed on 5-aza-2'-deoxycytidine-treated colorectal cancer cell line datasets. In parallel with the DNA methylation analysis, mutations of WNT pathway genes (APC, β-catenin/CTNNB1) were analyzed by 454 sequencing on GS Junior platform. Most differentially methylated CpG sites were localized in gene body regions (95% of WNT pathway genes). In the promoter regions, 33 of the 160 analyzed WNT pathway genes were differentially methylated in colorectal cancer vs. normal, including hypermethylated AXIN2, CHP1, PRICKLE1, SFRP1, SFRP2, SOX17, and hypomethylated CACYBP, CTNNB1, MYC; 44 genes in adenoma vs. NAT; and 41 genes in colorectal cancer vs. adenoma comparisons. Hypermethylation of AXIN2, DKK1, VANGL1, and WNT5A gene promoters was higher, while those of SOX17, PRICKLE1, DAAM2, and MYC was lower in colon carcinoma compared to adenoma. Inverse correlation between expression and methylation was confirmed in 23 genes, including APC, CHP1, PRICKLE1, PSEN1, and SFRP1. Differential methylation affected both canonical and noncanonical WNT pathway genes in colorectal normal-adenoma-carcinoma sequence. Aberrant DNA methylation appears already in adenomas as an early event of colorectal carcinogenesis.

Mohammadi Yeganeh S, Vasei M, Tavakoli R, et al.
The effect of miR-340 over-expression on cell-cycle-related genes in triple-negative breast cancer cells.
Eur J Cancer Care (Engl). 2017; 26(6) [PubMed] Related Publications
Breast cancer is a heterogeneous disease, and among all types, triple-negative breast cancer (TNBC) is characterised by high risk of recurrence. The discovery of microRNAs (miRNA) has opened the door for targeted therapy of TNBC. miR-340 down-regulation and sub-G1-accumulated cells in flowcytometry were observed in metastatic TNBC cells (data in publication), leading us to investigate the potential tumour suppressive role of this miRNA on cell-cycle-related genes. A lentiviral vector containing miR-340 was applied to over-express miR-340 in TNBC cell line, MDA-MB-231. Then, the expression of some cell-cycle-regulating genes including cyclin A2 (cyclin A2), Cyclin-dependent kinases 2 (CDK2), cyclin-dependent kinase inhibitors (P16, P18 and P27), Retinoblastoma (RB) and transcription factors (SMAD 4, SOX2 and SOX17) was investigated using quantitative RT-PCR. The results showed a decline in the expression of SOX2, P16 and P27 after miR-340 over-expression, whereas we observed an increase in the expression of cyclin A2, CDK2, SOX17, P18, SMAD 4 and RB. The over-expression of tumour suppressor genes such as RB and SOX17 and down-regulation of an oncogene such as SOX2 were in accordance to the inhibitory role of miR-340 that causes blockage of breast cancer metastasis which should be further investigated.

Liu H, Mastriani E, Yan ZQ, et al.
SOX7 co-regulates Wnt/β-catenin signaling with Axin-2: both expressed at low levels in breast cancer.
Sci Rep. 2016; 6:26136 [PubMed] Free Access to Full Article Related Publications
SOX7 as a tumor suppressor belongs to the SOX F gene subfamily and is associated with a variety of human cancers, including breast cancer, but the mechanisms involved are largely unclear. In the current study, we investigated the interactions between SOX7 and AXIN2 in their co-regulation on the Wnt/β-catenin signal pathway, using clinical specimens and microarray gene expression data from the GEO database, for their roles in breast cancer. We compared the expression levels of SOX7 and other co-expressed genes in the Wnt/β-catenin pathway and found that the expression of SOX7, SOX17 and SOX18 was all reduced significantly in the breast cancer tissues compared to normal controls. AXIN2 had the highest co-relativity with SOX7 in the Wnt/β-catenin signaling pathway. Clinicopathological analysis demonstrated that the down-regulated SOX7 was significantly correlated with advanced stages and poorly differentiated breast cancers. Consistent with bioinformatics predictions, SOX7 was correlated positively with AXIN2 and negatively with β-catenin, suggesting that SOX7 and AXIN2 might play important roles as co-regulators through the Wnt-β-catenin pathway in the breast tissue to affect the carcinogenesis process. Our results also showed Smad7 as the target of SOX7 and AXIN2 in controlling breast cancer progression through the Wnt/β-catenin signaling pathway.

Li J, Shen J, Wang K, et al.
The Roles of Sox Family Genes in Sarcoma.
Curr Drug Targets. 2016; 17(15):1761-1772 [PubMed] Related Publications
Sox (SRY-related HMG-box) family genes are important regulators of cell development, homeostasis, and regeneration. Deregulation of certain members of the Sox gene family has been implicated in a number of human malignancies, including in sarcoma. Accumulating evidence suggests that Sox genes play crucial roles in sarcoma cell pathogenesis, growth, and proliferation. Here, we review the biological relevance of Sox2 and Sox9 genes in osteosarcoma, chondrosarcoma and chordoma; Sox2, Sox6, and Sox17 genes in Ewing's sarcoma; Sox2, Sox9, and Sox10 genes in synovial sarcoma; Sox2 gene in fibrosarcoma; and Sox21 gene in liposarcoma. These findings potentiate the targeting of Sox genes for novel therapeutic interventions in sarcoma and may also hold valuable clinical potential to improve the care of patients with sarcoma.

Kushwaha R, Jagadish N, Kustagi M, et al.
Mechanism and Role of SOX2 Repression in Seminoma: Relevance to Human Germline Specification.
Stem Cell Reports. 2016; 6(5):772-783 [PubMed] Free Access to Full Article Related Publications
Human male germ cell tumors (GCTs) are derived from primordial germ cells (PGCs). The master pluripotency regulator and neuroectodermal lineage effector transcription factor SOX2 is repressed in PGCs and the seminoma (SEM) subset of GCTs. The mechanism of SOX2 repression and its significance to GC and GCT development currently are not understood. Here, we show that SOX2 repression in SEM-derived TCam-2 cells is mediated by the Polycomb repressive complex (PcG) and the repressive H3K27me3 chromatin mark that are enriched at its promoter. Furthermore, SOX2 repression in TCam-2 cells can be abrogated by recruitment of the constitutively expressed H3K27 demethylase UTX to the SOX2 promoter through retinoid signaling, leading to expression of neuronal and other lineage genes. SOX17 has been shown to initiate human PGC specification, with its target PRDM1 suppressing mesendodermal genes. Our results are consistent with a role for SOX2 repression in normal germline development by suppressing neuroectodermal genes.

Ma K, Cao B, Guo M
The detective, prognostic, and predictive value of DNA methylation in human esophageal squamous cell carcinoma.
Clin Epigenetics. 2016; 8:43 [PubMed] Free Access to Full Article Related Publications
Esophageal cancer is one of the most common malignancies in the world. Squamous cell carcinoma accounts for approximately 90 % of esophageal cancer cases. Genetic and epigenetic changes have been found to accumulate during the development of various cancers, including esophageal squamous carcinoma (ESCC). Tobacco smoking and alcohol consumption are two major risk factors for ESCC, and both tobacco and alcohol were found to induce methylation changes in ESCC. Growing evidence demonstrates that aberrant epigenetic changes play important roles in the multiple-step processes of carcinogenesis and tumor progression. DNA methylation may occur in the key components of cancer-related signaling pathways. Aberrant DNA methylation affects genes involved in cell cycle, DNA damage repair, Wnt, TGF-β, and NF-κB signaling pathways, including P16, MGMT, SFRP2, DACH1, and ZNF382. Certain genes methylated in precursor lesions of the esophagus demonstrate that DNA methylation may serve as esophageal cancer early detection marker, such as methylation of HIN1, TFPI-2, DACH1, and SOX17. CHFR methylation is a late stage event in ESCC and is a sensitive marker for taxanes in human ESCC. FHIT methylation is associated with poor prognosis in ESCC. Aberrant DNA methylation changes may serve as diagnostic, prognostic, and chemo-sensitive markers. Characterization of the DNA methylome in ESCC will help to better understand its mechanisms and develop improved therapies.

Kishino T, Niwa T, Yamashita S, et al.
Integrated analysis of DNA methylation and mutations in esophageal squamous cell carcinoma.
Mol Carcinog. 2016; 55(12):2077-2088 [PubMed] Related Publications
The recent development of next-generation sequencing technology for extensive mutation analysis, and beadarray technology for genome-wide DNA methylation analysis has made it possible to obtain integrated pictures of genetic and epigenetic alterations, using the same cancer samples. In this study, we aimed to characterize such a picture in esophageal squamous cell carcinomas (ESCCs). Base substitutions of 55 cancer-related genes and copy number alterations (CNAs) of 28 cancer-related genes were analyzed by targeted sequencing. Forty-four of 57 ESCCs (77%) had 64 non-synonymous somatic mutations, and 24 ESCCs (42%) had 35 CNAs. A genome-wide DNA methylation analysis using an Infinium HumanMethylation450 BeadChip array showed that the CpG island methylator phenotype was unlikely to be present in ESCCs, a different situation from gastric and colon cancers. Regarding individual pathways affected in ESCCs, the WNT pathway was activated potentially by aberrant methylation of its negative regulators, such as SFRP1, SFRP2, SFRP4, SFRP5, SOX17, and WIF1 (33%). The p53 pathway was inactivated by TP53 mutations (70%), and potentially by aberrant methylation of its downstream genes. The cell cycle was deregulated by mutations of CDKN2A (9%), deletions of CDKN2A and RB1 (32%), and by aberrant methylation of CDKN2A and CHFR (9%). In conclusion, ESCCs had unique methylation profiles different from gastric and colon cancers. The genes involved in the WNT pathway were affected mainly by epigenetic alterations, and those involved in the p53 pathway and cell cycle regulation were affected mainly by genetic alterations. © 2016 Wiley Periodicals, Inc.

Balgkouranidou I, Chimonidou M, Milaki G, et al.
SOX17 promoter methylation in plasma circulating tumor DNA of patients with non-small cell lung cancer.
Clin Chem Lab Med. 2016; 54(8):1385-93 [PubMed] Related Publications
BACKGROUND: SOX17 belongs to the high-mobility group-box transcription factor superfamily and down-regulates the Wnt pathway. The aim of our study was to evaluate the prognostic significance of SOX17 promoter methylation in circulating tumor DNA (ctDNA) in plasma of non-small cell lung cancer (NSCLC) patients.
METHODS: We examined the methylation status of SOX17 promoter in 57 operable NSCLC primary tumors and paired adjacent non-cancerous tissues and in ctDNA isolated from 48 corresponding plasma samples as well as in plasma from 74 patients with advanced NSCLC and 49 healthy individuals. SOX17 promoter methylation was examined by Methylation Specific PCR (MSP).
RESULTS: In operable NSCLC, SOX17 promoter was fully methylated in primary tumors (57/57, 100%), and in corresponding ctDNA (27/48, 56.2%) while it was detected in only 1/49 (2.0%) healthy individuals. In advanced NSCLC, SOX17 promoter was methylated in ctDNA in 27/74 (36.4%) patients and OS was significantly different in favor of patients with non-methylated SOX17 promoter (p=0.012). Multivariate analysis revealed that SOX17 promoter methylation in ctDNA was an independent prognostic factor associated with OS in patients with advanced but not operable NSCLC.
CONCLUSIONS: Our results show that SOX17 promoter is highly methylated in primary tumors and in corresponding plasma samples both in operable and advanced NSCLC. In the advanced setting, SOX17 promoter methylation in plasma ctDNA has a statistical significant influence on NSCLC patient's survival time. Detection of SOX17 promoter methylation in plasma provides prognostic information and merits to be further evaluated as a circulating tumor biomarker in patients with operable and advanced NSCLC.

Kim SB, Bozeman RG, Kaisani A, et al.
Radiation promotes colorectal cancer initiation and progression by inducing senescence-associated inflammatory responses.
Oncogene. 2016; 35(26):3365-75 [PubMed] Free Access to Full Article Related Publications
Proton radiotherapy is becoming more common as protons induce more precise DNA damage at the tumor site with reduced side effects to adjacent normal tissues. However, the long-term biological effects of proton irradiation in cancer initiation compared with conventional photon irradiation are poorly characterized. In this study, using a human familial adenomatous polyposis syndrome susceptible mouse model, we show that whole-body irradiation with protons are more effective in inducing senescence-associated inflammatory responses (SIRs), which are involved in colon cancer initiation and progression. After proton irradiation, a subset of SIR genes (Troy, Sox17, Opg, Faim2, Lpo, Tlr2 and Ptges) and a gene known to be involved in invasiveness (Plat), along with the senescence-associated gene (P19Arf), are markedly increased. Following these changes, loss of Casein kinase Iα and induction of chronic DNA damage and TP53 mutations are increased compared with X-ray irradiation. Proton irradiation also increases the number of colonic polyps, carcinomas and invasive adenocarcinomas. Pretreatment with the non-steroidal anti-inflammatory drug, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid-ethyl amide (CDDO-EA), reduces proton irradiation-associated SIR and tumorigenesis. Thus exposure to proton irradiation elicits significant changes in colorectal cancer initiation and progression that can be mitigated using CDDO-EA.

Johansson E, Andersson L, Örnros J, et al.
Revising the embryonic origin of thyroid C cells in mice and humans.
Development. 2015; 142(20):3519-28 [PubMed] Free Access to Full Article Related Publications
Current understanding infers a neural crest origin of thyroid C cells, the major source of calcitonin in mammals and ancestors to neuroendocrine thyroid tumors. The concept is primarily based on investigations in quail-chick chimeras involving fate mapping of neural crest cells to the ultimobranchial glands that regulate Ca(2+) homeostasis in birds, reptiles, amphibians and fishes, but whether mammalian C cell development involves a homologous ontogenetic trajectory has not been experimentally verified. With lineage tracing, we now provide direct evidence that Sox17+ anterior endoderm is the only source of differentiated C cells and their progenitors in mice. Like many gut endoderm derivatives, embryonic C cells were found to coexpress pioneer factors forkhead box (Fox) a1 and Foxa2 before neuroendocrine differentiation takes place. In the ultimobranchial body epithelium emerging from pharyngeal pouch endoderm in early organogenesis, differential Foxa1/Foxa2 expression distinguished two spatially separated pools of C cell precursors with different growth properties. A similar expression pattern was recapitulated in medullary thyroid carcinoma cells in vivo, consistent with a growth-promoting role of Foxa1. In contrast to embryonic precursor cells, C cell-derived tumor cells invading the stromal compartment downregulated Foxa2, foregoing epithelial-to-mesenchymal transition designated by loss of E-cadherin; both Foxa2 and E-cadherin were re-expressed at metastatic sites. These findings revise mammalian C cell ontogeny, expand the neuroendocrine repertoire of endoderm and redefine the boundaries of neural crest diversification. The data further underpin distinct functions of Foxa1 and Foxa2 in both embryonic and tumor development.

Majchrzak-Celińska A, Słocińska M, Barciszewska AM, et al.
Wnt pathway antagonists, SFRP1, SFRP2, SOX17, and PPP2R2B, are methylated in gliomas and SFRP1 methylation predicts shorter survival.
J Appl Genet. 2016; 57(2):189-97 [PubMed] Free Access to Full Article Related Publications
The deregulation of Wnt signaling is observed in various cancers, including gliomas, and might be related to the methylation of the genes encoding antagonists of this signaling pathway. The aim of the study was to assess the methylation status of the promoter regions of six Wnt negative regulators and to determine their prognostic value in clinical samples of gliomas of different grades. The methylation of SFRP1, SFRP2, PPP2R2B, DKK1, SOX17, and DACH1 was analyzed in 64 glioma samples using methylation-specific polymerase chain reaction (MSP). The results were analyzed in correlation with clinicopathological data. Promoter methylation in at least one of the analyzed genes was found in 81.3 % of the tumors. All benign tumors [grade I according to the World Health Organization (WHO) classification] lacked the methylation of the studied genes, whereas grade II, III, and IV tumors were, in most cases, methylation-positive. The methylation index correlated with the patient's age. The most frequently methylated genes were SFRP1 and SFRP2 (73.4 % and 46.9 %, respectively), followed by SOX17 (20.3 %) and PPP2R2B (10.9 %); DKK1 and DACH1 were basically unmethylated (1.6 %). SFRP1 methylation negatively correlated with patients' survival time, and was significantly more frequent in older patients and those with higher grade tumors. Overall, the results of this study indicate that aberrant promoter methylation of Wnt pathway antagonists is common in gliomas, which may be the possible cause of up-regulation of this signaling pathway often observed in these tumors. Moreover, SFRP1 promoter methylation can be regarded as a potential indicator of glioma patients' survival.

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