Prognostic CpG Methylation Biomarkers Identified by Methylation Array in Esophageal Squamous Cell Carcinoma Patients

Kuo, I-Ying; Chang, Jia‐Ming; Jiang, Shih Sheng; Chen, Chung‐Hsin; Chang, I‐Shou; Sheu, Bor–Shyang; Lu, Pei‐Jung; Chang, Wei‐Lun; Lai, Wu‐Wei; Wang, Yi‐Ching

doi:10.7150/ijms.7405

Cited by 33 publications

(33 citation statements)

References 27 publications

(29 reference statements)

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“…Similarly, Shaffer et al [22] demonstrated that extensive methylation of the FES promoter contributes to inhibition of FES expression in colorectal cancer cells. In addition, Kuo et al [23] showed that the high methylation level of FES is a biomarker for prognosis prediction in esophageal squamous cell carcinoma patients, via risk score analysis. In addition, the methylation level of FES is positively related with tumor stage in breast cancer [24].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of FES might inhibit cell proliferation, migration, and invasion of osteosarcoma cells

Zhao

Wang

et al. 2020

Cancer Cell Int

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Background: This study aimed to screen osteosarcoma (OS) prognosis relevant genes for methylation dysregulation, and the functional mechanisms of FES overexpression in OS cells were investigated. Methods: The OS prognosis relevant genes with differentially methylated positions (DMPs) identified from the GSE36001 and GSE36002 datasets, and the UCSC database, were used as a training set to construct a risk model, while the GSE21257 dataset was used as validation set. The expression levels of several key genes in OS cells after 5-Aza-2′-deoxycytidine treatment were detected by qPCR. The effects of FES overexpression on cell proliferation, cell cycle, migration, and invasion of MNNG/HOS were analyzed by CCK8, flow cytometry, and Transwell assays. Results: A total of 31 candidate genes, corresponding to 36 DMPs, were identified as OS prognosis relevant genes; from these, the top 10 genes were used to construct a risk model. Following validation of the risk model, FES, LYL1, MAP4K1, RIPK3, SLC15A3, and STAT3 showed expression changes between the OS and control samples. qPCR results showed that the expression of FES was significantly downregulated in three OS cell lines and increased after 5-Aza-DC treatment. The proliferation, cell cycle progression, migration, and invasion of MNNG/HOS cells were significantly inhibited after transfection with FES overexpression plasmid, and the protein expression of FYN and β catenin were decreased in MNNG/HOS cells by FES overexpression. Conclusions: The decrease in FES by hypermethylation was associated with OS prognosis, and might contribute to the proliferation, migration, and invasion of OS cells. FES, and its upstream FYN and β catenin, might coordinately exert a tumor suppressor effect in OS cells.

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Section: Discussionmentioning

confidence: 99%

Overexpression of FES might inhibit cell proliferation, migration, and invasion of osteosarcoma cells

Zhao

Wang

et al. 2020

Cancer Cell Int

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“…These data confirm the clinic-pathological and prognostic significance of SOX1 expression, and, to our knowledge, it is the first evidence of high SOX1 expression level as a negative prognostic biomarker in cancer. In fact, low expression of SOX1 protein and/or mRNA expression was correlated with shorter overall survival and poor prognosis in ovarian cancer22, human hepatocellular carcinoma2345, and esophageal squamous cell carcinoma4647. These two sets of observations are not conflicting per se because it is conceivable that the expression of SOX1 could be elevated or decreased depending on the epigenetic status or the cellular heterogeneity and plasticity.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic activity of SOX1 in glioblastoma

García

Aldaregia

Vićentić

et al. 2017

Sci Rep

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Glioblastoma remains the most common and deadliest type of brain tumor and contains a population of self-renewing, highly tumorigenic glioma stem cells (GSCs), which contributes to tumor initiation and treatment resistance. Developmental programs participating in tissue development and homeostasis re-emerge in GSCs, supporting the development and progression of glioblastoma. SOX1 plays an important role in neural development and neural progenitor pool maintenance. Its impact on glioblastoma remains largely unknown. In this study, we have found that high levels of SOX1 observed in a subset of patients correlate with lower overall survival. At the cellular level, SOX1 expression is elevated in patient-derived GSCs and it is also higher in oncosphere culture compared to differentiation conditions in conventional glioblastoma cell lines. Moreover, genetic inhibition of SOX1 in patient-derived GSCs and conventional cell lines decreases self-renewal and proliferative capacity in vitro and tumor initiation and growth in vivo. Contrarily, SOX1 over-expression moderately promotes self-renewal and proliferation in GSCs. These functions seem to be independent of its activity as Wnt/β-catenin signaling regulator. In summary, these results identify a functional role for SOX1 in regulating glioma cell heterogeneity and plasticity, and suggest SOX1 as a potential target in the GSC population in glioblastoma.

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“…Schmidt et al recently proposed quantitative measurement of methylated SHOX2 DNA in plasma as a useful tool to monitor therapy response in advanced stage lung cancer patients [36]. Furthermore, an increased methylation level of SEPT9 was a predictor of poor prognosis in esophageal squamous cell carcinoma, as well as in prostate cancer on androgen deprivation [52, 53]. Likewise, colorectal cancer patients with high SEPT9 serum methylation levels at 1-year follow-up were found to be at high risk of disease recurrence [64].…”

Section: Discussionmentioning

confidence: 99%

Promoter hypermethylation of SHOX2 and SEPT9 is a potential biomarker for minimally invasive diagnosis in adenocarcinomas of the biliary tract

et al. 2016

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BackgroundBiliary tract carcinoma (BTC) is a fatal malignancy which aggressiveness contrasts sharply with its relatively mild and late clinical presentation. Novel molecular markers for early diagnosis and precise treatment are urgently needed. The purpose of this study was to evaluate the diagnostic and prognostic value of promoter hypermethylation of the SHOX2 and SEPT9 gene loci in BTC.MethodsRelative DNA methylation of SHOX2 and SEPT9 was quantified in tumor specimens and matched normal adjacent tissue (NAT) from 71 BTC patients, as well as in plasma samples from an independent prospective cohort of 20 cholangiocarcinoma patients and 100 control patients. Receiver operating characteristic (ROC) curve analyses were performed to probe the diagnostic ability of both methylation markers. DNA methylation was correlated to clinicopathological data and to overall survival.Results SHOX2 methylation was significantly higher in tumor tissue than in NAT irrespective of tumor localization (p < 0.001) and correctly identified 71% of BTC specimens with 100% specificity (AUC = 0.918; 95% CI 0.865–0.971). SEPT9 hypermethylation was significantly more frequent in gallbladder carcinomas compared to cholangiocarcinomas (p = 0.01) and was associated with large primary tumors (p = 0.01) as well as age (p = 0.03). Cox proportional hazard analysis confirmed microscopic residual tumor at the surgical margin (R1-resection) as an independent prognostic factor, while SHOX2 and SEPT9 methylation showed no correlation with overall survival. Elevated DNA methylation levels were also found in plasma derived from cholangiocarcinoma patients. SHOX2 and SEPT9 methylation as a marker panel achieved a sensitivity of 45% and a specificity of 99% in differentiating between samples from patients with and without cholangiocarcinoma (AUC = 0.752; 95% CI 0.631–0.873).Conclusions SHOX2 and SEPT9 are frequently methylated in biliary tract cancers. Promoter hypermethylation of SHOX2 and SEPT9 may therefore serve as a minimally invasive biomarker supporting diagnosis finding and therapy monitoring in clinical specimens.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0299-x) contains supplementary material, which is available to authorized users.

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Prognostic CpG Methylation Biomarkers Identified by Methylation Array in Esophageal Squamous Cell Carcinoma Patients

Cited by 33 publications

References 27 publications

Overexpression of FES might inhibit cell proliferation, migration, and invasion of osteosarcoma cells

Overexpression of FES might inhibit cell proliferation, migration, and invasion of osteosarcoma cells

Oncogenic activity of SOX1 in glioblastoma

Promoter hypermethylation of SHOX2 and SEPT9 is a potential biomarker for minimally invasive diagnosis in adenocarcinomas of the biliary tract

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