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Featured researches published by Xuedan Chen.


International Journal of Cancer | 2012

CpG island methylation status of miRNAs in esophageal squamous cell carcinoma.

Xuedan Chen; Huamei Hu; Xingying Guan; Gang Xiong; Yan Wang; Kai Wang; Juan Li; Xueqing Xu; Kang Yang; Yun Bai

Previous studies on esophageal squamous cell carcinoma (ESCC) indicated that it contains much dysregulation of microRNAs (miRNAs). DNA hypermethylation in the miRNA 5′ regulatory region is a mechanism that can account for the downregulation of miRNA in tumors (Esteller, N Engl J Med 2008;358:1148–59). Among those dysregulated miRNAs, miR‐203, miR‐34b/c, miR‐424 and miR‐129‐2 are embedded in CpG islands, as is the promoter of miR‐34a. We investigated their methylation status in ESCC by bisulfite sequencing PCR (BSP) and methylation specific PCR (MSP). The methylation frequency of miR‐203 and miR‐424 is the same in carcinoma and in the corresponding non‐tumor tissues. The methylation ratio of miR‐34a, miR‐34b/c and miR‐129‐2 is 66.7% (36/54), 40.7% (22/54) and 96.3% (52/54), respectively in ESCC, which are significantly higher than that in the corresponding non‐tumor tissues(p < 0.01). Quantitative RT‐PCR analysis in clinical samples suggested that CpG island methylation is significantly correlated with their low expression in ESCC, 5‐aza‐2′‐deoxycytidine (DAC) treatment partly recovered their expression in EC9706 cell line. We conclude that CpG island methylation of miR‐34a, miR‐34b/c and miR‐129‐2 are frequent events and important mechanism for their low expression in ESCC. DNA methylation changes have been reported to occur early in carcinogenesis and are potentially good early indicators of carcinoma (Laird, Nat Rev Cancer 2003;3:253–66). The high methylation ratio of miR‐129‐2 indicated its potential as a methylation biomarker in early diagnosis of ESCC.


BMC Molecular Biology | 2012

Transcriptional activation of microRNA-34a by NF-kappa B in human esophageal cancer cells

Juan-Juan Li; Kai Wang; Xuedan Chen; Hui Meng; Min-Seop Song; Yanyan Wang; Xueqing Xu; Yun Bai

BackgroundmiR-34a functions as an important tumor suppressor during the process of carcinogenesis. However, the mechanism of miR-34a dysregulation in human malignancies has not been well elucidated. Our study aimed to further investigate the regulation mechanism of miR-34a.ResultsWe found that overexpression of NF-kappa B p65 subunit could increase miR-34a levels in EC109, an esophageal squamous cancer cell line, while ectopic expression of DN IkappaB leaded to a significant reduction of miR-34a expression. Bioinformatics analysis suggested three putative KB sites in promoter region of miR-34a gene. Mutation two of these KB sites impaired p65 induced miR-34a transcriptional activity. Chromatin immunoprecipitation and electrophoretic mobility shift assays both showed that NF-kappaB could specifically bind to the third KB site located in miR-34a promoter. In addition, we found that overexpression of NF-kappaB p65 could not successfully induce miR-34a expression in esophageal cancer cell lines with mutant p53 or decreased p53. Reporter assay further showed that NF-kappaB-induced miR-34a transcriptional activity was reduced by p53 impairment. Nevertheless, CHIP analysis suggested binding of NF-kappaB to miR-34a promoter was not affected in cells with mutant p53.ConclusionsOur work indicates a novel mechanism of miR-34a regulation that NF-kappaB could elevate miR-34a expression levels through directly binding to its promoter. And wildtype p53 is responsible for NF-kappaB-mediated miR-34a transcriptional activity but not for NF-kappaB binding. These findings might be helpful in understanding miR-34a abnormality in human malignancies and open new perspectives for the roles of miR-34a and NF-kappaB in tumor progression.


Journal of Cellular Physiology | 2015

miR‐203 Is a Direct Transcriptional Target of E2F1 and Causes G1 Arrest in Esophageal Cancer Cells

Kun Zhang; Limeng Dai; Bo Zhang; Xueqing Xu; Jiazhong Shi; Liyuan Fu; Xuedan Chen; Juan Li; Yun Bai

miR‐203 act as tumor repressor by inhibiting cell proliferation and is repressed in a variety of human tumors, although the molecular mechanisms responsible have not been elucidated. Here, we reveal that miR‐203 is regulated by E2F1, an important transcription factor that can induce cell proliferation by controlling cell cycle progression. We found that miR‐203 expression was induced by cisplatin, which also induced E2F1 protein accumulation in esophageal squamous cell carcinoma (ESCC) cell lines. miR‐203 expression was elevated upon activation of ectopic E2F1, whereas this induction was abolished when the E2F1 gene was silenced. Moreover, with luciferase reporter assays and chromatin immunoprecipitation (ChIP) assays, we demonstrated that E2F1 transactivates miR‐203 by directly binding to the miR‐203 gene promoter. In addition, we found that miR‐203 inhibited cell proliferation by inducing G1/S cell cycle arrest, but not apoptosis, in ESCC cell lines. Finally, we observed that miR‐203 negatively inhibited the expression of CDK6, subsequently decreasing E2F1 expression possibly through Rb phosphorylation. Taken together, our data show that cancer‐related miR‐203 is a novel transcriptional target of E2F1 and that it regulates cell cycle arrest by participating in a feedback loop with E2F1. J. Cell. Physiol. 230: 903–910, 2015.


Diseases of The Esophagus | 2009

Survivin expression in esophageal cancer: correlation with p53 mutations and promoter polymorphism

Xiaoya Yang; Gang Xiong; Xuedan Chen; Xueqing Xu; Kai Wang; Yong Fu; Kang Yang; Yun Bai

Survivin is an inhibitor of apoptosis protein, which is selectively up-regulated in various cancers including esophageal cancer. The underlying mechanism of survivin overexpression in cancers is still unclear. We investigated resected tumor specimens from 100 esophageal cancer patients. Reverse transcription polymerase chain reaction was performed to evaluate survivin gene expression. Polymerase chain reaction-single strand conformation polymorphism was performed to investigate mutations of p53. We found that the survivin expression in tumors with mutant p53 is higher than that in tumors with wild type p53. Furthermore, the distribution of three polymorphisms in survivin promoter region in esophageal cancer patients was studied. The result indicated that the survivin expression was caused by a C allele in the survivin promoter polymorphism -625G/C in some degree. The methylation profile of survivin exon1 was also evaluated using bisulfite sequencing PCR. Our result indicated that survivin mRNA overexpression in cancer was not caused by its dysmethylation status. Therefore, our results suggested that the survivin expression depended on the p53 status and the C allele in the survivin promoter polymorphism -625G/C might increase the possibility of the survivin overexpression in esophageal cancer patients.


Bioscience Reports | 2017

A novel long noncoding RNA linc00460 up-regulated by CBP/P300 promotes carcinogenesis in esophageal squamous cell carcinoma

Yan Liang; Yuanyuan Wu; Xuedan Chen; Shixin Zhang; Kai Wang; Xingying Guan; Kang Yang; Juan Li; Yun Bai

Esophageal cancer is one of the leading causes of cancer-related mortality because of poor prognosis. Long noncoding RNAs (lncRNAs) have been gradually demonstrated to play critical roles in cancer development. We identified a novel long noncoding RNA named linc00460 by microarray analysis using esophageal squamous cell carcinoma (ESCC) clinical samples, which has not been studied before. Our research indicated that linc00460 was overexpressed in the majority of tumor tissues and ESCC cell lines. Linc00460 expression was positively correlated with ESCC TNM stage, lymph node metastasis, and predicted poor prognosis. In vitro experiments showed that linc00460 depletion suppressed ESCC cell growth through regulating cell proliferation and cell cycle; in additional, linc00460 depletion accelerated ESCC cell apoptosis. We further revealed that linc00460 overexpression was manipulated by transcriptional co-activator CBP/P300 through histone acetylation. Given the high expression and important biological functions of linc00460, we suggest that linc00460 works as an oncogene and might be a valuable prognostic biomarker for ESCC diagnosis and treatment.


Molecular Cancer | 2017

Up-regulation of lncRNA CASC9 promotes esophageal squamous cell carcinoma growth by negatively regulating PDCD4 expression through EZH2

Yuanyuan Wu; Liwen Hu; Yan Liang; Juan Li; Kai Wang; Xuedan Chen; Hui Meng; Xingying Guan; Kang Yang; Yun Bai

BackgroundAbnormal expression of numerous long non-coding RNAs (lncRNAs) has been reported in esophageal squamous cell carcinoma (ESCC) recently, but the great majority of their roles and mechanisms remain largely unclear. We aim to identify the critical ESCC-associated lncRNAs and elucidate the functions and mechanisms in detail.MethodsMicroarrays were used to analyze the differentially expressed lncRNAs in ESCC tissues. qRT-PCR was used to verify the result of microarrays. The effects of the most up-regulated lncRNA, cancer susceptibility candidate 9(CASC9), on cell growth, proliferation and cell cycle were investigated by in vivo and in vitro assays. Microarrays and recovery tests were used to discover the regulatory targets of CASC9. RNA FISH and subcellular fractionation assays were used to detect the subcellular location of CASC9. Finally, the mechanism of CASC9 regulating PDCD4 was explored by RIP, RNA-protein pull down and ChIP assays.ResultsESCC tissue microarrays showed that CASC9 was the most up-regulated lncRNA. qRT-PCR analysis indicated that CASC9 expression was positively associated with tumor size and TNM stage, and predicted poor overall survival of ESCC patients. Knockdown of CASC9 inhibited ESCC cell growth in vitro and tumorigenesis in nude mice. Furthermore interfering CASC9 decreased cell proliferation and blocked cell cycle G1/S transition. CASC9-associated microarrays indicated that PDCD4 might be the target of CASC9. Consistent with this, PDCD4 expression was negatively associated with CASC9 expression in ESCC tissues and predicted good prognosis. Manipulating CASC9 expression in ESCC cells altered both PDCD4 mRNA and protein levels and cell cycle arrest caused by CASC9 knockdown could be rescued by suppressing PDCD4 expression. CASC9 located both in the nucleus and cytoplasm. Mechanistically, enhancer of zeste homolog2 (EZH2) could bind to both CASC9 and PDCD4 promoter region. Interfering CASC9 reduced the enrichment of EZH2 and H3K27me3 in the PDCD4 promoter region.ConclusionsOur study firstly demonstrates that lncRNA CASC9 functions as an oncogene by negatively regulating PDCD4 expression through recruiting EZH2 and subsequently altering H3K27me3 level. Our study implicates lncRNA CASC9 as a valuable biomarker for ESCC diagnosis and prognosis.


Journal of Cell Science | 2014

EGF-induced C/EBPβ participates in EMT by decreasing the expression of miR-203 in esophageal squamous cell carcinoma cells

Junxia Li; Fabo Shan; Gang Xiong; Xuedan Chen; Xingying Guan; Ju Ming Wang; Wen Lin Wang; Xueqing Xu; Yun Bai

ABSTRACT Epithelial–mesenchymal transition (EMT) is a developmental program that is associated with esophageal squamous cell carcinoma (ESCC) progression and metastasis. Recently, C/EBP&bgr; has been reported to be an EMT inducer in cancer. However, the detailed molecular mechanisms remain unclear. Here, we report for the first time, that the truncated CCAAT-enhancer-binding protein &bgr; (C/EBP&bgr;) LIP isoform is abnormally overexpressed and correlated with cancer metastasis in clinical specimens of human ESCC. Furthermore, we demonstrate that C/EBP&bgr; LIP mediates epithelial growth factor (EGF)-induced EMT and increases migration and invasion of esophageal cancer cells in a manner that is dependent on miR-203 inactivation. Finally, we identified miR-203 as a direct target of C/EBP&bgr; LIP. Disruption of C/EBP&bgr; LIP attenuated the EGF-mediated decrease in miR-203, whereas overexpression of C/EBP&bgr; LIP alone markedly suppressed miR-203. In addition, we demonstrated that C/EBP&bgr; LIP inhibited miR-203 transcription by directly interacting with a conserved distal regulatory element upstream of the miR-203 locus, and in doing so, orchestrated chromatin remodeling. In conclusion, our results have revealed a new regulatory mechanism that involves C/EBP&bgr;-LIP-mediated downregulation of miR-203, which plays a key role in EMT and metastasis.


Cell Death & Differentiation | 2018

LncRNA CASC9 promotes esophageal squamous cell carcinoma metastasis through upregulating LAMC2 expression by interacting with the CREB-binding protein

Yan Liang; Xuedan Chen; Yuanyuan Wu; Juan Li; Shixin Zhang; Kai Wang; Xingying Guan; Kang Yang; Yun Bai

Esophageal squamous cell carcinoma (ESCC) is the main subtype of esophageal cancer. Long noncoding RNAs (lncRNAs) are thought to play a critical role in cancer development. Recently, lncRNA CASC9 was shown to be dysregulated in many cancer types, but the mechanisms whereby this occurs remain largely unknown. In this study, we found that CASC9 was significantly upregulated in ESCC tissues, with further analysis revealing that elevated CASC9 expression was associated with ESCC prognosis and metastasis. Furthermore, we found that CASC9 knockdown significantly repressed ESCC migration and invasion in vitro and metastasis in nude mice in vivo. A microarray analysis and mechanical experiments indicated that CASC9 preferentially affected gene expression linked to ECM–integrin interactions, including LAMC2, an upstream inducer of the integrin pathway. We demonstrated that LAMC2 was consistently upregulated in ESCC and promoted ESCC metastasis. LAMC2 overexpression partially compromised the decrease of cell migration and invasion capacity in CASC9 knockdowns. In addition, we found that both CASC9 and LAMC2 depletion reduced the phosphorylation of FAK, PI3K, and Akt, which are downstream effectors of the integrin pathway. Moreover, the reduction in phosphorylation caused by CASC9 depletion was rescued by LAMC2 overexpression, further confirming that CASC9 exerts a pro-metastatic role through LAMC2. Mechanistically, RNA pull-down and RNA-binding protein immunoprecipitation (RIP) assay indicated that CASC9 could bind with the transcriptional coactivator CREB-binding protein (CBP) in the nucleus. Chromatin immunoprecipitation (ChIP) assay additionally illustrated that CASC9 increased the enrichment of CBP and H3K27 acetylation in the LAMC2 promoter, thereby upregulating LAMC2 expression. In conclusion, we demonstrate that CASC9 upregulates LAMC2 expression by binding with CBP and modifying histone acetylation. Our research reveals the prognostic and pro-metastatic roles for CASC9 in ESCC, suggesting that CASC9 could serve as a biomarker for prognosis and a target for metastasis treatment.


Journal of Cancer | 2015

Expression and Splice Variant Analysis of Human TCF4 Transcription Factor in Esophageal Cancer

Gang He; Xingying Guan; Xuedan Chen; Yan Wang; Chao Luo; Bo Zhang

Objective: The human T cell transcription factor-4 (TCF4) interacts functionally with β-catenin in the Wnt signaling pathway, whose deregulation is involved in the tumorigenesis of various types of cancers. Recent studies showed that TCF4 mRNAs were subject to alternative splicing, which was proposed to be important in regulating transactivational properties of the corresponding protein isoforms. Here we investigated the splicing isoforms and the roles of TCF4 in human esophageal squamous cell carcinoma. Methods: RT-PCR and subsequent cloning and sequencing were applied to identify the splicing isoforms. Western blotting and realtime PCR were used to analyze the expression of TCF4. Knockdown of TCF4 was achieved with siRNA and stable transfection of expression vectors was performed. Results: Our results showed there were a lot of different isoforms of TCF4 mRNA both in human esophageal cancers and cell line. Further, knockdown of TCF4E isoform expression in EC109 cells inhibited the cell growth, while overexpression of TCF4M isoform did not alter its transcription activity. Moreover, sixteen potential binding proteins of TCF4 were preliminarily identified by mass spectrometry. Conclusions: Our data suggested that deregulation of TCF4 isoforms may contribute to the tumorigenesis of ESCC.


Cancer Cell International | 2018

Overexpression of long non-coding RNA SOX2OT promotes esophageal squamous cell carcinoma growth

Yuanyuan Wu; Xuedan Chen; Yan Liang; Juan Li; Kun Zhang; Limeng Dai; Xingying Guan; Kai Wang; Yun Bai

BackgroundSOX2 overlapping transcript (SOX2OT) has been reported to be an important lncRNA in various cancers. SOX2 is embedded in an intron of the SOX2OT gene. But the role of SOX2OT in esophageal squamous cell carcinoma (ESCC) and the association between SOX2OT and SOX2 remain unclear.MethodsQuantitative PCR (qPCR) was used to detect the expression of SOX2OT and SOX2 in ESCC tissues and cells. The isoforms of SOX2OT were identified by PCR and confirmed by sequencing. CCK-8 and Edu assays were performed to investigate the effects of SOX2OT on cell growth. The relationship between SOX2OT and SOX2 was explored by luciferase reporter assay.ResultsBoth SOX2OT and SOX2 were upregulated in ESCC tissues and cells. SOX2OT expression was positively associated with SOX2 expression in ESCC tissues. NR_004053 was one of the major SOX2OT transcripts aberrantly expressed in ESCC tissues and cells. Overexpression of SOX2OT (NR_004053) promoted ESCC cell growth, antagonized the effect of DDP and increased cell proliferation ratio. Ectopic expression of SOX2 could increase the luciferase activity of SOX2OT-pGL3/Basic and SOX2OT expression, while overexpression of SOX2OT (NR_004053) had no effect on SOX2 expression.ConclusionOur study demonstrates that the major isoform of SOX2OT in ESCC, SOX2OT (NR_004053) contributes to cell growth. SOX2 promotes SOX2OT expression at transcriptional level.

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Yun Bai

Third Military Medical University

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Kai Wang

Third Military Medical University

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Xingying Guan

Third Military Medical University

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Juan Li

Third Military Medical University

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Gang Xiong

Third Military Medical University

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Kang Yang

Third Military Medical University

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Xueqing Xu

Third Military Medical University

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Hui Meng

Third Military Medical University

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Yan Liang

Third Military Medical University

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Yuanyuan Wu

Third Military Medical University

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