Bangliang Yin

Promoter Hypermethylation of the RUNX3 Gene in Esophageal Squamous Cell Carcinoma

Alteration in transforming growth factor-β (TGF-β) signaling pathway is one of the main causes of esophageal squamous cell carcinoma (ESCC). The human runt-related transcription factor 3 (RUNX3), an important component of TGF-β pathway which is located at 1p36, is commonly deleted in a variety of human cancers, including ESCC. Hypermethylation of RUNX3 promoter was frequently found in gastrointestinal cancers, including those of stomach, liver, colon and pancreas. However, RUNX3 promoter methylation status in ESCC has not been studied. The aim of this study was to determine whether promoter methylation of the RUNX3 gene correlates with ESCC tumor progression.Accordingly, we first determined RUNX3 mRNA expression and methylation status of its promoter region in 42 primary tumors with ESCC and Eca-109, an ESCC cell line. Loss of RUNX3 mRNA expression was detected by RT-PCR in 23 out of 42 (54.8%) ESCC specimens and Eca-109 cells. The Promoter hypermethylation was detected by Methylation Specific Polymerase Chain Reaction (MS-PCR) in 27 out of 42 (64.3%) ESCC specimen and Eca-109 cells.Importantly, we found positive correlations, not only between the promoter hypermethylation and tumor clinical pathologic stages (P = 0.003), but also between the loss of RUNX3 mRNA expression and the tumor progression (P = 0.016). Finally, we observed that the loss of RUNX3 mRNA expression is statistically correlated with the promoter hypermethylation in these tumors (P < 0.001). Our results suggest that epigenetic silencing of RUNX3 gene expression by promoter hypermethylation may play an important role in ESCC development.

Abnormal Histone Acetylation and Methylation Levels in Esophageal Squamous Cell Carcinomas

To investigate whether alterations in histone modifications occur in esophageal squamous cell carcinoma (ESCC), we measured histone H3/ H4 acetylation and H3K4/H3K27 methylation levels, as well as the expression of chromatin modifier genes in tumor and healthy esophageal tissue from ESCC patients. We found evidence of global H3 and H4 hypoacetylation, H3K4 and H3K27 hypermethylation in ESCC tissue. Both H3 hypoacetylation and H3K27 hypermethylation correlated with the severity and histological differentiation of the tumor, and H3K4 hypermethylation also correlated with tumor differentiation. Our results suggest that aberrant histone modifications may play an important role in the development and progression of ESCC.

DNA methylation in thoracic neoplasms.

Thoracic neoplasms, which include lung cancers, esophageal carcinoma, and thymic epithelial tumors, are the leading causes of tumor-related death and a major health concern worldwide. The development of neoplasms is a multistep process involving both genetic and epigenetic alterations. A growing body of research provides evidence that aberrant DNA methylation, including DNA hypermethylation in promoter regions, global DNA hypomethylation and the overexpression of DNA methyltransferases, plays an important role in tumorigenesis. In this review, we summarize published observations of methylation pattern disruptions in thoracic tumors, and discuss how these abnormalities contribute to the development of cancers. We review recent findings showing that suppressing the activity of the DNA methylating enzymes DNMTs can have potent anti-cancer effects, and discuss the possibility of developing novel therapies for thoracic tumors based on DNMT inhibition.

Regulation of Mcl-1 by constitutive activation of NF-kappaB contributes to cell viability in human esophageal squamous cell carcinoma cells

BackgroundEsophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies with a 5-year survival rate less than 15%. Understanding of the molecular mechanisms involved in the pathogenesis of ESCC becomes critical to develop more effective treatments.MethodsMcl-1 expression was measured by reverse transcription (RT)-PCR and Western blotting. Human Mcl-1 promoter activity was evaluated by reporter gene assay. The interactions between DNA and transcription factors were confirmed by electrophoretic mobility shift assay (EMSA) in vitro and by chromatin immunoprecipitation (ChIP) assay in cells.ResultsFour human ESCC cell lines, TE-1, Eca109, KYSE150 and KYSE510, are revealed increased levels of Mcl-1 mRNA and protein compare with HaCaT, an immortal non-tumorigenic cell line. Results of reporter gene assays demonstrate that human Mcl-1 promoter activity is decreased by mutation of kappaB binding site, specific NF-kappaB inhibitor Bay11-7082 or dominant inhibitory molecule DNMIkappaBalpha in TE-1 and KYSE150 cell lines. Mcl-1 protein level is also attenuated by Bay11-7082 treatment or co-transfection of DNMIkappaBalpha in TE-1 and KYSE150 cells. EMSA results indicate that NF-kappaB subunits p50 and p65 bind to human Mcl-1-kappaB probe in vitro. ChIP assay further confirm p50 and p65 directly bind to human Mcl-1 promoter in intact cells, by which regulates Mcl-1 expression and contributes to the viability of TE-1 cells.ConclusionsOur data provided evidence that one of the mechanisms of Mcl-1 expression in human ESCC is regulated by the activation of NF-kappaB signaling. The newly identified mechanism might provide a scientific basis for developing effective approaches to treatment human ESCC.

microRNAs in esophageal cancer (Review)

Esophageal cancer (EC) is one of the most common malignant tumors worldwide. EC is usually diagnosed at a locally advanced stage or at a stage with involvement of lymph nodes. Despite aggressive treatment, the overall five-year survival rate remains poor. microRNAs (miRNAs) are small, non-coding endogenous RNAs that negatively regulate gene expression at the post-transcriptional and/or translational level. Accumulating evidence suggests that the deregulation of miRNAs not only results in cancer progression, but also directly promotes tumor initiation. Previous studies found that miRNAs are frequently deregulated in EC, indicating that miRNAs are important in tumorigenesis. In this review, we summarize therecently recognized miRNA expression and its impact on the biology of EC and the potential applications for EC.

Aberrant DNA Methylation in Thymic Epithelial Tumors

Aberrant DNA methylation plays a critical role in the development and progression of many types of cancer. To investigate whether DNA methylation is abnormal in thymic epithelial tumors (TETs), we analyzed global methylation levels and the methylation status of 9 tumor suppressor gene (TSG) promoters in 65 TET samples. We found evidence of TSG promoter hypermethylation and decreased TSG expression in severe TETs. Furthermore, relative to early-stage TETs, global DNA methylation levels were reduced and DNA methyltransferase expression was increased in advanced-stage TETs. Our results suggest that aberrant DNA methylation is associated with TET development.

Genome-wide profiling of DNA methylation and gene expression in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is the leading cause of cancer-related death worldwide. Previous studies have suggested that DNA methylation involved in the development of ESCC. However, the precise mechanisms underlying the regulation and maintenance of the methylome as well as their relationship with ESCC remain poorly understood. Herein, we used methylated DNA immunoprecipitation sequencing (MeDIP-Seq) and RNA-Seq to investigate whole-genome DNA methylation patterns and the genome expression profiles in ESCC samples. The results of MeDIP-Seq analyses identified differentially methylated regions (DMRs) covering almost the entire genome with sufficient depth and high resolution. The gene ontology (GO) analysis showed that the DMRs related genes belonged to several different ontological domains, such as cell cycle, adhesion, proliferation and apoptosis. The RNA-Seq analysis identified a total of 6150 differentially expressed genes (3423 up-regulated and 2727 down-regulated). The significant GO terms showed that these genes belonged to several molecular functions and biological pathways. Moreover, the bisulfite-sequencing of genes MLH1, CDH5, TWIST1 and CDX1 confirmed the methylation status identified by MeDIP-Seq. And the mRNA expression levels of MLH1, TWIST1 and CDX1 were consistent with their DNA methylation profiles. The DMR region of MLH1 was found to correlate with survival. The identification of whole-genome DNA methylation patterns and gene expression profiles in ESCC provides new insight into the carcinogenesis of ESCC and represents a promising avenue through which to investigate novel therapeutic targets.

Microduplication of 7q36.3 encompassing the SHH long‑range regulator (ZRS) in a patient with triphalangeal thumb‑polysyndactyly syndrome and congenital heart disease

Triphalangeal thumb-polysyndactyly syndrome (TPT-PS) is an autosomal dominant disorder with complete penetrance and a variable expression consisting of opposable triphalangeal thumbs, duplication of the distal thumb phalanx, pre-axial polydactyly and duplication of the big toes (hallux). The causative gene of TPT-PS has been mapped to 7q36.3. Sonic hedgehog (SHH) expressed in the zone of polarizing activity (ZPA) has an important role in defining the anterior-posterior axis and numbers of digits in limb bud development. Point mutation or duplication in the ZPA regulatory sequence (ZRS), a cis-regulator of SHH, will lead to TPT-PS. The present study describes a 1-year-old female congenital heart disease (CHD) patient with TPT-PS phenotype. In this Han Chinese family with TPT-PS, high resolution single nucleotide polymorphism array technology identified a novel 0.29 Mb duplication comprising ZRS at 7q36.3 where LMBR1 is located. Additionally, a novel deletion of 22q11.21 was detected in the proband with Tetralogy of Fallot. However, the parents and other relatives of the patient did not harbor this genomic lesion nor CHD. The findings supported the hypothesis that an increased copy number variation of ZRS is the genetic mechanism underlying the phenotype of TPT-PS, and corroborated that 22q11.21 deletion is a genetic cause of CHD.

The Clinical Experience of Double-orifice Tricuspid Valve

BACKGROUND AND AIM OF THE STUDY Double-orifice tricuspid valve (DOTV) is an extremely rare congenital anomaly. By analysing the feature of its diagnosis and surgical treatment, we want to summarise the clinical experience of treating DOTV. MATERIALS AND METHODS Review two cases of DOTV treated by us between August 2009 and December 2011. One case was diagnosed as partial atrioventricular septum defect, and the other was tetralogy of Fallot. The defects were both identified during the operation for other congenital cardiac malformations and both accessory orifices were normal. But one of them was sutured because of its possible effect in future. RESULTS Cardiac colour Doppler echocardiogram was made at three to five days after operation and all results were normal. No operative complication or late deaths occurred. The time of follow-up were one month, three months, six months, one year and two years after operation, and all examinations were normal. CONCLUSIONS The accessory orifice of DOTV patients has its own independent chordae tendinea and mastoid muscle. So the gap of tricuspid valve should be excluded and the classification should be amended according to it. It should be surgically treated, when there is of dysfunction with it or potential harmful effect in sequent treatment.

Giant right atrial cystic hamartoma: a case report and literature review.

An 11-year-old boy presenting with palpitation and chest distress was found to have gross cardiomegaly on chest radiography. Subsequent echocardiography revealed an intramural giant cystic mass in the right atrium. An operative measure was planned to prevent acute cardiac tamponade and right coronary artery obstruction. The patient successfully underwent open cystectomy to remove the mass, which was located on the front wall of the right atrium and extended to the atrioventricular appendage. Histopathological examination confirmed a cystic hamartoma. To the best of our knowledge, this is the first reported case of a giant cystic hamartoma located on the right atrium. Trial registration number: 704640