No abstract

Purpose: Squamous esophageal cancer is common in non-Western countries and has a welldefined progression of preinvasive dysplasia leading to invasive squamous cell carcinoma. We examined the changes in promoter region methylation occurring during neoplastic progression. Experimental Design: The frequency of epigenetic changes in the promoter region of 14 genes epigenetically silenced in other cancers was determined and examined the most frequent changes in dysplastic lesions using methylation-specific PCR. Invasive squamous carcinomas, low to high grade dysplasia, and normal esophagus were then examined for methylation changes in the promoter region of each of the eight most commonly methylated genes. Results: Methylation was most frequent for CDKN2A/p16INK4a (52%) but was also common for O 6 -methylguanine-DNA methyltransferase, E-cadherin (CDH1), and retinoic acid receptor h2. Methylation at individual genes increased in frequency from normal to invasive cancer. Methylation of MLH1 was associated with microsatellite instability in most cases. The number of genes methylated in individual lesions increased as cellular atypia increased. In individual patients, cancers adjacent to dysplasia had the same epigenetic alterations as the less advanced lesions but often had additional methylation of other genes. Conclusions: These findings suggest that epigenetic progression parallels the histologic changes observed in the progression of squamous carcinoma of the esophagus.

We conducted a joint (pooled) analysis of three genome-wide association studies (GWAS) 1-3 of esophageal squamous cell carcinoma (ESCC) in ethnic Chinese (5,337 ESCC cases and 5,787 controls) with 9,654 ESCC cases and 10,058 controls for follow-up. In a logistic regression model adjusted for age, sex, study, and two eigenvectors, two new loci achieved genome-wide significance, marked by rs7447927 at 5q31.2 (per-allele odds ratio (OR) = 0.85, 95% CI 0.82-0.88; P=7.72x10−20) and rs1642764 at 17p13.1 (per-allele OR= 0.88, 95% CI 0.85-0.91; P=3.10x10−13). rs7447927 is a synonymous single nucleotide polymorphism (SNP) in TMEM173 and rs1642764 is an intronic SNP in ATP1B2, near TP53. Furthermore, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at highest risk for ESSC (OR=1.33, 95% CI 1.22-1.46; P=1.99x10−10). Our joint analysis identified new ESCC susceptibility loci overall as well as a new locus unique to the ESCC high risk Taihang Mountain region.

We previously found that antisense oligonucleotide specific to ClC-3 (ClC-3 antisense) prevented rat aortic smooth muscle cell proliferation, which was related to cell volume regulation. In the present study, we further characterized the regulation of intracellular Cl

Stretch of the vascular wall stimulates smooth muscle hypertrophy by activating the MAPK and Rho/Rho kinase (ROK) pathways. We investigated the role of calcium in this response. Stretch-stimulated expression of contractile and cytoskeletal proteins in mouse portal vein was inhibited at mRNA and protein levels by blockade of voltage-dependent Ca 2؉ entry (VDCE). In contrast, blockade of store-operated Ca 2؉ entry (SOCE) did not affect smooth muscle marker expression but decreased global protein synthesis. Activation of VDCE caused membrane translocation of RhoA followed by phosphorylation of its downstream effectors LIMK-2 and cofilin-2. Stretch-activated cofilin-2 phosphorylation depended on VDCE but not on SOCE. VDCE was associated with increased mRNA expression of myocardin, myocyte enhancer factor (MEF) -2A and -2D, and smooth muscle marker genes, all of which depended on ROK activity. SOCE increased ERK1/2 phosphorylation and c-Fos expression but had no effect on phosphorylation of LIMK-2 and cofilin-2 or on myocardin and MEF2 expression. Knockdown of MEF2A or -2D eliminated the VDCE-induced activation of myocardin expression and increased basal c-Jun and c-Fos mRNA levels. These results indicate that MEF2 mediates VDCEdependent stimulation of myocardin expression via the Rho/ ROK pathway. In addition, SOCE activates the expression of immediate-early genes, known to be regulated by MEF2 via Ca 2؉ -dependent phosphorylation of histone deacetylases, but this mode of Ca 2؉ entry does not affect the Rho/ROK pathway. Compartmentation of Ca2؉ entry pathways appears as one mechanism whereby extracellular and membrane signals influence smooth muscle phenotype regulation, with MEF2 as a focal point.