Cigarette Smoking and p16INK4α Gene Promoter Hypermethylation in Non-Small Cell Lung Carcinoma Patients: A Meta-Analysis

BACKGROUND:Aberrant methylation of promoter DNA and transcriptional repression of specific tumor suppressor genes play an important role in carcinogenesis. Recently, many studies have investigated the association between cigarette smoking and p16(INK4α) gene hypermethylation in lung cancer, but could not reach a unanimous conclusion. METHODS AND FINDINGS:Nineteen cross-sectional studies on the association between cigarette smoking and p16(INK4α) methylation in surgically resected tumor tissues from non-small cell lung carcinoma (NSCLC) patients were identified in PubMed database until June 2011. For each study, a 2×2 cross-table was extracted. In total, 2,037 smoker and 765 nonsmoker patients were pooled with a fixed-effects model weighting for the inverse of the variance. Overall, the frequency of p16(INK4α) hypermethylation was higher in NSCLC patients with smoking habits than that in non-smoking patients (OR = 2.25, 95% CI = 1.81-2.80). The positive association between cigarette smoking and p16(INK4α) hypermethylation was similar in adenocarcinoma and squamous-cell carcinoma. In the stratified analyses, the association was stronger in Asian patients and in the studies with larger sample sizes. CONCLUSION:Cigarette smoking is positively correlated to p16(INK4α) gene hypermethylation in NSCLC patients

Divergent Genomic and Epigenomic Landscapes of Lung Cancer Subtypes Underscore the Selection of Different Oncogenic Pathways during Tumor Development

For therapeutic purposes, non-small cell lung cancer (NSCLC) has traditionally been regarded as a single disease. However, recent evidence suggest that the two major subtypes of NSCLC, adenocarcinoma (AC) and squamous cell carcinoma (SqCC) respond differently to both molecular targeted and new generation chemotherapies. Therefore, identifying the molecular differences between these tumor types may impact novel treatment strategy. We performed the first large-scale analysis of 261 primary NSCLC tumors (169 AC and 92 SqCC), integrating genome-wide DNA copy number, methylation and gene expression profiles to identify subtype-specific molecular alterations relevant to new agent design and choice of therapy. Comparison of AC and SqCC genomic and epigenomic landscapes revealed 778 altered genes with corresponding expression changes that are selected during tumor development in a subtype-specific manner. Analysis of >200 additional NSCLCs confirmed that these genes are responsible for driving the differential development and resulting phenotypes of AC and SqCC. Importantly, we identified key oncogenic pathways disrupted in each subtype that likely serve as the basis for their differential tumor biology and clinical outcomes. Downregulation of HNF4α target genes was the most common pathway specific to AC, while SqCC demonstrated disruption of numerous histone modifying enzymes as well as the transcription factor E2F1. In silico screening of candidate therapeutic compounds using subtype-specific pathway components identified HDAC and PI3K inhibitors as potential treatments tailored to lung SqCC. Together, our findings suggest that AC and SqCC develop through distinct pathogenetic pathways that have significant implication in our approach to the clinical management of NSCLC

Transcriptional Analysis of the dd-Peptidase/Penicillin-Binding Protein-Encoding dac Gene of Streptomyces R61: Use of the Promoter and Signal Sequences in a Secretion Vector

The promoter region of the gene encoding the extracellular DD-peptidase/penicillin-binding protein of Streptomyces R61 has been identified by in vivo promoter probing and S1 mapping. A secretion vector, pDML116, was constructed by inserting into the multicopy Streptomyces plasmid pIJ702, a 247 bp DNA sequence that contained the transcriptional, translational and secretory signals and the 12 amino acid N-terminal region-encoding sequence of the mature Streptomyces DD-peptidase/penicillin-binding protein. Insertion, downstream of this 247 bp segment, of the Streptomyces R61 DD-peptidase-encoding gene or the Escherichia coli R-TEM beta-lactamase-encoding gene yielded plasmids pDML120 and pDML128, respectively, which allowed expression and secretion of the relevant enzymes by Streptomyces lividans. The maximal secretion levels obtained were 42 mg protein/ml for the autologous Streptomyces DD-peptidase and 0.9 mg protein/ml for the heterologous E. coli beta-lactamase

Hormonally mediated maternal effects shape offspring survival potential in stressful environments

In most egg-laying vertebrates, maternal responses to stressful conditions are translated into the release of glucocorticoid hormones such as cortisol, which are then transmitted to their developing embryos. Although such maternally transmitted hormonal resources have been shown to influence or even interfere with the optimal developmental trajectories of offspring in many taxa, their influence on the dynamics of wild fish populations remains largely unexplored. Here, we examined the extent to which simulated hormonally mediated maternal effects influence the development and early survival of the coral reef damselfish, Pomacentrus amboinensis. Concentrations of cortisol in the eggs were manipulated within naturally occurring limits by immersion. We found that the proportion of embryos that delayed hatching when exposed to high levels of cortisol was considerably lower than in the other two treatments (low cortisol dose and control). High cortisol levels in P. amboinensis eggs resulted in increased egg mortality and greater asymmetry in hatchlings. For embryos that successfully hatched, individuals from the elevated cortisol treatments (especially low dose) survived longer after hatching. Although individuals that originated from eggs with elevated cortisol levels survived longer after hatching, they may not gain an overall survival advantage. Our results suggest that subtle increases in the allocation of maternally derived hormones, such as cortisol, to offspring are a direct way for stressed mothers to endow their young with an immediate survival advantage. We propose that this immediate benefit outweighs the developmental costs which may be expressed as reduced fitness at later life stages