An investigation into the function and regulation Of ERG Exon 7b

The ETS family transcription factor ERG is a key oncoprotein in bone, blood, vascular and most notably prostate cancer where it is activated in at least 50% of cases. Of the several splice isoforms of ERG with variable biological activity those that include the cassette exon 7b are associated with aggressiveness and progression of disease in prostate cancer. Inclusion of exon 7b adds 24 amino-acids in frame to the central ‘alternative domain’ which also contains binding sites for other transcriptional regulators. Alignment of the amino acids of exon 7b showed it is evolutionary conserved in echinoderms emphasizing its functional importance. Splice switching oligonucleotides (SSO) targeting the splice sites for exon 7b were designed to induce exon 7b skipping. Successful SSO-induced skipping of exon 7b in the osteosarcoma MG63 cell line resulted in decreased cell migration, invasion and proliferation and increased apoptosis in vitro and reduced tumour growth in vivo. ERG was shown to bind to the promoter of tissue non-specific alkaline phosphatase, a marker of cell differentiation, and SSO-induced skipping of exon 7b attenuated its expression. Moreover several splicing regulatory elements and proteins were identified using bioinformatics prediction methods and an RNA pull down of the 3´ splice site of exon 7b identified several potential splicing regulatory proteins for this exon. This study provides evidence that exon 7b enhances the oncogenic activity of ERG. It also confirms that SSOs can be used to modify the splicing of key oncogenes, significantly affecting their function. SSOs that target oncogenes could potentially be developed as therapeutic agents. It also highlights the requirement to understand splicing regulation of disease associated splicing events in ETS transcription factors and has provided pilot data for further study of ERG exon 7b splicing regulation

The oncogenic transcription factor ERG represses the transcription of the tumour suppressor gene PTEN in prostate cancer cells

© 2017, Spandidos Publications. All rights reserved. The oncogene ETS-related gene (ERG) encodes a transcription factor with roles in the regulation of haematopoiesis, angiogenesis, vasculogenesis, inflammation, migration and invasion. The ERG oncogene is activated in >50% of prostate cancer cases, generally through a gene fusion with the androgen-responsive promoter of transmembrane protease serine 2. Phosphatase and tensin homologue (PTEN) is an important tumour suppressor gene that is often inactivated in cancer. ERG overexpression combined with PTEN inactivation or loss is often associated with aggressive prostate cancer. The present study aimed to determine whether or not ERG regulates PTEN transcription directly. ERG was demonstrated to bind to the PTEN promoter and repress its transcription. ERG overexpression reduced endogenous PTEN expression, whereas ERG knockdown increased PTEN expression. The ability of ERG to repress PTEN may contribute to a more cancer-permissive environment

The effectiveness of bariatric surgery on long term psychosocial quality of life – A systematic review

© 2015 Asia Oceania Association for the Study of Obesity Background Little is known about the psychological effects of bariatric surgery. This review aimed to assess long term effectiveness of bariatric surgery on psychosocial quality of life (QoL) of obese adults compared to non-surgical interventions. Methods A systematic review of the literature was conducted, six electronic databases, plus other relevant sources were searched from inception to January 2014. The main outcome sought was a QoL measure with a minimum 12 months follow-up. Three reviewers screened records, extracted data and independently read through full articles for eligibility and quality using standardised forms. Findings were analysed using narrative synthesis. Results Of 4383 identified references included in the review, 11 studies showed bariatric surgery to be effective long term for overall QoL than non-surgical treatments with specifically modest benefits psychosocially. Significant improvements in psychosocial QoL alongside improved physical QoL were observed after 2 year follow-up post-surgery compared to non-surgical interventions. However improvements in psychosocial QoL after surgery at 10 year follow up were minimal when compared to non-surgical interventions. When compared to untreated control groups, long term psychosocial QoL did not improve after bariatric surgery despite major improvements in physical QoL, significant weight loss and co-morbidities. Conclusions Results on long term psychosocial QoL remain uncertain with some suggestion of psychological disorder persisting. This highlights need for psychological intervention post-surgery and further research to provide more data on long-term psychosocial QoL following bariatric surgery

Whole Blood Levels of the n-6 Essential Fatty Acid Linoleic Acid Are Inversely Associated with Stunting in 2-to-6 Year Old Tanzanian Children: A Cross-Sectional Study.

BACKGROUND:In Tanzania, 35% of all children below five years of age are stunted. Dietary fatty acids (FA) are critical for growth and development. However, whole blood FA levels in Tanzanian children are poorly described. OBJECTIVE:The objectives of this cross-sectional study were to assess 1) whole blood levels of essential fatty acids and 2) the association between whole blood FA levels and growth parameters in Tanzanian children 2-6 years of age. METHODS:A drop of blood was collected on an antioxidant treated card and analyzed for FA composition. Weight and height were measured and z-scores calculated. Relationships between FAs and growth parameters were analyzed by linear regression. RESULTS:Of the 334 children that participated, 30.3% were stunted. The average whole blood level of Mead acid was 0.15%. The anthropometric z-score height-for-age (HAZ) was inversely associated with Mead acid, the Mead acid to arachidonic acid (T/T) ratio, and total n-9 FA. Additionally, HAZ was positively associated with linoleic acid and total n-6 FA. BMI-for-age was positively associated with oleic acid, total n-9 FA and T/T ratio but inversely associated with arachidonic acid and total n-6 FA. Weight-for-height was inversely associated with arachidonic acid and total n-6 FAs and positively associated with oleic acid and total n-9 FA. Weight-for-age was not associated with any FA tested. Total n-3 FAs were not associated with any growth parameters measured. CONCLUSIONS:The EFA linoleic acid and the markers of FA deficiency were associated with HAZ, an indicator for stunting in 2-6 year old Tanzanian children. Total n-6, total n-9, and a number of individual FAs were associated with growth. Increasing dietary intake of EFA and n-6 FAs may be a strategy to combat stunting in this population

Regression¹ Results Between HAZ and Selected Fatty Acids.

<p>Regression<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0154715#t004fn001" target="_blank">¹</a> Results Between HAZ and Selected Fatty Acids.</p

Nutrition and Growth Status of Children¹.

<p>Nutrition and Growth Status of Children<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0154715#t002fn001" target="_blank">¹</a>.</p

Demographic Characteristics of the Participants¹.

<p>Demographic Characteristics of the Participants<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0154715#t001fn001" target="_blank">¹</a>.</p

Whole Blood Fatty Acid Proportions¹.

<p>Whole Blood Fatty Acid Proportions<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0154715#t003fn001" target="_blank">¹</a>.</p

Regression¹ Results Between BAZ and Selected Fatty Acids.

<p>Regression<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0154715#t005fn001" target="_blank">¹</a> Results Between BAZ and Selected Fatty Acids.</p

Summary of Significant Associations Between Fatty Acids and Growth Parameters.

<p>Summary of Significant Associations Between Fatty Acids and Growth Parameters.</p