Purpose: MicroRNAs regulate gene expression by binding to the 3′-untranslated region (UTR) of target genes. Single-nucleotide polymorphisms of critical genes may affect their regulation by microRNAs. We have identified a single-nucleotide polymorphism within the miR-502 seed binding region in the 3′-UTR of the SET8 gene. SET8 methylates TP53 and regulates genome stability. We investigated the role of this SET8 singlenucleotide polymorphism and in concert with the TP53 codon 72 single-nucleotide polymorphism in the propensity for onset of breast cancer. Experimental Design: We measured the SET8 single-nucleotide polymorphisms in a case-control study on 1,110 breast cancer cases and 1,097 controls. Results: The SET8 CC and TP53 GG genotypes were independently associated with an earlier age of breast cancer onset in an allele-dose-dependent manner (for SET8, 52.2 years for TT, 51.4 for TC, and 49.5 for CC; and for TP53, 53.1 years for CC, 51.5 for GC, 50.7 for GG). Individuals with combined SET8 CC and TP53 GG genotypes developed cancer at a median age of 47.7 years as compared with 54.6 years for individuals with combined SET8 TT and TP53 CC genotypes. In the 51 breast cancer tissue samples tested, the SET8 CC genotype was associated with reduced SET8, but not miR-502, transcript levels. Conclusions: These data suggest that the miR-502-binding site single-nucleotide polymorphism in the 3′-UTR of SET8 modulates SET8 expression and contributes to the early development of breast cancer, either independently or together with the TP53 codon 72 single-nucleotide polymorphism. Larger studies with multiethnic groups are warranted to validate our findings. (Clin Cancer Res 2009;15(19):6292-300)

BackgroundGrowth arrest-specific 5 (GAS5) was reported to be implicated and aberrantly express in multiple cancers. However, the expression and mechanism of action of GAS5 were largely poor understood in endometrial carcinoma.ResultsAccording to the result of real-time reverse-transcriptase polymerase chain reaction (RT-PCR) and flow cytometry analysis, we identified that GAS5 was down-regulated in endometrial cancer cells and stimulated the apoptosis of endometrial cancer cells. To investigate the expression of GAS5, PTEN and miR-103, RT-PCR was performed. And we found that the expression of PTEN was up-regulated when endometrial cancer cells overexpressed GAS5. The prediction of bioinformatics online revealed that GAS5 could bind to miR-103, which was further found to be regulated by GAS5. Finally, we found that miR-103 mimic could decrease the mRNA and protein levels of PTEN through luciferase reporter assay and western blotting, and GAS5 plasmid may reverse this regulation effect in endometrial cancer cells.ConclusionIn summary, we demonstrate that GAS5 acts as an tumor suppressor lncRNA in endometrial cancer. Through inhibiting the expression of miR-103, GAS5 significantly enhanced the expression of PTEN to promote cancer cell apoptosis, and, thus, could be an important mediator in the pathogenesis of endometrial cancer.

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Establishment of functional and stable collaterals in the ischemic myocardium is crucial to restoring cardiac function after myocardial infarction. Here, we show that only dual delivery of a combination of angiogenic and arteriogenic factors to the ischemic myocardium could significantly reestablish stable collateral networks and improve myocardial perfusion and function. A combination of FGF-2 with PDGF-BB, two factors primarily targeting endothelial cells and vascular smooth muscle cells, remarkably promotes myocardial collateral growth and stabilizes the newly formed collateral networks, which significantly restore myocardial perfusion and function. Using various members of the PDGF family together with FGF-2 in an angiogenesis assay, we demonstrate that PDGFR-␣ is mainly involved in angiogenic synergism, whereas PDGFR-␤ mediates vessel stability signals. Our findings provide conceptual guidelines for the clinical development of proangiogenic/arteriogenic factors for the treatment of ischemic heart disease.angiogenesis ͉ growth factor ͉ ischemia ͉ myocardial infarction ͉ neovascularization A therosclerosis-induced coronary artery disease is the leading cause of morbidity and mortality in Western societies and increases at an alarming rate in developing countries (1). Usually, progressive atherosclerosis results in plaque rupture and thrombosis of major coronary arteries, leading to angina, myocardial infarction, and heart failure (2). Except for surgical interventions, an effective therapeutic method for treatment has been lacking. Although delivery of proangiogenic factors to the ischemic myocardium to stimulate collaterogenesis and to improve myocardial perfusion and function is a straightforward idea proposed for Ͼ30 years, clinical evaluation of these individual proangiogenic molecules has produced unfulfilled promises (3-5). After more than a decade of clinical practice with different single proangiogenic factors for the treatment of ischemic disorders, almost all large randomized, double-blinded, and placebo-controlled human trials have proven to be nonbeneficial (6-8).The clinical failures with this attractive approach have raised several unresolved fundamental issues regarding the basic mechanisms of cardiovascular biology. These include the underlying mechanisms of angiogenesis versus arteriogenesis, choice of proangiogenic agents, monotherapy versus combinatorial therapy, appropriate animal models for preclinical evaluation, optimal drug release systems, and time line of delivery. For improvement of perfusion of high-oxygenated blood in ischemic tissues, it is essential to reestablish functional arterial vascular networks, which should remain stable long-term. Most previous preclinical and clinical studies on the development of proangiogenic therapies for treating ischemic myocardium have been based on monotherapeutic approaches (9-20). These approaches usually lack rationales for understanding the molecular mechanisms of arteriogenesis, for defining molecular targets of the deliverable proangiogeni...

Summary Apoptosis plays critical role in diabetic cardiomyopathy and endoplasmic reticulum stress (ERS) is one of intrinsic apoptosis pathways. For previous studies have shown that endoplasmic reticulum become swell in diabetic myocardium and ERS was involved in diabetes mellitus and heart failure, this study aimed to demonstrate whether ERS was induced in myocardium of streptozocin (STZ)-induced diabetic rats. We established type 1 diabetic rat model with STZ intraperitoneal injection, used echocardiographic evaluation, hematoxylineosin staining and the terminal deoxynucleotidyl transferase-mediated DNA nick-end labeling staining to identify the existence of diabetic cardiomyopathy and enhanced apoptosis in the diabetic heart. We performed immunohistochemistry, Western blot and real time PCR to analysis two hallmarks of ERS, glucose regulated protein78 (Grp78) and Caspase12. We found both Grp78 and Caspase12 had enhanced expression in protein and mRNA levels in diabetic myocardium than normal rat's, and Caspase12 was activated in diabetic heart. Those results suggested that ERS was induced in STZ-induced diabetic rats' myocardium, and ERS-associated apoptosis took part in the pathophysiology of diabetic cardiomyopathy.