Mechanisms and role of microRNA deregulation in cancer onset and progression

MicroRNAs are key regulators of various fundamental biological processes and, although representing only a small portion of the genome, they regulate a much larger population of target genes. Mature microRNAs (miRNAs) are single-stranded RNA molecules of 20–23 nucleotide (nt) length that control gene expression in many cellular processes. These molecules typically reduce the stability of mRNAs, including those of genes that mediate processes in tumorigenesis, such as inflammation, cell cycle regulation, stress response, differentiation, apoptosis and invasion. MicroRNA targeting is mostly achieved through specific base-pairing interactions between the 5′ end (‘seed’ region) of the miRNA and sites within coding and untranslated regions (UTRs) of mRNAs; target sites in the 3′ UTR diminish mRNA stability. Since miRNAs frequently target hundreds of mRNAs, miRNA regulatory pathways are complex. Calin and Croce were the first to demonstrate a connection between microRNAs and increased risk of developing cancer, and meanwhile the role of microRNAs in carcinogenesis has definitively been evidenced. It needs to be considered that the complex mechanism of gene regulation by microRNAs is profoundly influenced by variation in gene sequence (polymorphisms) of the target sites. Thus, individual variability could cause patients to present differential risks regarding several diseases. Aiming to provide a critical overview of miRNA dysregulation in cancer, this article reviews the growing number of studies that have shown the importance of these small molecules and how these microRNAs can affect or be affected by genetic and epigenetic mechanisms

Positive association of the hepatic lipase gene polymorphism c.514C > T with estrogen replacement therapy response

<p>Abstract</p> <p>Background</p> <p>Hepatic lipase (HL), an enzyme present in the hepatic sinusoids, is responsible for the lipolysis of lipoproteins. Human HL contains four polymorphic sites: G-250A, T-710C, A-763G, and C-514T single-nucleotide polymorphism (SNPs). The last polymorphism is the focus of the current study. The genotypes associated with the C-514T polymorphism are CC (normal homozygous - W), CT (heterozygous - H), and TT (minor-allele homozygous - M). HL activity is significantly impaired in individuals of the TT and CT genotypes. A total of 58 post-menopausal women were studied. The subjects were hysterectomized women receiving hormone replacement therapy consisting of 0.625 mg of conjugated equine estrogen once a day. The inclusion criteria were menopause of up to three years and normal blood tests, radiographs, cervical-vaginal cytology, and densitometry. DNA was extracted from the buccal and blood cells of all 58 patients using a commercially available kit (GFX^®- Amersham-Pharmacia, USA).</p> <p>Results</p> <p>Statistically significant reductions in triglycerides (t = 2.16; n = 58; p = 0.03) but not in total cholesterol (t = 0.14; n = 58; p = 0.89) were found after treatment. This group of good responders were carriers of the T allele; the CT and TT genotypes were present significantly more frequently than in the group of non-responders (p = 0.02 or p = 0.07, respectively). However, no significant difference in HDL-C (t = 0.94; n = 58; p = 0.35) or LDL-C (t = -0.83; n = 58; p = 0.41) was found in these patients.</p> <p>Conclusions</p> <p>The variation in lipid profile associated with the C-514T polymorphism is significant, and the T allele is associated with the best response to ERT.</p

Isoflavone regulates Vascular Endothelial Growth Factor Expression in urinary tract of castrated rats

Objective: the purpose of this Study was to investigate Vascular Endothelial Growth Factor Expression (VEGF) gene regulation by isoflavone in urinary tract tissues of castrated adult rats.Design: Forty-five adult rats, 90 days old, weighting 200g were used, receiving a soy-free ration. the animals were castrated for drug administration for 30 days (125 mu g genisteine/g body weight/day) and sacrificed, divided into three groups: Group I-control: Group II-started isoflavone administration on the 5th day after castration; Group III-starred isoflavone administration on the 28th day after castration. RNA was isolated from each bladder and urethra. Determination of VEGF gene regulated by isoflavone was obtained using a semiquantitative RT-PCR and immunohistochemistry of total RNA isolated from bladder and urethra.Results: Our results demonstrate that isoflavone was able to upregulate mRNA level of the VEGF gene in the lower urinary tract of rats in Group II, where isoflavone administration was started at an early phase of estrogen deprivation, while in Group III, where isoflavone administration was started in the late phase of hypoestrogenism, did not show alteration of bladder and urethra VEGF gene expression, compared to placebo, maintaining the same level of the castrated rats without treatment.Conclusions: the data indicate that VEGF expression in rats is also regulated by isoflavone in early phase of hypoestrogenism. (C) 2009 Elsevier Ireland Ltd. All rights reserved.Universidade Federal de São Paulo, Lab Mol Gynecol, Dept Gynecol, São Paulo, BrazilUniversidade Federal de São Paulo, Lab Mol Gynecol, Dept Gynecol, São Paulo, BrazilWeb of Scienc