Epigenetics in bladder cancer

Bladder cancer (BC) is the second most common malignancy of the genitourinary tract and the second leading cause of cancer death in patients with urinary tract malignancies. DNA methylation and histone modifications are important epigenetic mechanisms of gene regulation and play essential roles both independently and cooperatively in tumor initiation and progression. Aberrant epigenetic events such as DNA hypermethylation and altered histone acetylation have both been observed in bladder cancer, in which they affect a large number of genes. Although the list of aberrantly epigenetically regulated genes continues to grow, combination analysis including several candidate genes has given promising results of potential tumor biomarkers for the early diagnosis and risk assessment of bladder cancer. Thus, large-scale screening of aberrant epigenetic events such as DNA hypermethylation is needed to identify bladder cancer-specific epigenetic fingerprints. The reversibility of epigenetic aberrations has made them attractive targets for cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases, leading to the reactivation of silenced genes. In this review, we examine the current literature on epigenetic changes in bladder cancer and discuss the clinical potential of cancer epigenetics for the diagnosis and treatment of this disease.     

An overview of biomarkers for the ovarian cancer diagnosis

Even though there are a lot of options in treating gynecological malignancies, ovarian cancer still remains a leading cause of death. Diagnosis at an early stage is the most important determinant of survival. Current diagnostic tools applied at clinics have had very limited success in early detection. Discovery of new diagnostic biomarkers/panels for early diagnosis of ovarian cancer is one of the main challenges of modern medicine. With the progress of techniques in genomics and proteomics, numerous molecular biomarkers/panels were identified and showed promise for ovarian cancer diagnosis, but still need further validation. This article summarizes various types of markers investigated by different strategies/technologies for the ovarian cancer diagnosis at present, including gene-, protein-based and emerging ovarian cancer indicators (such as microRNA-, metabolite-based). Before biomarker tests are translated for routine use, more researches, such as retrospective and prospective clinical trials, are needed to evaluate the overall clinical utility of the tests.     

Epirubicin-mediated expression of miR-302b is involved in osteosarcoma apoptosis and cell cycle regulation

Epirubicin is widely used in osteosarcoma chemotherapy. Growing evidence indicates that the microRNA (miRNA) expression levels which are induced by chemotherapeutic agents play an important role in osteosarcoma development and progression. In this study we investigate the alterations of miRNA expression in the osteosarcoma cells after epirubicin treatment and whether miRNAs can enhance its anti-osteosarcoma effect. After epirubicin exposure, microarray shows 40 miRNAs are differentially expressed in osteosarcoma cells including 24 down-regulated miRNAs. Notably, miR-302b, which is stably low-expressed in osteosarcoma, could be induced by the epirubicin. Furthermore, we find that miR-302b can inhibit the osteosarcoma cell proliferation, promote cell apoptosis and cell cycle arrest MiR-302b can activate caspase-3 and regulate the Akt/pAkt, Bcl-2, Bim expression to increase the cell apoptosis. Meanwhile, miR-302b also attenuates cyclin D1 and CDKs expression to induce cell cycle arrest. Therefore, our results suggest miR-302b can play an essential role in osteosarcoma treatment as a potential tumor suppressor.     

Human blastocysts exhibit unique microrna profiles in relation to maternal age and chromosome constitution

Purpose

To determine microRNA (miRNA) expression in human blastocysts relative to advanced maternal age and chromosome constitution.

Methods

Cryopreserved human blastocysts were warmed and underwent a trophectoderm biopsy for comprehensive chromosomal screening. Select blastocysts were then lysed, reverse transcribed, and pre-amplified prior to running real-time PCR. Statistical analysis was performed using an internal constant housekeeping miRNA. Significant microRNA’s of interest were then analyzed for their predicted genes and biological pathways. Additional cryopreserved blastocysts were warmed and stained for the SIRT1 protein for validation.

Results

Human blastocysts exhibit unique miRNA expression profiles in relation to maternal age and chromosome constitution. miR-93 was exclusively expressed in blastocysts from women in their forties and further up-regulated with an abnormal chromosome complement. Up-regulated miR-93 resulted in an inverse down-regulation of targets like SIRT1, resulting in reduced oxidative defense.

Conclusions

MiRNAs play an important role in aging as well as chromosome constitution and have downstream effects that regulate proteins which can compromise embryonic development.     

MicroRNA-related polymorphisms in pseudoexfoliation syndrome,pseudoexfoliative glaucoma,and primary open-angle glaucoma

Background: Pseudoexfoliation syndrome (PEX) and glaucoma (pseudoexfoliative glaucoma; PEXG, primary open-angle glaucoma; POAG) have mainly been studied for their associations with genes’ polymorphisms. The purpose of this exploratory study was to investigate the role of polymorphisms in genes encoding for micro RNAs (miRNAs) and in genes related to miRNA biogenesis.

Material and Methods: In the present genetic association study, ninety-two polymorphisms were investigated for their contribution to PEX (n = 203), PEXG (n = 38), and POAG (n = 40) pathogenesis compared to a control group (n = 188). The next generation sequencing (NGS) genotypic analysis revealed data for additional 28 variants.

Results: A protective association was found between PEX and polymorphism 11382316 (mir-3161) [odds ratio (OR) = 0.64, 95% confidence interval (CI): 0.47–0.86, p = 0.003], rs2155248 (mir-1304) [OR = 0.66, 95%CI: 0.47–0.94, p = 0.019], and rs28635903 (mir-1268a) [OR = 0.30, 95%CI: 0.10–0.94, p = 0.029]. Polymorphism rs113297757 (mir-3196) was associated with an increased risk of POAG [OR = 7.75, 95%CI: 2.13–28.76, p = 3 × 10^?4]. Polymorphism rs1057035 (DICER) and rs55671916 (XPO5) in the 3?-UTR of genes related to miRNA biogenesis was associated with decreased risk of PEX [OR = 0.65, 95%CI: 0.46–0.92, p = 0.014] and increased risk of PEXG [OR = 2.84, 95%CI: 1.02–7.94, p = 0.038], respectively. The aforementioned associations according to the allelic model were further supported by the genotypic models of statistical analyses.

Conclusions: This is the first study to report distinct associations of PEX, PEXG, and POAG in the same population with variants of genes involved in miRNA biogenesis and with miRNA genes’ polymorphisms. Further studies in larger groups of patients of various origins are needed to confirm the reported preliminary results.     

Identification of Differentially Expressed MicroRNAs in the Ovary of Polycystic Ovary Syndrome with Hyperandrogenism and Insulin Resistance

Background:Polycystic ovary syndrome (PCOS) is the commonest endocrinopathy in women of reproductive age.The patients often develop insulin resistance (IR) or hyperinsulinemia despite manifesting anovu...     

Enhancing adoptive T cell immunotherapy with microRNA therapeutics

Adoptive T cell-based immunotherapies can mediate complete and durable regressions in patients with advanced cancer, but current response rates remain inadequate. Maneuvers to improve the fitness and antitumor efficacy of transferred T cells have been under extensive exploration in the field. Small non-coding microRNAs have emerged as critical modulators of immune system homeostasis and T cell immunity. Here, we summarize recent advances in our understanding of the role of microRNAs in regulating T cell activation, differentiation, and function. We also discuss how microRNA therapeutics could be employed to fine-tune T cell receptor signaling and enhance T cell persistence and effector functions, paving the way for the next generation of adoptive immunotherapies.