RESUMO
Prostate cancer is one of the leading causes of mortality among aging males. There is an unmet requirement of clinically useful biomarkers for early detection of prostate cancer to reduce the liabilities of overtreatment and accompanying morbidity. The present population-based study investigates the factors disrupting expression of multiple functionally related genes of DNA mismatch repair pathway in prostate cancer patients to identify molecular attributes distinguishing adenocarcinoma from benign hyperplasia of prostate. Gene expression was compared between tissue samples from prostate cancer and benign prostatic hyperplasia using real-time-PCR, western blot and immunohistochemistry. Assessment of genotypes of seven single-nucleotide-polymorphisms of three MMR genes was conducted using PCR-coupled RFLP and sequencing. Promoter methylation was interrogated by methylation-specific-PCR and bisulfite-sequencing. Interaction between microRNAs and MMR genes was verified by 3'UTR-based dual luciferase assays. Concurrent reduction of three MMR genes namely hMLH1, hMSH6 and hMSH2 (34-85%, P<0.05) was observed in prostate cancer tissues. hMSH6 polymorphism rs1800932(Pro92Pro) conferred a borderline protection in cancer patients (OR = 0.33, 95% CI = 0.15-0.75). Relative transcript level of hMLH1 was inversely related (r = -0.59, P<0.05) with methylation quotient of its promoter which showed a significantly higher methylation density (P = 0.008, Z = -2.649) in cancer patients. hsa-miR-155, hsa-miR-141 and hsa-miR-21 gene expressions were significantly elevated (66-85%, P<0.05) in tumor specimens and negatively correlated (r = -0.602 to -0.527, P<0.05) with that of MMR genes. hsa-miR-155 & hsa-miR-141 and hsa-miR-155 & hsa-miR-21 were demonstrated to bind to their putative seed sequences in hMLH1 and hMSH6 3'UTRs respectively. Relatively higher expression of DNA methyl-transferases (DNMT1 and DNMT3b) and HIF-1α genes (34-50%, P<0.05) were also detected in tumor tissues. This study provides statistical evidence that MMR deficiency is correlated with hypermethylation of hMLH1 promoter and upregulation of hsa-miR-155, hsa-miR-141 and hsa-miR-21 in prostate cancer. This comparative study reflects that microRNA expression level, particularly hsa-miR-155, exhibits predictive signature of prostate adenocarcinoma.
Assuntos
Reparo de Erro de Pareamento de DNA/genética , Hiperplasia Prostática/genética , Hiperplasia Prostática/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Transdução de Sinais , Regiões 3' não Traduzidas , Idoso , Alelos , Sequência de Bases , Sítios de Ligação , Biomarcadores Tumorais , Ilhas de CpG , Metilação de DNA , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Frequência do Gene , Genótipo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , MicroRNAs/química , MicroRNAs/genética , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Hiperplasia Prostática/diagnóstico , Neoplasias da Próstata/diagnóstico , Interferência de RNA , Análise de Sequência de DNARESUMO
Schwannomas, also known as neurilemmomas, are benign peripheral nerve sheath tumors. Trigeminal schwannomas are rare intracranial tumors. Here, we report a 35-year-old female presenting with an axial proptosis of right eyeball with right-sided III, IV and VI cranial nerve palsy. Her best corrected visual acuity in the right eye was perception of light absent and in the left eye was 20/20. MRI scan revealed a large right-sided heterogeneous, extra-axial middle cranial fossa mass that extended to the intraconal space of right orbit. A diagnosis of intracranial trigeminal nerve schwannoma with right orbital extension was made. Successful surgical excision of the mass with preservation of the surrounding tissues and orbital exenteration was done. Post-operative period was uneventful.