RESUMO
Gastric cancer (GC) remains a virtually incurable disease when metastatic and requires early screening tools for detection of early tumor stages. Therefore, finding effective strategies for prevention or recurrence of GC has become a major overall initiative. RNA-interference (RNAi) is an innovative technique that can significantly regulate the expression of oncogenes involved in gastric carcinogenesis, thus constituting a promising epigenetic approach to GC therapy. This review presents recent advances concerning the promising biomolecular mechanism of RNAi for GC treatment.
Assuntos
Recidiva Local de Neoplasia/prevenção & controle , RNA Interferente Pequeno/uso terapêutico , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Transformação Celular Neoplásica/genética , Citocinas/biossíntese , Citocinas/genética , Humanos , Recidiva Local de Neoplasia/genética , Proteínas Oncogênicas/biossíntese , Proteínas Oncogênicas/genética , Interferência de RNA , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genéticaRESUMO
Multidrug resistance (MDR) is a major impediment to successful chemotherapy of gastric cancer. Our aim was to establish an epirubicin-resistant cell subline (AGS/EPI) and to elucidate the mechanisms involved in acquired EPI resistance. The AGS/EPI cell subline developed by exposing parental AGS cells to stepwise increasing concentrations of EPI demonstrated 2.52-fold resistance relative to the AGS cell line, and mRNA expression of the ATP-dependent drug-efflux pump P-glycoprotein (Pgp), more recently known as ABCB1 protein, was similarly upregulated. An AGS/EPI cell subline could thus be effectively established, and MDR mechanism of these cells was shown to be related to the overexpression of mRNA of the ABCB1 gene.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Epirubicina/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/biossíntese , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Apoptose/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/genética , Humanos , RNA Mensageiro/biossíntese , Neoplasias Gástricas/genéticaRESUMO
Colorectal cancer (CRC) is the fourth most common cause of cancer-related mortality worldwide. Genetic alterations have been associated with an increased risk of cancer and greater tumor aggressiveness. Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) genes are important in cell cycle regulation, tumor growth and prostaglandin synthesis. The aim of the present study was to investigate the association between polymorphisms in the COX-2 and 5-LOX genes and the risk of CRC. A case-control study was conducted in patients with CRC matched for gender and age to a control group. DNA was extracted from peripheral leukocytes, and the polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism and gene sequencing. A specific questionnaire was applied to evaluate smoking, excessive alcohol consumption, physical activity, non-steroidal anti-inflammatory drug use and meat, fiber and fat intake. A total of 185 patients with CRC and 146 controls were studied. The heterozygous GC genotype of the COX-2 gene polymorphism was the most common in the two groups (60.0% in CRC patients and 52.7% in controls). The CC genotype was associated with an increased risk of CRC (odds ratio, 3.63; 95% confidence interval, 1.31-10.1; P=0.013). The homozygous wild-type genotype of the 5-LOX gene polymorphism was detected in 72.4% of the CRC patients and in 71.2% of the control subjects. The homozygous mutant genotype (CC) of the COX-2 gene is an independent risk factor for CRC. No association was found between 5-LOX genotypes and CRC.
RESUMO
AIM: To investigate the possible association between meat intake, cigarette smoking and N-acetyltransferase 2 (NAT2) genetic polymorphisms on colorectal cancer (CRC) risk. METHODS: Patients with CRC were matched for gender and age to healthy controls. Meat intake and cigarette smoking were assessed using a specific frequency questionnaire. DNA was extracted from peripheral blood and the genotypes of the polymorphism were assessed by polymerase chain reaction-restriction fragment length polymorphism. Five NAT2 alleles were studied (WT, M1, M2, M3 and M4) using specific digestion enzymes. RESULTS: A total of 147 patients with colorectal cancer (76 women and 90 men with colon cancer) and 212 controls were studied. The mean age of the two groups was 62 years. More than half the subjects (59.8% in the case group and 51.9% in the control group) were NAT2 slow acetylators. The odds ratio for colorectal cancer was 1.38 (95% CI: 0.90-2.12) in slow acetylators. Although the number of women was small (n = 76 in the case group), the cancer risk was found to be lower in intermediate (W/Mx) acetylators [odds ratio (OR): 0.55, 95% confidence interval (95% CI): 0.29-1.02]. This difference was not observed in men (OR: 0.56, 95% CI: 0.16-2.00). Among NAT2 fast acetylators (W/W or W/Mx), meat consumption more than 3 times a week increased the risk of colorectal cancer (OR: 2.05, 95% CI: 1.01-4.16). In contrast, cigarette smoking increased the risk of CRC among slow acetylators (OR: 1.97, 95% CI: 1.02-3.79). CONCLUSION: The risk of CRC was higher among fast acetylators who reported a higher meat intake. Slow NAT2 acetylation was associated with an increased risk of CRC.
