RESUMO
Octamerbinding transcription factor 4 (OCT4) is one of the factors associated with selfrenewal and differentiation in cancer stem cells, and is crucial for the progression of various types of human malignancy. However, the expression and function of OCT4 in human pancreatic cancer has not been fully elucidated. The purpose of the present study was to investigate the function and molecular mechanisms of OCT4 in pancreatic cancer cells. The clinical significance of OCT4 expression was assessed by an immunohistochemical assay using a tissue microarray procedure in pancreatic cancer tissues and cells with different degrees of differentiation. A lossoffunction approach was used to examine the effects of a lentivirusmediated OCT4 small hairpin RNA vector on biological behaviors, including cell proliferative activity and invasive potential. The results demonstrated that the expression levels of OCT4 protein in cancer tissues were significantly elevated compared with those in adjacent noncancerous tissues (65.0 vs. 42.5%; P=0.005), which was correlated with tumor differentiation (P=0.008). The knockdown of OCT4 inhibited the proliferation and invasion of pancreatic cancer cells (Panc1) expressing high levels of OCT4, accompanied with decreased expression of AKT, proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase2 (MMP2). In conclusion, the present study reveals that the increased expression of OCT4 is correlated with the differentiation of pancreatic cancer, while knockdown of OCT4 suppresses the growth and invasion of pancreatic cancer cells through inhibition of AKT pathwaymediated PCNA and MMP2 expression, suggesting that OCT4 might serve as a potential therapeutic target for the treatment of pancreatic cancer.
Assuntos
Fator 3 de Transcrição de Octâmero/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Terapia Genética , Humanos , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Neoplasias Pancreáticas/patologia , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de SinaisRESUMO
OBJECTIVE: The aim of this study was to evaluate the effects of XRCCl gene polymorphisms and its haplotype on the susceptibility of pancreatic carcinoma. METHODS: Peripheral blood DNA was extracted from 210 pancreatic carcinoma patients and 213 control subjects. SNaPshot technique was used for genotyping seven SNP sites of the XRCCl gene (rs3213403, rs25487, rs1799782, rs731420, rs1001581, rs12611088, and rs3213282). Logistic regression model was performed to analyze the relationship of different genotypes or haplotype and the susceptibility of pancreatic carcinoma. RESULTS: The frequency for allele A at site rs25487 in the case group was significantly higher than that in the control group (P < 0.05). The frequency of GG, GA and AA genotype between the case group and control group had statistically significant differences (P < 0.05). Compared with GG genotype, the risk of pancreatic carcinoma in the subjects carrying mutated allele A (GA+AA) was increased by 0.648 times (P < 0.05). Among them the pancreatic carcinoma risk of individuals carrying A allele was increased by 0.552 times compared with the individuals carrying G allele. The frequency of allele and genotype at site rs1799782 in the case group and control group had a significant difference (P < 0.05). Compared with the CC genotype, the risk of pancreatic carcinoma in the subjects carrying mutated allele T (CT+TT) was increased by 0.683 times. Among them the pancreatic carcinoma risk of individuals carrying T allele was increased by 0.549 times compared with the individuals carrying C allele. Significant differences were observed in linkage disequilibrium between any two of the seven SNPs (P < 0.05), the frequency of H4-AGCCCGC, H6-GGCCCGG or H7-AGCCTAG haplotypes was significantly lower in the case group than that in the control group (P < 0.05). CONCLUSIONS: The single nucleotide polymorphisms of rs25487 and rs1799782 for XRCC1 gene may be correlated with the occurrence of pancreatic carcinoma. The haplotypes of H4-AGCCCGC, H6-GGCCCGG and H7-AGCCTAG might be a potential genetic protective factor for the occurrence of pancreatic carcinoma.
