RESUMO
Cancer is a major health problem. Most of the treatments exhibit systemic toxicity, as they are not targeted or specific to cancerous cells and tumors. Adenoviruses are very promising gene delivery vectors and have immense potential to deliver targeted therapy. Here, we review a wide range of strategies that have been tried, tested, and demonstrated to enhance the specificity of oncolytic viruses towards specific cancer cells. A combination of these strategies and other conventional therapies may be more effective than any of those strategies alone.
RESUMO
Genetic changes in colon cancer are known to parallel the tissue abnormalities associated with the disease, namely adenoma and adenocarcinoma. The role of microRNA dysregulation in dysplastic progression, however, is not well understood. Here, we show that miR-182 and miR-503 undergo sequential up-regulation and drive the progression of colon adenoma to adenocarcinoma by cooperatively down-regulating the tumour suppressor FBXW7. We identified that increased expression of miR-182 is a feature of adenomas. A subsequent increase in miR-503 expression works cooperatively with miR-182 to induce transformation of an adenoma to adenocarcinoma. We show that introducing miR-503 into AAC1 cells, which are derived from a benign adenoma, confers tumourigenic potential. We also demonstrated that blocking both miR-182 and miR-503 in HCT116 colon cancer cells resulted in increased FBXW7 expression and significantly reduced tumour size in xenograft models. We confirmed relevance of these results in patients by examining the expression levels of miR-182 and miR-503 in over 200 colon cancer patients with 12 year survival outcome data. Decreased patient survival was correlated with elevated expression of both miRNAs, suggesting that elevated levels of both miR-182 and miR-503 define a novel prognostic biomarker for colon cancer patients. In conclusion, we show that a sequential expression of miR-182 and miR-503 in benign adenoma cooperatively regulates the tumour suppressor FBXW7, contributing to the malignant transformation of colon adenoma to adenocarcinoma and miR-182 and miR-503 may prove to be novel therapeutic targets. Array data are available at: http://www.oncomir.umn.edu/
Assuntos
Adenocarcinoma/genética , Adenoma/genética , Proteínas de Ciclo Celular/biossíntese , Transformação Celular Neoplásica/genética , Neoplasias do Colo/genética , Proteínas F-Box/biossíntese , MicroRNAs/genética , Ubiquitina-Proteína Ligases/biossíntese , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenoma/mortalidade , Adenoma/patologia , Animais , Proteínas de Ciclo Celular/genética , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Proteínas F-Box/genética , Proteína 7 com Repetições F-Box-WD , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Hibridização In Situ , Estimativa de Kaplan-Meier , Camundongos , Camundongos Nus , Análise de Sequência com Séries de Oligonucleotídeos , Modelos de Riscos Proporcionais , Ubiquitina-Proteína Ligases/genéticaRESUMO
RNA interference (RNAi) is a novel and essential biological process, as well as a powerful experimental tool with the potential to be used in therapeutic development. RNAi-based strategies have the capability of being able to be driven from bench to bedside. It is very important to develop the precise tools for designing the siRNAs to get the most efficient knockdown of the target genes and to reduce any off-target effects. In this review we have discussed the strategies and parameters required for effective siRNA designing and synthesis, based on already published literature.
Assuntos
Desenho de Fármacos , Técnicas de Silenciamento de Genes/normas , RNA Interferente Pequeno/síntese química , Estabilidade de Medicamentos , Humanos , Modelos Genéticos , Interferência de RNA/efeitos dos fármacos , RNA Interferente Pequeno/uso terapêutico , SoftwareRESUMO
RNA interference (RNAi) is a sequence-specific mechanism to control the expression of target genes. This technique has proven potentials both in vivo and in vitro. The main hurdle for using RNAi-based therapy is the effective delivery of RNAi-based drugs to the target cells or tissues in vivo. The aspects of off-target effects, delivery methods, induction of immune response and dose determination for delivery should, however, be considered carefully. If these challenges associated with siRNA can be met, then the potentials of RNAi could be exploited to the full for the development of therapeutic tools and drugs.
