RESUMEN
The insulin-like growth factor-I (IGF-IR) and androgen (AR) receptors are important players in prostate cancer. Functional interactions between the IGF-I and androgen signaling pathways have crucial roles in the progression of prostate cancer from early to advanced stages. DNA methylation is a major epigenetic alteration affecting gene expression. Hypermethylation of tumor suppressor promoters is a frequent event in human cancer, leading to inactivation and repression of specific genes. The aim of the present study was to identify the entire set of methylated genes ("methylome") in a cellular model that replicates prostate cancer progression. The methylation profiles of the P69 (early stage, benign) and M12 (advanced stage, metastatic) prostate cancer cell lines were established by treating cells with the demethylating agent 5-aza-2'-deoxycytidine (5-Aza) followed by DNA microarray analysis. Comparative genome-wide methylation analyses of 5-Aza-treated versus untreated cells identified 297 genes overexpressed in P69 and 191 genes overexpressed in M12 cells. 102 genes were upregulated in both benign and metastatic cell lines. In addition, our analyses identified the PITX2 gene as a master regulator upstream of the AR and IGF-IR genes. The PITX2 promoter was semi-methylated in P69 cells but fully methylated (i. e., silenced) in M12 cells. Epigenetic regulation of PITX2 during the course of the disease may lead to orchestrated control of the AR and IGF signaling pathways. In summary, our results provide new insights into the epigenetic changes associated with progression of prostate cancer from an organ confined, androgen-sensitive disorder to an aggressive, androgen-insensitive disease.
Asunto(s)
Metilación de ADN/genética , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/metabolismo , Neoplasias de la Próstata/genética , Receptor IGF Tipo 1/genética , Receptores Androgénicos/genética , Factores de Transcripción/metabolismo , Genes Relacionados con las Neoplasias/genética , Proteínas de Homeodominio/genética , Humanos , Masculino , Persona de Mediana Edad , Regiones Promotoras Genéticas/genética , Receptor IGF Tipo 1/metabolismo , Receptores Androgénicos/metabolismo , Factores de Transcripción/genética , Proteína del Homeodomínio PITX2RESUMEN
About forty years ago, Henry Kaplan and collaborators reported that four weekly X-ray doses of 160 rads each were highly leukemogenic in C57BL mice. A single dose of 350 Rads had a week leukemogenic effect. These authors also demonstrated that lead shielding of the thigh during irradiation prevented the development of leukemia. They reported that intravenous injection of syngeneic bone marrow cells into irradiated mice facilitated the regeneration of the thymus and prevented the development of X-ray-induced tumors. We characterized the thymic Ia+ dendritic cells (DC) with the aid of a fluorescence-activated cell-sorter (FACS). It was found that exposure of mice to a leukemogenic regimen of fractionated X-irradiation treatment led to a gradual decrease in the number of thymic DC. The disappearance of thymic DC and the development of leukemia were prevented by intravenous injection of syngeneic bone marrow or by lead shielding of the femur during irradiation. These results indicated that the fractionated irradiation caused a decline in the number of DC and, as a result, diminution of the natural defense against the developing tumor. Homing of the injected bone marrow DC into the thymus can be connected to the prevention of tumor development. Since leukemogenic T cells produce interleukin-4(IL-4), we tested the effect of the conditioned medium in which YAB-3 cells (tumorigenic Th cells: CD4+, CD8-, Thy-1+) were cultivated. Following injection of the conditioned medium into the mouse footpads, the number of skin Langerhans cells (LC) decreased.(ABSTRACT TRUNCATED AT 250 WORDS)