RESUMO
OBJECTIVE: Although DCC has been considered as a candidate tumor suppressor, the roles it plays in the uterine endometrium and in the carcinogenic process remains unclear. To define these roles more clearly, we examined the expression of DCC and its ligand, netrin-1, in the normal endometrium and in endometrial cancer. METHODS: The expression of DCC and netrin-1 in normal endometrial glands and in cancer cell lines was examined by RT-PCR and immunohistochemistry. The effects of exogenous DCC and netrin-1 expression were observed together with the respective expression vector transfection. RESULTS: Endometrial glands in the proliferative and early secretory phase expressed both DCC and netrin-1, but glands in the late-secretory phase tended to silence DCC expression. In addition, all of the endometrial cancer cell lines lost normal DCC expression. Restored DCC expression in the cancer cell lines in the absence of netrin-1 induced apoptosis. However, no changes were observed in the presence of netrin-1. CONCLUSION: Our observations suggest that DCC/netrin-1 signaling may commit cells to the transition of endometrial gland architecture or function from a proliferating to a secretory phase. In addition, the silencing of DCC expression may contribute to the escape of endometrial cancer cells from a DCC-regulated apoptotic program, thereby promoting malignant phenotypes.
Assuntos
Moléculas de Adesão Celular/biossíntese , Neoplasias do Endométrio/metabolismo , Endométrio/metabolismo , Fatores de Crescimento Neural/biossíntese , Proteínas Supressoras de Tumor/biossíntese , Adulto , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/farmacologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Receptor DCC , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Endométrio/fisiologia , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/farmacologia , Netrina-1 , Receptores de Superfície Celular , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Transfecção , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/farmacologiaRESUMO
We used microarray analysis to investigate expression profiles of 589 known genes committed to cell growth control to characterize regulatory circuitry for cell proliferation in complete moles (CMs). CMs are characterized by hyperplastic trophoblast and have a high propensity to give rise to choriocarcinoma. Characteristic alterations in gene expression profiles were observed when compared with normal villi. Fifty-seven genes were significantly up-regulated in CMs and involved the Ras-Map kinase 3, Jak-STAT5, and Wnt signal pathways, implicating growth factor or cytokine-mediated signal pathways in the trophoblastic hyperplasia of CMs. Several genes associated with anti-apoptosis, cell structuring, and/or cell attachment were also up-regulated in CMs. In contrast, relatively fewer genes were down-regulated and these involved IGFBPs, versican, interleukin-1, tumor necrosis factor receptor, CD44, and RAD52. Genes identified in this study may elucidate regulation mechanisms of trophoblastic proliferation and mechanisms causing a pathological phenotype in CMs.
Assuntos
Vilosidades Coriônicas/metabolismo , Mola Hidatiforme/genética , Mola Hidatiforme/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Trofoblastos/metabolismo , Neoplasias Uterinas/genética , Neoplasias Uterinas/metabolismo , Apoptose/genética , Apoptose/fisiologia , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Feminino , Genes cdc/fisiologia , Substâncias de Crescimento/genética , Substâncias de Crescimento/metabolismo , Humanos , GravidezRESUMO
OBJECTIVE: To study the causative conception of malignant gestational trophoblastic neoplasms (GTNs), we analyzed malignant GTNs by microsatellite PCR markers. METHOD: DNAs extracted from 12 malignant GTNs were subjected to PCR for five different chromosomal locations. RESULT: Of the 7 cases after a complete mole (CM), 5 were derived from androgenesis, but the remaining 2 were from normal fertilization. Of the 5 cases after nonmolar pregnancies, 2 placental site trophoblastic tumors had alleles from both parents. Of the other 3 choriocarcinomas, 1 was from normal fertilization after spontaneous abortion but 2 originated from androgenesis, suggesting that 1 was from a CM prior to the antecedent abortion, transforming after a long interval. CONCLUSION: By combining the previous cases with these, our analysis of 39 cases demonstrated that trophoblastic neoplasms can arise from at least three different modes of origin (androgenesis, normal fertilization, and parthenogenesis), and antecedent pregnancy is not always identical to the causative conception. Placental site trophoblastic tumors might have different machinery for carcinogenesis because of the predominance of paternal and maternal contributions. In addition, a long dormancy of trophoblasts before malignant transformation, especially for those originating from normal fertilization, was also suggested.
