RESUMO
The nuclear factor-kappaB (NF-kappaB) family of transcription factors regulates a wide variety of cellular processes including cell growth, differentiation, and apoptosis. NF-kappaB has been shown to be activated through several signaling pathways that involve growth factor receptors. The aim of the study was to assess the immunohistochemical expression of members of the NF-kappaB family and the putative targets of NF-kappaB in a series of medullary thyroid carcinomas (MTCs), in correlation with RET mutational status. A tissue microarray was constructed from paraffin-embedded blocks of 48 MTCs (13 familial, 35 sporadic) previously evaluated for germ line and somatic RET mutations. Immunohistochemical evaluation included members of the NF-kappaB (p50, p65, p52, c-Rel, RelB) family, as well as putative targets of NF-kappaB such as Flip, Bcl-xL, and cyclin D1. Nuclear immunostaining for members of NF-kappaB was frequent in MTCs (p50, 19%; p65, 68%; p52, 86.6%; c-Rel, 75%; RelB, 36%). MTCs with germ line or somatic RET mutations (29 cases) showed NF-kappaB nuclear translocation (particularly of p65, P = .035) more frequently than MTCs without RET mutations (19 cases). Immunostaining for putative targets of NF-kappaB showed a significant statistical association between p65 and Bcl-xL (P = .024). In addition, Bcl-xL expression was statistically higher in the tumors with exon 16 RET mutation in comparison with those with exon 10 and 11 RET mutations or wild-type RET (P = .002). Moreover, the significance of RETsignaling in NF-kappaB activation was evaluated in the RET-mutated TT cell line. TT cells were infected with lentiviruses carrying short hairpin RNA to knock down RET expression, and NF-kappaB activity was assessed by luciferase reporter assays. Silencing of RET in the TT cell line produced a significant decrease in NF-kappaB activation and reduction in ERK1/2. The results suggest that the NF-kappaB is frequently activated in MTCs. The results also support the hypothesis that RET activation by somatic or germ line mutations may be responsible for NF-kappaB activation in MTCs.
Assuntos
Carcinoma Medular/genética , Mutação em Linhagem Germinativa , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias da Glândula Tireoide/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Medular/metabolismo , Carcinoma Medular/patologia , Linhagem Celular Tumoral , Humanos , Imuno-Histoquímica , Proteínas Proto-Oncogênicas c-ret/metabolismo , Interferência de RNA , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Análise Serial de Tecidos , Fator de Transcrição RelA/metabolismo , Proteína bcl-X/metabolismoRESUMO
Atypical polypoid adenomyoma (APA) is an uncommon and benign tumor of the uterus. In some patients, however, APA has been found to coexist with or to precede the development of an endometrioid adenocarcinoma similarly to complex endometrial hyperplasia. The molecular changes underlying the progression from APA to adenocarcinoma are unknown. DNA from paraffin-embedded tissue of 6 APAs was evaluated for microsatellite instability (MI), MLH-1 promoter hypermethylation, and CTNNB-1 mutations. Tissue sections were also subjected to MLH-1, MSH-2, and beta-catenin immunostaining. MI was not detected in any case. Two tumors exhibited MLH-1 promoter hypermethylation and showed focal negative MHL-1 immunostaining; 1 of these showed marked architectural complexity and cellular pleomorphism. Five cases presented beta-catenin nuclear immunoreactivity, but none of them had CTNNB-1 mutations. The results of this study suggest that APA and complex endometrial hyperplasia may share some molecular alterations. Some APAs exhibit MLH-1 promoter hypermethylation with focal lack of MLH-1 immunostaining, a molecular abnormality involved in the transition from complex atypical hyperplasia to endometrioid adenocarcinoma.
Assuntos
Adenomioma/genética , Neoplasias Uterinas/genética , Proteínas Adaptadoras de Transdução de Sinal , Adenomioma/metabolismo , Adenomioma/patologia , Adulto , Idoso , Proteínas de Transporte , Proteínas do Citoesqueleto/genética , Metilação de DNA , Análise Mutacional de DNA , DNA de Neoplasias/análise , Feminino , Humanos , Imuno-Histoquímica , Repetições de Microssatélites , Proteína 1 Homóloga a MutL , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares , Reação em Cadeia da Polimerase , Transativadores/genética , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia , beta CateninaAssuntos
Neoplasias dos Genitais Femininos/patologia , Segunda Neoplasia Primária/patologia , Neoplasias Peritoneais/patologia , Células Clonais/patologia , Análise Mutacional de DNA , DNA de Neoplasias/genética , Mecanismo Genético de Compensação de Dose , Feminino , Neoplasias dos Genitais Femininos/etiologia , Neoplasias dos Genitais Femininos/genética , Humanos , Perda de Heterozigosidade , Metástase Neoplásica , Segunda Neoplasia Primária/genética , Neoplasias Peritoneais/genéticaRESUMO
The clinical, histologic, and molecular pathologic features of two cases of malignant mullerian mixed tumor (MMMT) arising from ovarian papillary serous carcinoma are presented. Identical p53 mutations were detected in the primary ovarian carcinoma and the subsequent MMMT in each case.