RESUMO
The objective of this study was to explore the pathophysiological relevance of WISP-2/CCN5 in progression of human pancreatic adenocarcinoma (PAC). We found WISP-2/CCN5 mRNA and protein expression was faint and sporadic in PAC and detected in only 8.7-20% of the samples with varying grades as compared to adjacent normal and chronic pancreatitis samples where expression was very high in the ducts and acini. Colocalization studies in tissue-microarray slides revealed WISP-2/CCN5 mRNA loss was associated with p53 overexpression in PAC. Like tissue samples, p53 mutant-PAC cell lines show loss of WISP-2/CCN5. Moreover, functional analysis studies demonstrate exposure of pancreatic cancer cells to WISP-2/CCN5 recombinant protein enhances mesenchymal-epithelial-transition (MET). Collectively, we suggest WISP-2/CCN5 silencing may be a critical event during differentiation and progression of PAC and mutant p53 is possibly an important player in pursuing this episode.
Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/genética , Neoplasias Pancreáticas/patologia , Transdução de Sinais/genética , Fatores de Transcrição/genética , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Northern Blotting , Western Blotting , Proteínas de Sinalização Intercelular CCN , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Progressão da Doença , Epitélio/metabolismo , Epitélio/patologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Hibridização In Situ , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Mesoderma/metabolismo , Mesoderma/patologia , Pâncreas/química , Pâncreas/metabolismo , Pâncreas/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Pancreatite Crônica/genética , Pancreatite Crônica/metabolismo , Pancreatite Crônica/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Proteínas Repressoras , Transdução de Sinais/fisiologia , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
BACKGROUND: Prenatal exposure to testicular hormones influences the development of brain structures and behavior in many non-human mammalian species. Less understood is the role of possessing a Y chromosome, independent of testicular hormones, on psychosexual differentiation. HYPOTHESIS: Phenotypic women affected by complete gonadal dysgenesis possess a 46,XY chromosome complement and streak gonads. This population is suitable to test the influence of an absence of androgens and Müllerian inhibiting substance on psychosexual development in genetic males. PATIENTS: Three 46,XY women diagnosed with complete gonadal dysgenesis participated. METHODS: Psychosexual development, medical outcome and knowledge of medical condition were assessed with a written questionnaire and a physical examination. RESULTS: All participants were healthy, compliant with their hormone therapy, and exhibited female-typical psychosexual development. However, participants were poorly informed about their condition and the fertility treatment options available to them. CONCLUSIONS: These data indicate no obvious role for genes on the Y chromosome, outside of its pseudoautosomal region and SRY, on psychosexual differentiation in genetic males who do not produce testicular hormones. Greater efforts need to be made to educate affected women about their pregnancy options.