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1.
Gastroenterology ; 141(3): 1091-101, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21699781

RESUMO

BACKGROUND & AIMS: Rb1 encodes a cell-cycle regulator that is functionally disrupted in most human cancers. Pancreatic ductal adenocarcinomas (PDACs) have a high frequency of mutations in KRAS and INK4A/CDKN2A that might allow cells to bypass the regulatory actions of retinoblastoma (RB). To determine the role of loss of RB function in PDAC progression, we investigated the effects of Rb disruption during pancreatic malignant transformation initiated by oncogenic Kras. METHODS: We generated mice with pancreas-specific disruption of Rb, in the absence or presence of oncogenic Kras, to examine the role of RB in pancreatic carcinogenesis. RESULTS: In the presence of oncogenic Kras, loss of Rb from the pancreatic epithelium accelerated formation of pancreatic intraepithelial neoplasia (PanIN), increased the frequency of cystic neoplasms, and promoted rapid progression toward PDAC. Early stage cancers were characterized by acute pancreatic inflammation, associated with up-regulation of proinflammatory cytokines within the pancreas. Despite the presence of markers associated with oncogene-induced senescence, low-grade PanIN were highly proliferative and expressed high levels of p53. Pancreatic cancer cell lines derived from these mice expressed high levels of cytokines, and transcriptional activity of p53 was impaired. CONCLUSIONS: Rb encodes a tumor suppressor that attenuates progression of oncogenic Kras-induced carcinogenesis in the pancreas by mediating the senescence response and promoting activity of the tumor suppressor p53.


Assuntos
Carcinoma in Situ/fisiopatologia , Senescência Celular/fisiologia , Deleção de Genes , Neoplasias Pancreáticas/fisiopatologia , Lesões Pré-Cancerosas/fisiopatologia , Proteínas Proto-Oncogênicas p21(ras)/fisiologia , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/fisiologia , Adenocarcinoma/patologia , Adenocarcinoma/fisiopatologia , Animais , Carcinoma in Situ/patologia , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/fisiopatologia , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/patologia , Citocinas/fisiologia , Modelos Animais de Doenças , Progressão da Doença , Camundongos , Camundongos Mutantes , Neoplasias Pancreáticas/patologia , Lesões Pré-Cancerosas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/fisiologia
2.
Cancer Epidemiol Biomarkers Prev ; 18(1): 57-64, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19124481

RESUMO

PURPOSE: The inability to predict clinical outcome of prostate cancer is a major impediment to effective treatment decisions and patient counseling. New markers of recurrence are needed to improve the accuracy of risk assessment and treatment of prostate cancer. Our previous studies identified a mismatch repair protein, PMS2, to be elevated in prostate cancer; here, we investigate the prognostic potential of this marker. We hypothesized that the elevation of PMS2 would correlate with disease outcome. EXPERIMENTAL DESIGN: Retrospective quantitative immunohistochemistry was done to measure PMS2 in high-grade cancers of 166 men treated by radical prostatectomy with a biochemical recurrence rate of 56%. Associations between PMS2 levels, pathologic variables, and biochemical recurrence over time were determined. RESULTS: The mean level of PMS2 protein was consistently higher in both cancer-associated benign epithelium and cancer cells of patients who recurred, compared with nonrecurrent patients. PMS2 was an independent predictor of time-to-recurrence in Cox multivariate analyses and significantly stratified patients based on outcome. PMS2 was able to improve the sensitivity of total percent Gleason 4/5 as a risk factor for recurrence in this cohort. CONCLUSIONS: PMS2 protein levels were shown to be a predictor of time-to-recurrence after surgery. This study is the first to document that the elevation of a mismatch repair protein negatively correlates with prognosis and has implications in patient diagnosis and molecular profiling.


Assuntos
Adenosina Trifosfatases/metabolismo , Reparo de Erro de Pareamento de DNA , Enzimas Reparadoras do DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Recidiva Local de Neoplasia/metabolismo , Neoplasias da Próstata/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Prostatectomia , Neoplasias da Próstata/cirurgia , Estudos Retrospectivos , Taxa de Sobrevida
3.
Prostate ; 67(2): 214-25, 2007 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-17044039

RESUMO

BACKGROUND: Defects in mismatch repair (MMR) proteins have been identified in various types of cancer. However, an association with prostate cancer has been controversial. Defective MMR results in genome instability with detrimental consequences that significantly contribute to tumorigenesis. This study determined alterations in key MMR protein levels in prostate cancer with the goal to identify prognostic markers. METHODS: Prostatectomy samples were immunohistochemically stained and the relative presence or absence of key proteins MSH2, MLH1, and PMS2 determined. Cancer tissue of distinct grades was compared with the normal surrounding tissue. Microsatellite instability (MSI) in altered tissues was determined according to NCI guidelines. RESULTS: In contrast to reports that associate a lack of individual MMR proteins with tumorigenesis, a significant increase in PMS2 levels was identified in PIN lesions and prostate cancer tissue. This elevation in PMS2 was independent of changes in levels in its heterodimeric partner, MLH1. Prostate tumors with elevated levels of PMS2 were genetically unstable, which was corrected by MLH1 co-elevation. CONCLUSIONS: This is the first documentation of detrimental consequences associated with the increase in a MMR protein in human cancer. This study recognizes PMS2 elevation as a prognostic marker in pre-neoplastic and prostate cancer lesions. This result has significant implications for future diagnostic and treatment measures.


Assuntos
Adenocarcinoma/genética , Adenosina Trifosfatases/genética , Reparo de Erro de Pareamento de DNA , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Neoplasias da Próstata/genética , Proteínas Adaptadoras de Transdução de Sinal , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenosina Trifosfatases/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Masculino , Repetições de Microssatélites/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Prognóstico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia
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