RESUMO
PURPOSE: Although mucinous adenocarcinomas represent 6% to 19% of all colorectal adenocarcinomas, little is known about the genome-wide alterations associated with this malignancy. We have sought to characterize both the gene expression profiles of mucinous adenocarcinomas and their clinicopathologic features. METHODS: Tumors from 171 patients with primary colorectal cancer were profiled using the Affymetrix HG-U133Plus 2.0 GeneChip with characterization of clinicopathologic data. Gene ontology software was used to identify altered biologic pathways. RESULTS: Twenty (11.7%) mucinous adenocarcinomas and 151 (89.3%) nonmucinous adenocarcinomas were identified. Mucinous adenocarcinomas were more likely to be diagnosed with lymph node (LN) metastases (75% vs 51%, P = .04) and at a more advanced stage (85% vs 54%, P = .006) but long-term survival (5-y survival 58.9% vs 58.7%, P = NS) was similar. Mucinous adenocarcinomas displayed 182 upregulated and 135 downregulated genes. The most upregulated genes included those involved in cellular differentiation and mucin metabolism (eg, AQP3 + 4.6, MUC5AC +4.2, MUC2 + 2.8). Altered biologic pathways included those associated with mucin substrate metabolism (P = .002 and .02), amino acid metabolism (P = .02), and the mitogen-activated protein kinase cascade (P = .02). DISCUSSION: Using gene expression profiling of mucinous adenocarcinomas, we have identified the differential upregulation of genes involved in differentiation and mucin metabolism, as well as specific biologic pathways. These findings suggest that mucinous adenocarcinomas represent a genetically distinct variant of colorectal adencarcinoma and have implications for the development of targeted therapies.
Assuntos
Adenocarcinoma Mucinoso/genética , Adenocarcinoma/genética , Neoplasias Colorretais/genética , Perfilação da Expressão Gênica , Adenocarcinoma/patologia , Adenocarcinoma Mucinoso/patologia , Análise de Variância , Aquaporina 3/genética , Distribuição de Qui-Quadrado , Neoplasias Colorretais/patologia , Humanos , Metástase Linfática , Análise em Microsséries , Mucina-5AC/genética , Mucina-2/genética , Modelos de Riscos Proporcionais , Taxa de SobrevidaRESUMO
Stat transcription factors are activated by cytokines and can activate pathways important in oncogenesis. Although previous studies have identified an oncogenic role of Stat3 in lung cancer cells, the role of Stat1 is unclear. Using a mutant of Stat1 with constitutive activity (Stat1C), we examined the effect of persistent Stat1 activity on lung cancer cell growth, survival and gene expression. We identified no significant effect of Stat1C alone or with interferon-gamma (IFN-gamma) on lung cancer cell growth or survival. Consistent with prior reports, Stat1C expression alone elicited minimal changes in gene expression and required costimulatory IFN-gamma for full activity. Using oligonucleotide gene arrays and quantitative real-time PCR, we identified numerous proinflammatory gene products and chemokines regulated by IFN-gamma/Stat1C signaling. These results suggest the major role of IFN-gamma and Stat1 in lung cells is to direct a proinflammatory gene expression program rather than have major effects on cell growth or survival or both.
Assuntos
Antivirais/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Interferon gama/farmacologia , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Quimiocinas/biossíntese , Quimiocinas/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Inflamação/genética , Inflamação/metabolismo , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/genéticaRESUMO
Green tea catechins (GTCs) exert chemopreventive effects in many cancer models. Several studies implicate the DNA synthesis marker minichromosome maintenance protein 7 (MCM7) in prostate cancer progression, growth and invasion; representing a novel therapeutic target. In this study, we investigated the effect of GTCs on MCM7 expression in the transgenic adenocarcinoma mouse prostate model (TRAMP). DNA microarray, immunohistochemistry and western blot analysis showed that GTCs significantly suppressed MCM7 in the TRAMP mice treated with GTCs. Our study indicates that the cellular DNA replication factor MCM7 is involved in prostate cancer (CaP) and MCM7 gene expression was reduced by GTCs. Together, these results suggest a possible role of GTCs in CaP chemoprevention in which MCM7 plays a critical role.
