Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Proteínas Quinases Associadas a Fase S/antagonistas & inibidores , Inibidor de Quinase Dependente de Ciclina p27/genética , Inibidor de Quinase Dependente de Ciclina p27/fisiologia , Sistemas de Liberação de Medicamentos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Mutação/fisiologia , Neoplasias/genética , RNA Interferente Pequeno/uso terapêutico , Resultado do Tratamento , Células Tumorais CultivadasRESUMO
This review aims in presenting the established and putative prognostic markers in non-small cell lung carcinoma (NSCLC). We have focused on the molecular/genetic alterations accompanying the pathogenesis of this malignancy, which may derange the cellular response to external and internal stimuli. A variety of factors influencing cell cycle progression, programmed cell death, drug resistance and immune evasion seem to obtain a predictive--though sometimes argued--role. Taking into account that a great number of these factors develope "cross-talking" protein-complex networks, their combined evaluation is likely to contribute towards a more accurate prediction of the clinical outcome in NSCLC patients.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , PrognósticoRESUMO
The accurate execution of DNA replication requires a strict control of the replication licensing factors hCdt1 and hCdc6. The role of these key replication molecules in carcinogenesis has not been clarified. To examine how early during cancer development deregulation of these factors occurs, we investigated their status in epithelial lesions covering progressive stages of hyperplasia, dysplasia, and full malignancy, mostly from the same patients. Abnormal accumulation of both proteins occurred early from the stage of dysplasia. A frequent cause of unregulated hCdc6 and hCdt1 expression was gene amplification, suggesting that these components can play a role per se in cancer development. Overexpression of hCdt1 and hCdc6 promoted rereplication and generated a DNA damage response, which activated the antitumor barriers of senescence and apoptosis. Generating an inducible hCdt1 cellular system, we observed that continuous stimulus by deregulated hCdt1 led to abrogation of the antitumor barriers and resulted in the selection of clones with more aggressive properties. In addition, stable expression of hCdc6 and hCdt1 in premalignant papilloma cells led to transformation of the cells that produced tumors upon injection into nude mice depicting the oncogenic potential of their deregulation.
Assuntos
Proteínas de Ciclo Celular/biossíntese , Regulação Neoplásica da Expressão Gênica , Neoplasias/metabolismo , Proteínas Nucleares/biossíntese , Animais , Antineoplásicos/uso terapêutico , Proteínas de Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Humanos , Hiperplasia , Camundongos , Camundongos SCID , Invasividade Neoplásica , Transplante de Neoplasias , Proteínas Nucleares/fisiologia , FenótipoRESUMO
Knowing the status of molecules involved in cell cycle control in cancer is vital for therapeutic approaches aiming at their restoration. The p27(KIP1) and p57(KIP2) cyclin-dependent kinase inhibitors are nodal factors controlling normal cell cycle. Their expression in normal lung raises the question whether they have a mutual exclusive or redundant role in nonsmall cell lung cancer (NSCLC). A comparative comprehensive analysis was performed in a series of 70 NSCLCs. The majority of cases showed significantly reduced expression of both members compared to normal counterparts. Low KIP protein levels correlated with increased proliferation, which seems to be histological subtype preponderant. At mechanistic level, degradation by SKP2 was demonstrated, in vivo and in vitro, by siRNA-methodology, to be the most important downregulating mechanism of both KIPs in NSCLC. Decreased p57(KIP) (2)-transcription complements the above procedure in lowering p57(KIP2)-protein levels. Methylation was the main cause of decreased p57(KIP) (2)-mRNA levels. Allelic loss and imprinting from LIT1 mRNA contribute also to decreased p57(KIP2) transcription. In vitro recapitulation of the in vivo findings, in A549 lung cells (INK4A-B((-/-))), suggested that inhibition of the SKP2-degradation mechanism restores p27(KIP1) and p57(KIP2) expression. Double siRNA treatments demonstrated that each KIP is independently capable of restraining cell growth. An additional demethylation step is required for complete reconstitution of p57(KIP2) expression in NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Inibidor de Quinase Dependente de Ciclina p27/genética , Inibidor de Quinase Dependente de Ciclina p57/genética , Metilação de DNA , Regulação para Baixo , Neoplasias Pulmonares/genética , Proteínas Quinases Associadas a Fase S/fisiologia , Sequência de Bases , Primers do DNA , Humanos , Perda de Heterozigosidade , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
The aim of this review is to present the advances in our understanding of the progression of tumorigenesis in neuroendocrine lung tumors. Current information on established and putative diagnostic and prognostic markers of neuroendocrine tumors are evaluated, with a special reference to small-cell lung carcinoma, due to its higher incidence and aggressive behavior. The genetic and molecular changes that accompany these neoplasms are highlighted, and factors that influence cell-cycle progression, apoptosis, drug resistance, and escape from immune surveillance are critically assessed.