RESUMO
The evasion of anti-growth signaling is an important characteristic of cancer cells. In order to continue to proliferate, cancer cells must somehow uncouple themselves from the many signals that exist to slow down cell growth. Here, we define the anti-growth signaling process, and review several important pathways involved in growth signaling: p53, phosphatase and tensin homolog (PTEN), retinoblastoma protein (Rb), Hippo, growth differentiation factor 15 (GDF15), AT-rich interactive domain 1A (ARID1A), Notch, insulin-like growth factor (IGF), and Krüppel-like factor 5 (KLF5) pathways. Aberrations in these processes in cancer cells involve mutations and thus the suppression of genes that prevent growth, as well as mutation and activation of genes involved in driving cell growth. Using these pathways as examples, we prioritize molecular targets that might be leveraged to promote anti-growth signaling in cancer cells. Interestingly, naturally occurring phytochemicals found in human diets (either singly or as mixtures) may promote anti-growth signaling, and do so without the potentially adverse effects associated with synthetic chemicals. We review examples of naturally occurring phytochemicals that may be applied to prevent cancer by antagonizing growth signaling, and propose one phytochemical for each pathway. These are: epigallocatechin-3-gallate (EGCG) for the Rb pathway, luteolin for p53, curcumin for PTEN, porphyrins for Hippo, genistein for GDF15, resveratrol for ARID1A, withaferin A for Notch and diguelin for the IGF1-receptor pathway. The coordination of anti-growth signaling and natural compound studies will provide insight into the future application of these compounds in the clinical setting.
Assuntos
Carcinogênese/genética , Proliferação de Células/genética , Neoplasias/genética , Neoplasias/terapia , Transdução de Sinais , Proteínas de Ligação a DNA , Fator 15 de Diferenciação de Crescimento/genética , Via de Sinalização Hippo , Humanos , Fatores de Transcrição Kruppel-Like/genética , Terapia de Alvo Molecular , Proteínas Nucleares/genética , PTEN Fosfo-Hidrolase/genética , Proteínas Serina-Treonina Quinases/genética , Proteína do Retinoblastoma/genética , Somatomedinas/genética , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/genéticaAssuntos
Carcinoma Basocelular/metabolismo , Neoplasias Cutâneas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Epiderme/metabolismo , Histonas/metabolismo , Humanos , Imuno-Histoquímica , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Proteína Tumoral p73/metabolismo , Proteínas Supressoras de Tumor/metabolismoRESUMO
In a multicenter study, we determined the expression profiles of 863 microRNAs by array analysis of 454 blood samples from human individuals with different cancers or noncancer diseases, and validated this 'miRNome' by quantitative real-time PCR. We detected consistently deregulated profiles for all tested diseases; pathway analysis confirmed disease association of the respective microRNAs. We observed significant correlations (P = 0.004) between the genomic location of disease-associated genetic variants and deregulated microRNAs.
Assuntos
Doença/genética , MicroRNAs/sangue , MicroRNAs/genética , Perfilação da Expressão Gênica , Variação Genética/genética , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: Insulin-like growth factor-1 receptor (IGF-1R) is a key regulator of cell transformation and controls the expression of genes that governs cell cycling and cell survival. The aim of this pilot study was to gain insight into the expression pattern of IGF-1R in conventional cutaneous squamous cell carcinoma (CSCC) using immunohistochemical analysis. MATERIALS AND METHODS: Five cases of normal human paraffin-embedded skin sections, 4 cases of actinic keratosis, and 28 cases of paraffin-embedded sections of different histological subtypes of CSCC were selected for immunohistochemical analysis. RESULTS: In normal skin, IGF-1R expression was detected in the epidermal basal cell layer. In actinic keratosis, IGF-1R was expressed in the lower part of the epidermis. IGF-1R was detected in the cell surface membrane of well-differentiated CSCC. In moderately differentiated CSCC, IGF-1R was expressed predominantly in the cytoplasm. Interestingly, IGF-1R was expressed in the nuclei of tumor cells of poorly differentiated CSCC. CONCLUSIONS: The strong and differential expression of IGF-1R in different histological degrees of CSCC indicates a possible role for IGF-insulin receptor in the carcinogenesis and differentiation of this disease and identifies IGF-1R as an interesting target for prevention and treatment of CSCC that deserves further investigation.
Assuntos
Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Receptor IGF Tipo 1/biossíntese , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Humanos , Imuno-Histoquímica , Gradação de Tumores , Receptor IGF Tipo 1/análiseRESUMO
While nuclear cofactors that contribute to vitamin D receptor (VDR)-mediated gene transcription, including retinoid X receptors, nuclear co-activators and co-repressors, have been extensively investigated, little is known about cytoplasmic VDR-binding partners and the physiological relevance of their interaction. To gain new insight into this topic, we isolated whole-cell protein extracts of 1,25-dihydroxyvitamin D3 stimulated and UV-B-irradiated vs. non-irradiated HEK 293T cells transfected with a plasmid called pURB VDR C-Term TAP tag. VDR complex was purified by tandem affinity purification (TAP). The nuclear tumor-suppressor protein p53 and its negative regulator novel INHAT repressor (NIR), in addition to 43 other nuclear or cytoplasmatic VDR binding partners, were identified using nano high-performance liquid chromatography-electrospray ionization tandem mass spectrometric analysis. VDR binding to p53 was confirmed by western blot analysis. Future studies are required to further elucidate the functional significance of these interactions.
Assuntos
Cromatografia de Afinidade/métodos , Cromatografia Líquida de Alta Pressão/métodos , Mapas de Interação de Proteínas , Receptores de Calcitriol/metabolismo , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos , Proteína Supressora de Tumor p53/metabolismo , Células HEK293 , Humanos , Nanotecnologia , Ligação Proteica , Raios UltravioletaRESUMO
Graft versus host disease (GvHD) is one of the most feared adverse events of allogeneic hematopoietic stem cell transplantation. In severe grades of GvHD patients die from infections due to impairment of their immune defense or therapy-refractory involvement of intestines, liver and lung. Extracorporeal photopheresis is an effective treatment for acute and chronic graft versus host disease without severe impairment of the recipient's immune system. It is generally better known for its effect on skin GvHD but all other manifestations of GvHD can respond as well. Herein we report a brief review of its history and give an overview of the current knowledge of extracorporeal photopheresis in non-skin GvHD.