RESUMO
An adverse early life environment can increase the risk of metabolic and other disorders later in life. Genetic variation can modify an individual's susceptibility to these environmental challenges. These gene by environment interactions are important, but difficult, to dissect. The nucleus is the primary organelle where environmental responses impact directly on the genetic variants within the genome, resulting in changes to the biology of the genome and ultimately the phenotype. Understanding genome biology requires the integration of the linear DNA sequence, epigenetic modifications and nuclear proteins that are present within the nucleus. The interactions between these layers of information may be captured in the emergent spatial genome organization. As such genome organization represents a key research area for decoding the role of genetic variation in the Developmental Origins of Health and Disease.
Assuntos
Epigênese Genética , Predisposição Genética para Doença , Variação Genética , Genoma Humano , Humanos , FenótipoRESUMO
Metastasis is the primary mediator of prostate cancer (PCA) lethality and poses a significant clinical obstacle. The identification of factors involved in the metastasis of PCA is imperative. We demonstrate herein that trefoil factor 1 (TFF1) promotes PCA cell migration and invasion in vitro and metastasis in vivo. The capacity of TFF1 to enhance cell migration/invasion is mediated by transcriptional repression of E-CADHERIN. Consideration of targeted inhibition of TFF1 to prevent metastasis of prostate carcinoma is warranted.
Assuntos
Caderinas/metabolismo , Movimento Celular , Neoplasias Pulmonares/metabolismo , Neoplasias da Próstata/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Antígenos CD , Caderinas/genética , Linhagem Celular Tumoral , Regulação para Baixo , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Genótipo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Masculino , Camundongos , Camundongos Nus , Invasividade Neoplásica , Fenótipo , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Interferência de RNA , Transdução de Sinais , Transcrição Gênica , Transfecção , Fator Trefoil-1 , Proteínas Supressoras de Tumor/genéticaRESUMO
We have previously identified an oncogenic role of artemin (ARTN), a member of glial cell derived neurotrophic factor family of ligands, in mammary carcinoma. We herein report that ARTN is an estrogen-inducible gene. Meta-analysis of gene expression data sets showed that ARTN expression is positively correlated to estrogen receptor (ER) status in human mammary carcinoma. Furthermore, in patients with ER-positive mammary carcinoma treated with tamoxifen, high ARTN expression is significantly correlated with decreased survival. Forced expression of ARTN in ER-positive human mammary carcinoma cells increased ER transcriptional activity, promoted estrogen-independent growth and produced resistance to tamoxifen and fulvestrant in vitro and to tamoxifen in xenograft models. ARTN-stimulated resistance to tamoxifen and fulvestrant is mediated by increased BCL-2 expression. Conversely, depletion of endogenous ARTN by small-interfering RNA or functional antagonism of ARTN by antibody enhanced the efficacy of antiestrogens. Tamoxifen decreased ARTN expression in tamoxifen-sensitive mammary carcinoma cells whereas ARTN expression was increased in tamoxifen-resistant cells and not affected by tamoxifen treatment. Antibody inhibition of ARTN in tamoxifen-resistant cells improved tamoxifen sensitivity. Functional antagonism of ARTN therefore warrants consideration as an adjuvant therapy to enhance antiestrogen efficacy in ER-positive mammary carcinoma.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Estradiol/farmacologia , Moduladores de Receptor Estrogênico/farmacologia , Proteínas do Tecido Nervoso/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Invasividade Neoplásica , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA Interferente Pequeno/genética , Receptores de Estrogênio/biossíntese , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Tamoxifeno/farmacologia , Transcrição GênicaRESUMO
We report that artemin, a member of the glial cell line-derived neurotrophic factor family of ligands, is oncogenic for human mammary carcinoma. Artemin is expressed in numerous human mammary carcinoma cell lines. Forced expression of artemin in mammary carcinoma cells results in increased anchorage-independent growth, increased colony formation in soft agar and in three-dimensional Matrigel, and also promotes a scattered cell phenotype with enhanced migration and invasion. Moreover, forced expression of artemin increases tumor size in xenograft models and leads to highly proliferative, poorly differentiated and invasive tumors. Expression data in Oncomine indicate that high artemin expression is significantly associated with residual disease after chemotherapy, metastasis, relapse and death. Artemin protein is detectable in 65% of mammary carcinoma and its expression correlates to decreased overall survival in the cohort of patients. Depletion of endogenous artemin with small interfering RNA, or antibody inhibition of artemin, decreases the oncogenicity and invasiveness of mammary carcinoma cells. Artemin is therefore oncogenic for human mammary carcinoma, and targeted therapeutic approaches to inhibit artemin function in mammary carcinoma warrant consideration.
Assuntos
Neoplasias da Mama/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Animais , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Nus , Invasividade Neoplásica , Transplante de Neoplasias , Transplante HeterólogoRESUMO
Several reports have indicated that proteinase inhibitors can act as both stimulators and inhibitors of the growth of cultured cells. To confirm and extend these reports, we have purified the trypsin inhibitor from human urine (UTI). We have demonstrated a biphasic effect of this protein on the proliferation of human fibroblasts, and have identified two types of cellular binding site which may be responsible for the stimulatory and inhibitory aspects of this effect. Both aspects of UTI action have also been observed in human tumour cell cultures, but they are not consistently associated in these cells.
Assuntos
Divisão Celular/efeitos dos fármacos , Glicoproteínas/farmacologia , Inibidores da Tripsina/farmacologia , Sequência de Aminoácidos , Animais , Sítios de Ligação , Bovinos , Células Cultivadas , DNA/biossíntese , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Glicoproteínas/química , Glicoproteínas/isolamento & purificação , Humanos , Mitógenos/farmacologia , Dados de Sequência Molecular , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/metabolismoRESUMO
Hydrolysis of p-nitrophenyl guanidinobenzoate is characteristic of a tumour cell surface proteinase. We found this activity in three transformed or tumour cell lines, but not in two normal fibroblast strains. Immunochemical inhibition of plasminogen activator activity did not affect guanidinobenzoatase activity.