RESUMO
This study aimed to investigate intratumoural estradiol and estrogen-receptors (ERα, ERß and GPR30) in malignant pleural mesothelioma (MPM) to understand their function. Here, we report that immunohistochemistry of estradiol showed cytoplasmatic staining in 95% of fifty-seven human MPM samples with a trend toward a negative correlation between estradiol levels and the median post-diagnosis survival time. ERß was only focally positive in 5.3% of cases, GPR30 and ERα were negative in our cases of MPM. GPR30 was detected mainly in glycosylated form in MPM cells. Moreover, G15, a GPR30 antagonist, induced MPM cell death. Altogether, these data suggest that MPM cells produce E2 interact with glycosylated forms of GPR30, and this facilitates tumour growth. Estradiol was found in MPM cells and plasma from mice mesothelioma xenografts. Concurrent reduction in tumour mass and plasmatic estradiol levels were observed in the mice treated with exemestane, suggesting that the reduction of E2 levels inhibit MPM growth. Thus, it appears that agents reducing estradiol levels could be useful to MPM therapy.
Assuntos
Estradiol/metabolismo , Mesotelioma/metabolismo , Neoplasias Pleurais/metabolismo , Idoso , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Imuno-Histoquímica , Masculino , Mesotelioma/patologia , Camundongos , Neoplasias Pleurais/patologiaRESUMO
BACKGROUND: Recent evidence suggests that aromatase may be involved in the pathogenesis of malignant mesothelioma. Here, we evaluated the effect of exemestane, an inhibitor of aromatase, in the treatment of mesothelioma using in vitro and in vivo preclinical models. RESULTS: We show a significant reduction of cell proliferation, survival, migration and block of cells in S phase of cell cycle in mesothelioma cells upon exemestane treatment. Moreover, we find that CD44, which is involved in mesothelioma cells migration, was modulated by exemestane via cAMP and pCREB. Most importantly, in mice mesothelioma xenograft exemestane causes a significant decrease in tumor size and the association pemetrexed/exemestane is more effective than pemetrexed/cisplatin. CONCLUSION: The preclinical mesothelioma model suggests that exemestane might be beneficial in mesothelioma treatment.
Assuntos
Androstadienos/administração & dosagem , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/biossíntese , AMP Cíclico/genética , Receptores de Hialuronatos/biossíntese , Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma/tratamento farmacológico , Animais , Inibidores da Aromatase/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Cisplatino/administração & dosagem , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Receptores de Hialuronatos/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mesotelioma/genética , Mesotelioma/patologia , Mesotelioma Maligno , Camundongos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Deregulated proliferation is a hallmark of cancer cells. Here, we show that microRNA-10b* is a master regulator of breast cancer cell proliferation and is downregulated in tumoural samples versus matched peritumoural counterparts. Two canonical CpG islands (5 kb) upstream from the precursor sequence are hypermethylated in the analysed breast cancer tissues. Ectopic delivery of synthetic microRNA-10b* in breast cancer cell lines or into xenograft mouse breast tumours inhibits cell proliferation and impairs tumour growth in vivo, respectively. We identified and validated in vitro and in vivo three novel target mRNAs of miR-10b* (BUB1, PLK1 and CCNA2), which play a remarkable role in cell cycle regulation and whose high expression in breast cancer patients is associated with reduced disease-free survival, relapse-free survival and metastasis-free survival when compared to patients with low expression. This also suggests that restoration of microRNA-10b* expression might have therapeutic promise.
Assuntos
Neoplasias da Mama/genética , Ciclo Celular , Regulação para Baixo , MicroRNAs/genética , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/fisiopatologia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Ciclina A2/genética , Ciclina A2/metabolismo , Metilação de DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos SCID , MicroRNAs/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Quinase 1 Polo-LikeRESUMO
In vivo imaging involving the use of genetically engineered animals is an innovative powerful tool for the noninvasive assessment of the molecular and cellular events that are often targets of therapy. On the basis of the knowledge that the activity of the nuclear factor-Y (NF-Y) transcription factor is restricted in vitro to proliferating cells, we have generated a transgenic reporter mouse, called MITO-Luc (for mitosis-luciferase), in which an NF-Y-dependent promoter controls luciferase expression. In these mice, bioluminescence imaging of NF-Y activity visualizes areas of physiological cell proliferation and regeneration during response to injury. Using this tool, we highlight for the first time a role of NF-Y activity on hepatocyte proliferation during liver regeneration. MITO-Luc reporter mice should facilitate investigations into the involvement of genes in cell proliferation and provide a useful model for studying aberrant proliferation in disease pathogenesis. They should be also useful in the development of new anti/proproliferative drugs and assessment of their efficacy and side effects on nontarget tissues.
