RESUMO
Iodine is crucial for thyroid hormone production. However, recent epidemiologic studies have shown that breast cancer patients have an elevated risk of developing thyroid cancer and vice versa. A notable finding in this study is that iodine stimulated the transcriptional activity of estrogen receptor-α (ER-α) in breast cancer cells. Iodine stimulated expression of several ER-α regulated gene including PS2, Cathepsin D, CyclinD1, and PR both in vitro and in nude mice, which is consistent with its stimulation of both anchorage-dependent and -independent growth of ER-α positive breast cancer cells and the effect to dampen tumor shrinkage of MCF-7 xenograft in ovariectomized nude mice. Analyses of clinical urine samples from breast cancer patients undergoing surgery demonstrated that urinary iodine levels were significantly higher than that in controls; and this increased level is due to the antiseptic use of iodine during breast surgery. The present study indicates that excess iodine intake may be an unfavorable factor in breast cancer by stimulation of ER-α transcriptional activity.
RESUMO
Hsp90 is an important driver of stabilization and activation of several oncogenic proteins in many key pathways in oncogenesis, including HER2. The present study demonstrated that synuclein gamma (SNCG) prevents the protein degradation and protects the function of HER2 in the condition when the function of Hsp90 is blocked. Disruption of Hsp90 resulted in a significant degradation of HER2 and the loss of activity. However, SNCG completely recovered Hsp90 disruption-mediated losses of HER2 and the function. SNCG bound to HER2 in the presence and absence of Hsp90. Specifically, the C-terminal (Gln106-Asp127) of SNCG bound to the loop connecting αC helix and ß4 sheet of the kinase domain of HER2. SNCG renders resistance to 17-AAG-induced tumor suppression in tumor xenograft. Crossing SNCG transgenic mice with HER2 mice stimulated HER2-induced tumor growth and rendered resistance to Hsp90 disruption. The present study indicates that SNCG protects Hsp90 client protein of HER2, and renders resistance to Hsp90 disruption.
Assuntos
Neoplasias da Mama/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Receptor ErbB-2/metabolismo , gama-Sinucleína/metabolismo , Animais , Benzoquinonas , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Proteínas de Choque Térmico HSP90/genética , Humanos , Imunoprecipitação , Lactamas Macrocíclicas , Leupeptinas , Camundongos , Camundongos Nus , Camundongos Transgênicos , Receptor ErbB-2/genética , gama-Sinucleína/genéticaRESUMO
Polo-like kinase 1 (PLK1), a variety of serine/threonine-protein kinase, has been reported to play important roles in malignant transformation. The purpose of this study was to investigate the clinicopathological significance of PLK1 expression in malignant glioma. A semi-quantitative RT-PCR assay was performed to detect the expression of PLK1 mRNA in 68 cases of glioma tissues and corresponding non-cancerous brain tissues. Additionally, the correlation of PLK1 mRNA expression with clinicopathological factors or prognosis of glioma patients was statistically analyzed. Multivariate analysis of prognostic factors was performed using the Cox proportional hazard model. Small interfering RNA was used to knockdown PLK1 expression in a glioma cell line and analyze the effects of PLK1 inhibition on growth, cell cycle, apoptosis and chemo- or radiosensitivity of glioma cells. Results showed that the expression of PLK1 mRNA was significantly higher in glioma tissues than in corresponding normal brain tissues. The expression of PLK1 mRNA was closely correlated with WHO grade, KPS and tumor recurrence of glioma patients (P=0.022, 0.030 and 0.041, respectively). Meanwhile, the disease-free and overall survival rates of patients with high PLK1 mRNA expression were obviously lower than those of patients with low PLK1 mRNA expression. Multivariate analysis showed that high PLK1 mRNA expression was a poor prognostic factor for glioma patients (P=0.028). The expression of PLK1 mRNA and protein was significantly down-regulated in stably transfected U251-S cells. PLK1 down-regulation could inhibit growth, induce cell arrest in G2/M phase of cell cycle and apoptosis enhancement in glioma cells. Further, PLK1 down-regulation could enhance the sensitivity of glioma cells to cisplatin or irradiation. Thus, the status of PLK1 mRNA expression might be an independent prognostic factor for glioma patients and targeting PLK1 could be a novel strategy for chemo- or radiosensitization of human malignant gliomas.
Assuntos
Proteínas de Ciclo Celular/genética , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Adulto , Idoso , Proteínas de Ciclo Celular/antagonistas & inibidores , Feminino , Perfilação da Expressão Gênica , Glioma/diagnóstico , Glioma/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/genética , RNA Interferente Pequeno/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto Jovem , Quinase 1 Polo-LikeRESUMO
BACKGROUND: The aim of this study is to investigate clinical significance of miR-155 expression in breast cancer. METHODS: TaqMan real-time RT-PCR was performed to detect miR-155 expression in breast cancer tissues. The correlation of miR-155 expression with clinicopathological factors and prognosis of breast cancer patients was analyzed. Then, the prognostic value of miR-155 expression was analyzed by univariate and multivariate analyses. Moreover, the effect of miR-155 expression on phenotypes of breast cancer cell was determined by antisense technology. RESULTS: The relative expression of miR-155 was significantly higher in breast cancer tissues than in corresponding nontumor tissues. High miR-155 expression was correlated with higher tumor grade, advanced tumor stage and lymph node metastasis (P = 0.012, 0.001, and 0.003, respectively). Kaplan-Meier survival analysis indicated that the disease-free and overall survival rates of high miR-155 group were significantly lower than those of low miR-155 group (P = 0.038 and 0.029, respectively). Multivariate analysis showed that high miR-155 expression was a poor prognostic factor (P = 0.009). Furthermore, antisense targeting miR-155 could inhibit growth, induce cell arrest in G(0) /G(1) phase, enhance apoptosis, and increase radiosensitivity in breast cancer cells. CONCLUSIONS: MiR-155 expression might be an independent prognostic factor and a therapeutic target for human breast cancer.