RESUMEN
BACKGROUND: Glioblastoma multiforme (GBM) is the most common high-grade malignant brain tumour in adults and arises from the glial cells in the brain. The prognosis of treated GBM remains very poor with 5-year survival rates of 5%, a figure which has not improved over the last few decades. Currently, there is a modest 14-month overall median survival in patients undergoing maximum safe resection plus adjuvant chemoradiotherapy. HOX gene dysregulation is now a widely recognised feature of many malignancies. METHODS: In this study we have focused on HOX gene dysregulation in GBM as a potential therapeutic target in a disease with high unmet need. RESULTS: We show significant dysregulation of these developmentally crucial genes and specifically that HOX genes A9, A10, C4 and D9 are strong candidates for biomarkers and treatment targets for GBM and GBM cancer stem cells. We evaluated a next generation therapeutic peptide, HTL-001, capable of targeting HOX gene over-expression in GBM by disrupting the interaction between HOX proteins and their co-factor, PBX. HTL-001 induced both caspase-dependent and -independent apoptosis in GBM cell lines. CONCLUSION: In vivo biodistribution studies confirmed that the peptide was able to cross the blood brain barrier. Systemic delivery of HTL-001 resulted in improved control of subcutaneous murine and human xenograft tumours and improved survival in a murine orthotopic model.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Adulto , Animales , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Genes Homeobox , Glioblastoma/tratamiento farmacológico , Glioblastoma/terapia , Humanos , Ratones , Péptidos/genética , Distribución TisularRESUMEN
BACKGROUND & AIMS: Individuals with Down syndrome have a low risk for many solid tumors, prompting the search for tumor suppressor genes on human chromosome 21 (HSA21). We aimed to identify and explore potential mechanisms of tumor suppressors on HSA21 in hepatocellular carcinoma (HCC). METHODS: We compared expression of HSA21 genes in 14 pairs of primary HCC and adjacent noncancer liver tissues using the Affymetrix HG-U133 Plus 2.0 array (Affymetrix, Santa Clara, CA). HCC tissues and adjacent normal liver tissues were collected from 108 patients at a hospital in China for real-time polymerase chain reaction and immunohistochemical analyses; expression levels of regulator of calcineurin 1 (RCAN1) isoform 4 (RCAN1.4) were associated with clinical features. We overexpressed RCAN1.4 from lentiviral vectors in MHCC97H and HCCLM3 cells and knocked expression down using small interfering RNAs in SMMC7721 and Huh7 cells. Cells were analyzed in proliferation, migration, and invasion assays. HCC cells that overexpressed RCAN1.4 or with RCAN1.4 knockdown were injected into livers or tail veins of nude mice; tumor growth and numbers of lung metastases were quantified. We performed bisulfite pyrosequencing and methylation-specific polymerase chain reaction analyses to analyze CpG island methylation. We measured phosphatase activity of calcineurin in HCC cells. RESULTS: RCAN1.4 mRNA and protein levels were significantly decreased in primary HCC compared with adjacent noncancer liver tissues. Reduced levels of RCAN1.4 mRNA were significantly associated with advanced tumor stages, poor differentiation, larger tumor size, and vascular invasion. Kaplan-Meier survival analysis showed that patients with HCCs with lower levels of RCAN1.4 mRNA had shorter time of overall survival and time to recurrence than patients whose tumors had high levels of RCAN1.4 mRNA. In HCC cell lines, expression of RCAN1.4 significantly reduced proliferation, migration, and invasive activity. HCC cells that overexpressed RCAN1.4 formed smaller xenograft tumors, with fewer metastases and blood vessels, than control HCC cells. In HCC cells, RCAN1.4 inhibited expression of insulin-like growth factor 1 and vascular endothelial growth factor A by reducing calcineurin activity and blocking nuclear translocation of nuclear factor of activated T cells (NFAT1). HCC cells incubated with the calcineurin inhibitor cyclosporin A had decreased nuclear level of NFAT1. HCC cells had hypermethylation of a CpG island in the 5' regulatory region of RCAN1.4, which reduced its expression. CONCLUSIONS: RCAN1.4 is down-regulated in HCC tissues, compared with non-tumor liver tissues. RCAN1.4 prevents cell proliferation, migration, and invasion in vitro; overexpressed RCAN1.4 in HCC cells prevents growth, angiogenesis, and metastases of xenograft tumors by inhibiting calcineurin activity and nuclear translocation of NFAT1.
Asunto(s)
Calcineurina/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Proteínas Musculares/genética , Factores de Transcripción NFATC/metabolismo , ARN Mensajero/análisis , Adulto , Anciano , Animales , Carcinoma Hepatocelular/química , Carcinoma Hepatocelular/secundario , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Cromosomas Humanos Par 21 , Islas de CpG/genética , Metilación de ADN , Proteínas de Unión al ADN , Supervivencia sin Enfermedad , Regulación hacia Abajo , Femenino , Expresión Génica , Humanos , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Péptidos y Proteínas de Señalización Intracelular/análisis , Hígado/química , Neoplasias Hepáticas/química , Masculino , Ratones , Persona de Mediana Edad , Proteínas Musculares/análisis , Factores de Transcripción NFATC/genética , Clasificación del Tumor , Invasividad Neoplásica , Estadificación de Neoplasias , Trasplante de Neoplasias , Isoformas de Proteínas/genética , Transporte de Proteínas/efectos de los fármacos , Secuencias Reguladoras de Ácidos Nucleicos , Transducción de Señal , Tasa de Supervivencia , Carga Tumoral , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Reprogrammed metabolism has been identified as an emerging hallmark in cancer cells. It has been demonstrated that fructose-1, 6-bisphosphatase 1 (FBP1) as a rate-limiting enzyme in gluconeogenesis plays critical roles in tumor initiation and progression in several cancer types. However, function of FBP1 in hepatocellular carcinoma (HCC) is still not clear. In this study, we observed that the expression of FBP1 was obviously downregulated in the cell lines and tissues of HCC. Downregulation of FBP1 in HCC tissues was correlated with a lower overall survival rate and had a relatively higher tendency of tumor recurrence (n = 224). Silencing FBP1 could significantly promote colony formation, proliferation and metastasis of HCC cells, while ectopic overexpression of FBP1 resulted in impaired abilities of colony formation, proliferation and metastasis in vitro and in vivo. Mechanistically, silencing FBP1 facilitated glycolysis in HCC cell lines, which may be responsible for aggressiveness of HCC cells. We further found that targeting the Warburg effect using the specific inhibitor FX11 could suppress the aggressiveness of HCC cells which was mediated by loss of FBP1. These findings indicate that FBP1 appears to be a tumor suppressor in HCC. Strategies to restore the levels and activities of FBP1 might be developed to treat patients with HCC.
Asunto(s)
Carcinoma Hepatocelular/genética , Transformación Celular Neoplásica/genética , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Neoplasias Hepáticas/genética , Animales , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Proliferación Celular/genética , ADN Helicasas/antagonistas & inhibidores , Proteínas de Unión al ADN/antagonistas & inhibidores , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Gluconeogénesis/efectos de los fármacos , Gluconeogénesis/genética , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Ratones , Naftalenos/administración & dosificación , Metástasis de la Neoplasia , Proteínas de Unión al ARN , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Persistent androgen receptor (AR) signalling is the main driver of prostate cancer (PCa). Truncated isoforms of the AR called androgen receptor variants (AR-Vs) lacking the ligand binding domain often emerge during treatment resistance against AR pathway inhibitors such as Enzalutamide. This review discusses how AR-Vs drive a more aggressive form of PCa through the regulation of some of their target genes involved in oncogenic pathways, enabling disease progression. There is a pressing need for the development of a new generation of AR inhibitors which can repress the activity of both the full-length AR and AR-Vs, for which the knowledge of differentially expressed target genes will allow evaluation of inhibition efficacy. This review provides a detailed account of the most common variant, AR-V7, the AR-V7 regulated genes which have been experimentally validated, endeavours to understand their relevance in aggressive AR-V driven PCa and discusses the utility of the downstream protein products as potential drug targets for PCa treatment.