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Suppression of signal transducers and activators of transcription 1 in hepatocellular carcinoma is associated with tumor progression.

ABSTRACT: Signal transducers and activators of transcription (STAT) 1 plays a pivotal role in cell-cycle and cell-fate determination, and vascular endothelial growth factor (VEGF) also contributes tumor growth. Recently, interferon (IFN) ? has been reported to be effective for prevention of hepatocellular carcinomas (HCCs) recurrence, but the detailed mechanisms remain elusive. In vitro, cobalt chloride-treated VEGF induction and hypoxia responsive element (HRE) promoter activity were inhibited by IFNs and this abrogation was cancelled by introduction of small interfering RNA for STAT1. Immunoprecipitation/chromatin immunoprecipitation analyses showed STAT1 bound to hypoxia-inducible factor (HIF)-1? and dissociated HIF-complex from HRE promoter lesion. In a xenograft model using Balb/c nude mice, tumor growth was suppressed by IFN? through inhibition of VEGF expression and it was oppositely enhanced when STAT1-deleted cells were injected. This augmentation was due to upregulation of VEGF and hyaluronan synthase 2. In human samples, 29 HCCs were resected, divided into two groups based on STAT1 activation in tumor and the clinical features were investigated. Patients with suppressed STAT1 activity had a shorter recurrence-free survival. Histological and reverse transcriptase-polymerase chain reaction (RT-PCR) analyses showed portal vein microinvasion and increased VEGF levels in tumors from suppressed STAT1 group. These human samples also showed a reverse correlation between VEGF and STAT1-regulated genes expression. These results in vitro and in vivo suggested that IFN? are potential candidates for prevention of vessel invasion acting through inhibition of VEGF expression and need to be properly used when STAT1 expression is suppressed.

SUBMITTER: Hosui A

PROVIDER: S-EPMC3541944 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Suppression of signal transducers and activators of transcription 1 in hepatocellular carcinoma is associated with tumor progression.

Hosui Atsushi A Klover Peter P Tatsumi Tomohide T Uemura Akio A Nagano Hiroaki H Doki Yuichiro Y Mori Masaki M Hiramatsu Naoki N Kanto Tatsuya T Hennighausen Lothar L Hayashi Norio N Takehara Tetsuo T

International journal of cancer 20120628 12

Signal transducers and activators of transcription (STAT) 1 plays a pivotal role in cell-cycle and cell-fate determination, and vascular endothelial growth factor (VEGF) also contributes tumor growth. Recently, interferon (IFN) α has been reported to be effective for prevention of hepatocellular carcinomas (HCCs) recurrence, but the detailed mechanisms remain elusive. In vitro, cobalt chloride-treated VEGF induction and hypoxia responsive element (HRE) promoter activity were inhibited by IFNs an ...[more]

PMID: 22488367

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Project description:Signal Transducer and Activator of Transcription STAT5 is a key mediator of cell proliferation, differentiation and survival. While STAT5 activity is tightly regulated in normal cells, its constitutive activation directly contributes to oncogenesis and is associated with a broad range of hematological and solid tumor cancers. Therefore the development of compounds able to modulate pathogenic activation of this protein is a very challenging endeavor. A crucial step of drug design is the understanding of the protein conformational features and the definition of putative binding site(s) for such modulators. Currently, there is no structural data available for human STAT5 and our study is the first footprint towards the description of structure and dynamics of this protein. We investigated structural and dynamical features of the two STAT5 isoforms, STAT5a and STAT5b, taken into account their phosphorylation status. The study was based on the exploration of molecular dynamics simulations by different analytical methods. Despite the overall folding similarity of STAT5 proteins, the MD conformations display specific structural and dynamical features for each protein, indicating first, sequence-encoded structural properties and second, phosphorylation-induced effects which contribute to local and long-distance structural rearrangements interpreted as allosteric event. Further examination of the dynamical coupling between distant sites provides evidence for alternative profiles of the communication pathways inside and between the STAT5 domains. These results add a new insight to the understanding of the crucial role of intrinsic molecular dynamics in mediating intramolecular signaling in STAT5. Two pockets, localized in close proximity to the phosphotyrosine-binding site and adjacent to the channel for communication pathways across STAT5, may constitute valid targets to develop inhibitors able to modulate the function-related communication properties of this signaling protein.

Project description:BackgroundSignal transducers and activators of transcription (STAT) transcription factors, a family of genes encoding transcription factors, have been linked to the development of numerous types of tumors. However, there is a relative paucity of a comprehensive investigation of the expression and functional analysis of STATs in ovarian cancer (OV).MethodGene expression profile interaction analysis (GEPI2A), Metascape, The Cancer Genome Atlas (TCGA), Kaplan-Meier Plotter, Linkedomics, and CancerSEA databases were used for expression analysis and functional enrichment of STATs in ovarian cancer patients. We screened potential predictive genes and evaluated their prognostic value by constructing the minor absolute shrinkage and selection operator (LASSO) Cox proportional risk regression model. We explored STAT5A expression and its effects on cell invasion using ovarian cancer cells and a tissue microarray.ResultsThe expression level of STAT1 was higher, but that of STAT2-6 was lower in cancerous ovarian tissues compared to normal tissues, which were closely associated with the clinicopathological features. Low STAT1, high STAT4, and 6 mRNA levels indicated high overall survival. STAT1, 3, 4, and 5A were collectively constructed as prognostic risk models. STAT3, and 5A, up-regulating in the high-risk group, were regarded as risk genes. In subsequent validation, OV patients with a low level of P-STAT5A but not low STAT5A had a longer survival time (P=0.0042). Besides, a negative correlation was found between the expression of STAT5A and invasion of ovarian cancer cells (R= -0.38, p < 0.01), as well as DNA repair function (R= -0.36, p < 0.01). Furthermore, transient overexpression of STAT5A inhibited wound healing (21.8%, P<0.0001) and cell migration to the lower chamber of the Transwell system (29.3%, P<0.0001), which may be achieved by regulating the expression of MMP2.ConclusionIt is suggested that STAT1, STAT4, and STAT6 may be potential targets for the proper treatment of ovarian cancer. STAT5A and P-STAT5A, biomarkers identified in ovarian cancer, may offer new perspectives for predicting prognosis and assessing therapeutic effects.

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Suppression of signal transducers and activators of transcription 1 in hepatocellular carcinoma is associated with tumor progression.

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Suppression of signal transducers and activators of transcription 1 in hepatocellular carcinoma is associated with tumor progression.

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