Wnt/β-catenin signalling induces MLL to create epigenetic changes in salivary gland tumours

We show that activation of Wnt/{beta}-catenin and attenuation of Bmp signals, by combined gain- and loss-of-function mutations of {beta}-catenin and Bmpr1a, respectively, results in rapidly growing, aggressive squamous cell carcinomas (SCC) in the salivary glands of mice. Tumours contain transplantable and hyperproliferative tumour propagating cells, which can be enriched by fluorescence activated cell sorting (FACS). Single mutations stimulate stem cells, but tumours are not formed. We show that {beta}-catenin, CBP and Mll promote self-renewal and H3K4 tri-methylation in tumour propagating cells. Blocking {beta}-catenin-CBP interaction with the small molecule ICG-001 and small-interfering RNAs against {beta}-catenin, CBP or Mll abrogate hyperproliferation and H3K4 tri-methylation, and induce differentiation of cultured tumour propagating cells into acini-like structures. ICG-001 decreases H3K4me3 at promoters of stem cell-associated genes in vitro and reduces tumour growth in vivo. Remarkably, high Wnt/{beta}-catenin and low Bmp signalling also characterize human salivary gland SCC and head and neck SCC in general. Our work defines mechanisms by which {beta}-catenin signals remodel chromatin and control induction and maintenance of tumour propagating cells. Further, it supports new strategies for the therapy of solid tumours

Hospitalizations for varicella in children and adolescents in a referral hospital in Hong Kong, 2004 to 2008: A time series study

Background: Varicella accounts for significant morbidities and remains a public health issue worldwide. Climatic factors have been shown to associate with the incidence and transmission of various infectious diseases. We describe the epidemiology of varicella in paediatric patients hospitalized at a tertiary referral hospital in Hong Kong from 2004 to 2008, and to explore the possible association between the occurrence of varicella infection and various climatic factors. Methods. The hospital discharge database of Princess Margaret Hospital was retrospectively analyzed for admissions associated with varicella from 2004 to 2008. Meteorological data were obtained from the monthly meteorological reports from the Hong Kong Observatory website. Time series analysis was performed with Poisson regression using a Generalized Estimating Equation (GEE) approach. Results: During the study period, 598 children were hospitalized for varicella. The mean age on admission was 57.6 months, and the mean duration of hospitalization was 3.7 days. The overall complication rate was 47%. The mean monthly relative humidity, especially in cool seasons, was inversely correlated with the monthly varicella cases of the same month. Conclusions: Varicella can lead to serious complications and prolonged hospitalization, even in previously healthy children. Lower relative humidity in cool seasons is associated with higher number of paediatric varicella hospital admissions. These findings are useful for a better understanding of the pattern of paediatric varicella hospitalization in Hong Kong. © 2011 Chan et al; licensee BioMed Central Ltd.link_to_subscribed_fulltex

Ectopic Expression of E2F1 Stimulates β-Cell Proliferation and Function

OBJECTIVE-Generating functional beta-cells by inducing their proliferation may provide new perspectives for cell therapy in diabetes. Transcription factor E2F1 controls G(1)- to S-phase transition during the cycling of many cell types and is required for pancreatic beta-cell growth and function. However, the consequences of overexpression of E2F1 in beta-cells are unknown. RESEARCH DESIGN AND METHODS-The effects of E2F1 overexpression on beta-cell proliferation and function were analyzed in isolated rat beta-cells and in transgenic mice. RESULTS-Adenovirus AdE2F1-mediated overexpression of E2F1 increased the proliferation of isolated primary rat beta-cells 20-fold but also enhanced beta-cell death. Coinfection with adenovirus Ad Akt expressing a constitutively active form of Akt (protein kinase B) suppressed beta-cell death to control levels. At 48 h after infection, the total beta-cell number and insulin content were, respectively, 46 and 79% higher in AdE2F1+AdAkt-infected cultures compared with untreated. Conditional overexpression of E2F1 in mice resulted in a twofold increase of beta-cell proliferation and a 70% increase of pancreatic insulin content, but did not increase beta-cell mass. Glucose-challenged insulin release was increased, and the mice showed protection against toxin-induced diabetes. CONCLUSIONS-Overexpression of E2F1, either in vitro or in vivo, can stimulate beta-cell proliferation activity. In vivo E2F1 expression significantly increases the insulin content and function of adult beta-cells, making it a strategic target for therapeutic manipulation of beta-cell function. Diabetes 59:1435-1444, 201

Context-Dependent Requirement for dE2F during Oncogenic Proliferation

The Hippo pathway negatively regulates the cell number in epithelial tissue. Upon its inactivation, an excess of cells is produced. These additional cells are generated from an increased rate of cell division, followed by inappropriate proliferation of cells that have failed to exit the cell cycle. We analyzed the consequence of inactivation of the entire E2F family of transcription factors in these two settings. In Drosophila, there is a single activator, dE2F1, and a single repressor, dE2F2, which act antagonistically to each other during development. While the loss of the activator dE2F1 results in a severe impairment in cell proliferation, this defect is rescued by the simultaneous loss of the repressor dE2F2, as cell proliferation occurs relatively normally in the absence of both dE2F proteins. We found that the combined inactivation of dE2F1 and dE2F2 had no significant effect on the increased rate of cell division of Hippo pathway mutant cells. In striking contrast, inappropriate proliferation of cells that failed to exit the cell cycle was efficiently blocked. Furthermore, our data suggest that such inappropriate proliferation was primarily dependent on the activator, de2f1, as loss of de2f2 was inconsequential. Consistently, Hippo pathway mutant cells had elevated E2F activity and induced dE2F1 expression at a point when wild-type cells normally exit the cell cycle. Thus, we uncovered a critical requirement for the dE2F family during inappropriate proliferation of Hippo pathway mutant cells

Genes involved in the metastatic cascade of medullary thyroid tumours

The process of how a benign tumour turns invasive and capable to survive in distant organs remains poorly understood, despite the evidence that metastasis formation is the primary cause of cancer patient mortality. This ignorance is partly due to the lack of appropriate animal models from which to investigate this complex process. The retinoblastoma (Rb) tumour suppressor pathway (pRb/E2F) is mutated in almost all human tumours, and a number of laboratories have now established pRb- or E2F-deficient mouse models. Consistent with the role of mutation in retinoblastoma in cancer biology, Rb heterozygous mice are prone to develop tumours. Among the ensuing tumours, the medullary thyroid carcinomas (MTCs) have a lessened tendency to form secondary cancers and metastases. Intriguingly, if an E2f3 mutation is introduced in this genetic background, more aggressive MTCs develop, which metastasize more frequently. Gene chip microarrays, however, provide an unbiased approach for examining the genome-wide expression levels and enable identification of a large set of metastasis-enriched gene sets. The identified genes may simply represent putative markers of the disease stage. Alternatively, genes may be identified that causally determine a link to the onset of metastasis. We describe the use of gene chip microarrays for identification of putative markers enriched in metastatic mouse MTCs. The chapter details how the most promising candidates are verified using additional methods, such as quantitative real-time PCR. In this case, co-transfection of the E2F-transcription factor using a heterologous reporter gene system is suggestive of E2Fs directly regulating putative metastasis markers

Wnt signaling in stem and cancer stem cells

Canonical Wnt signaling support the formation and maintenance of stem and cancer stem cells. Recent studies have elucidated epigenetic mechanisms that control pluripotency and stemness, and allow a first assessment how embryonic and tissue stem cells are generated and maintained, and how Wnt signaling might be involved. The core of this review highlights the roles of Wnt signaling in stem and cancer stem cells of tissues such as skin, intestine and mammary gland. Lastly, we refer to the characterization of novel and powerful inhibitors of canonical Wnt signaling and describe attempts to bring these compounds into preclinical and clinical studies