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Sekido Y.,Aichi Cancer Center Research Institute | Sekido Y.,Nagoya University
Cancer Science | Year: 2010

Malignant mesothelioma (MM) is a tumor with poor prognosis associated with asbestos exposure. While it remains to be clarified how asbestos fibers confer genetic/epigenetic alterations and induce cellular transformation in normal mesothelial cells, the understanding of key molecular mechanisms of MM cell development, proliferation, and invasion has progressed. MM shows frequent genetic inactivation of tumor suppressor genes of p16INK4a/. p14ARF and neurofibromatosis type 2 (NF2) which encodes Merlin, and epigenetic inactivation of RASSF1A. However, no frequent mutations of well-known oncogenes such as K-RAS and PIK3CA have been identified. Activation of multiple receptor tyrosine kinases including the epidermal growth factor receptor (EGFR) family and MET, and subsequent deregulations of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)-AKT signaling cascades are frequently observed in most MM cells. The tumor suppressive function of Merlin in MM cells is also being investigated by dissecting its possible downstream signaling cascade called the Hippo pathway. Further comprehensive delineation of dysregulated signaling cascades in MM cells will lead to identification of key addiction pathways for cell survival and proliferation of MM cells, which strongly promote establishment of a new molecular target therapy for MM. © 2009 Japanese Cancer Association. Source

Fujii M.,Aichi Cancer Center Research Institute
Journal of Biochemistry | Year: 2012

Yes-associated protein (YAP) has been shown to play a critical role in the growth of various tumours. Phosphorylation of Ser127 of YAP leads to the inhibition of YAP translocation into nucleus and subsequent failure to regulate the expression of target genes that induce cell proliferation. Chemical manipulation of YAP localization or expression may provide an efficient method for cancer treatment. In a recent work published by Bao et al. (J. Biochem. 2011;150:199-208), various compounds were screened in human osteosarcoma cells that stably express Green Fluorescent Protein-labeled YAP by monitoring subcellular localization of GFP-YAP. Using this cell-based assay, they found that dobutamine, a β-adrenergic receptor agonist, attenuated YAP-dependent transcription by inhibiting its nuclear translocation. © 2012 The Authors. Source

Tsuzuki S.,Aichi Cancer Center Research Institute
Nature Genetics | Year: 2016

The oncogenic mechanisms underlying acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA; 15–39 years old) remain largely elusive. Here we have searched for new oncogenes in AYA-ALL by performing RNA-seq analysis of Philadelphia chromosome (Ph)-negative AYA-ALL specimens (n = 73) with the use of a next-generation sequencer. Interestingly, insertion of D4Z4 repeats containing the DUX4 gene into the IGH locus was frequently identified in B cell AYA-ALL, leading to a high level of expression of DUX4 protein with an aberrant C terminus. A transplantation assay in mice demonstrated that expression of DUX4-IGH in pro-B cells was capable of generating B cell leukemia in vivo. DUX4 fusions were preferentially detected in the AYA generation. Our data thus show that DUX4 can become an oncogenic driver as a result of somatic chromosomal rearrangements and that AYA-ALL may be a clinical entity distinct from ALL at other ages. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. Source

Seto M.,Aichi Cancer Center Research Institute
Blood | Year: 2013

In this issue of Blood, Salaverria et al report that more than half of Cyclin D1-(CCND1) negative SOX11-positive mantle cell lymphoma (MCL) had CCND2 gene rearrangement predominantly with immunoglobulin (IG) light chain genes.1. Source

Kamijo T.,Aichi Cancer Center Research Institute
Pediatric research | Year: 2012

Neuroblastoma (NB) is the most common pediatric solid malignant tumor derived from the sympathetic nervous system. High-risk NB is still one of the most difficult tumors to cure, with only 40% long-term survival despite intensive multimodal therapy. The clinical presentation and treatment response of advanced NB, which results in relapse and a refractory state after a good response to the initial chemotherapy, suggests that cancer stem cells (CSCs) likely exist in NB tumors. Putative CSCs using primary tumor sphere formation from NB patients were reported previously, and several molecules will be elucidated from the tumor sphere to develop CSC-targeting therapies. Recently, our group reported that a CSC marker for several malignancies, CD133, and the stemness-related polycomb BMI1 have functions to repress NB cell differentiation. Depletion of CD133 or BMI1 effectively induced neurite elongation and marker molecules for differentiation in NB cells. Of note, CD133-related NB cell differentiation and RET (rearranged during transfection) repression were considerably dependent on p38MAPK and phosphoinositide 3-kinase (PI3K)/AKT pathways. Intriguingly, both CD133 and BMI1 also have a role in xenograft tumor formation and tumor sphere formation. These observations suggest that CD133 and BMI1 may be candidates for the development of CSC-targeting therapies for refractory NB patients. Source

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