DOCSLIB.ORG

MUC1 Signaling Directly Reprograms Transcription of CTGF

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
MUC1 Signaling Directly Reprograms Transcription of CTGF Oncogene (2010) 29, 5667–5677 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 www.nature.com/onc ORIGINAL ARTICLE The reactive tumor microenvironment: MUC1 signaling directly reprograms transcription of CTGF ME Behrens1,2, PM Grandgenett1, JM Bailey1, PK Singh1,2, C-H Yi1,FYu3 and MA Hollingsworth1,2 1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA; 2Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA and 3Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE, USA The MUC1 cytoplasmic tail (MUC1.CT) conducts mediate transcription factor activity in a context-dependent signals from spatial and extracellular cues (growth factor manner to achieve wide spread and robust changes in gene and cytokine stimulation) to evoke a reprogramming of expression and facilitate creation of the reactive tumor the cellular transcriptional profile. Specific phosphory- microenvironment. lated forms of the MUC1.CT achieve this function by Oncogene (2010) 29, 5667–5677; doi:10.1038/onc.2010.327; differentially associating with transcription factors and published online 9 August 2010 redirecting their transcriptional regulatory capabilities at specific gene regulatory elements. The specificity of Keywords: MUC1; CTGF; signal transduction; interaction between MUC1.CT and several transcription transcriptional activation; pancreatic cancer factors is dictated by the phosphorylation pattern of the 18 potential phosphorylation motifs within the MUC1.CT. To better appreciate the scope of differential gene expression triggered by MUC1.CT activation, we per- Introduction formed microarray gene expression analysis and chromatin immunoprecipitation (ChIP)–chip promoter analysis and Acquisition of the metastatic phenotype requires a identified the genome-wide transcriptional targets of variety of changes within a tumor cell, including MUC1.CT signaling in pancreatic cancer. On a global activation of signaling pathways involved in motility scale, MUC1.CT preferentially targets genes related to and invasion. Successful primary tumor progression to invasion, angiogenesis and metastasis, suggesting that metastatic disease is dependent on other nearby cell MUC1.CT signaling contributes to establishing a reactive types and the extracellular composition of the niche in tumor microenvironment during tumor progression to which the tumor cell resides, collectively referred to as metastatic disease. We examined in detail the molecular the tumor microenvironment. A highly reactive tumor mechanisms of MUC1.CT signaling that induces the environment facilitates tumor cell invasion, angiogenesis expression of connective tissue growth factor (CTGF/ and metastasis in part by providing cues in the form of CCN2), a potent mediator of ECM remodeling and growth factors and cytokines that promote the dis- angiogenesis. We demonstrate a robust induction of semination of tumor cells to distal sites. The tumor itself CTGF synthesis and secretion in response to serum participates in formation of this dynamic niche by factors that is enabled only when MUC1 is highly synthesis and release of secreted factors that contribute expressed. We demonstrate the requirement of phosphor- to the establishment of a reactive tumor microenviron- ylation at distinct tyrosine motifs within the MUC1.CT ment, by recruiting fibroblasts and endothelial cells, for MUC1-induced CTGF expression and demonstrate a promoting neovascularization and regulating the activ- phosphorylation-specific localization of MUC1.CT to the ity of protease capable of remodeling the extracellular CTGF promoter. We found that MUC1 reorganizes matrix. Identifying the key players acting within tumor transcription factor occupancy of genomic regions up- cells that orchestrate formation of the reactive tumor stream of the CTGF gene, directing b-catenin and mutant microenvironment identifies promising targets for the p53 to CTGF gene regulatory elements to promote CTGF treatment of metastatic carcinoma. expression and destabilizing the interaction at these Expression of the cell surface mucin MUC1 is regions of the transcriptional repressor, c-Jun. With this elevated in most tumor types, including pancreatic example we illustrate the capacity of MUC1.CT to ductal adenocarcinoma (Burdick et al., 1997; Qu et al., 2004). MUC1 promotes tumor pathogenesis by influen- cing cell proliferation (Tsutsumida et al., 2006; Yuan Correspondence: Dr MA Hollingsworth, Eppley Institute for Research et al., 2008) and apoptosis (Agata et al., 2008; Raina in Cancer and Allied Diseases, University of Nebraska Medical et al., 2008; Gao et al., 2009) and also contributes to the Center, Omaha, NE 68198-5950, USA. invasive and metastatic potential of pancreatic tumors E-mail: [email protected] Received 27 February 2010; revised 23 April 2010; accepted 4 May 2010; (Masaki et al., 1999; Kohlgraf et al., 2003; Tsutsumida published online 9 August 2010 et al., 2006; Singh et al., 2007). MUC1 is a type I MUC1 signaling activates CTGF transcription ME Behrens et al 5668 transmembrane protein comprised primarily of a large in a manner that demonstrates both specificity and extracellular domain, containing a variable number of complexity, redirecting transcription factor regulatory differentially O-glycosylated, tandemly repeated se- function to influence gene expression and dramatically quences rich in serine, threonine and proline residues, alter the behavior of the cell. Signaling through the and an autoproteolytic SEA (sperm protein-enterokinase- MUC1.CT directly regulates the expression of connec- agrin) domain. Much of the oncogenic activity of MUC1 tive tissue growth factor (CTGF/CCN2), a 36–38-kDa in malignant tissues can be attributed to robust repro- protein in the CCN (CTGF/Cyr61/Nov) family of gramming of the cellular transcriptional profile that is secreted factors that have diverse biological activities, dictated by the small, 72-amino acid cytoplasmic tail, including roles in chemotaxis, motility, adhesion, which functions as a molecular sensor and shows a unique apoptosis and cell growth (Brigstock, 2003; Bennewith capacity to convey information to the nucleus about the et al., 2009). CTGF expression is observed in a variety of activation status and spatial orientation of receptor cell types, including endothelial cells and fibroblasts and tyrosine kinases (RTKs) and other cell surface signaling is elevated in many tumor types and cell lines, including molecules. pancreatic ductal adenocarcinoma, suggesting a role in The highly conserved cytoplasmic tail of MUC1 tumor progression and metastasis (Wenger et al., 1999; receives post-translational modifications from growth Chu et al., 2008). CTGF has been detected in tumor factor RTKs and engages in specific interactions with a cells, stromal cells, as well as proliferating endothelial variety of transcription factors, directly impacting their cells, implicating CTGF in the formation of a reactive transcriptional regulatory capacity (Singh and Hollings- tumor microenvironment. Studies using recombinant worth, 2006; Carson, 2008). MUC1.CT contains 18 human CTGF in vitro have demonstrated a potency in serine, threonine and tyrosine sites of potential phos- inducing angiogenesis that is greater than the well- phorylation and the phosphorylation pattern of studied angiogenic factors bFGF and VEGF (Shimo MUC1.CT directs its physical association with cell et al., 1999). Targeting CTGF in vivo using a humanized signaling mediators and transcription factors (Singh and monoclonal antibody recognizing CTGF (FG-3019) Hollingsworth, 2006). Several intracellular kinases and significantly reduced tumor cell proliferation, tumor RTKs have been shown to phosphorylate MUC1.CT volume and CD31 immunoreactivity of tumor sections in vivo and in vitro (Li et al., 1998, 2001a, b; Singh et al., in an orthotopic mouse model of pancreatic ductal 2007, 2008). Activation of Met by HGF stimulation adenocarcinoma (Aikawa et al., 2006). We report induces physical association of MUC1.CT and Met, as CTGF is a novel target of MUC1.CT signaling and well as phosphorylation of MUC1.CT, at the tyrosine illustrates for the first time a molecular mechanism for residue within its YHPM motif. The specific phospho- the phosphorylation-dependent regulation of transcrip- rylation of MUC1.CT at YHPM enables its interaction tion factor activity and gene expression by MUC1.CT. with p53 (Singh et al., 2008). Similarly, phosphorylation of MUC1.CT at the tyrosines within the YVPP and YHPM motifs by PDGFR-b following PDGF-BB Results stimulation enhances colocalization with b-catenin (Singh et al., 2007), demonstrating a specificity in the MUC1 increases CTGF/CCN2 expression in pancreatic binding of MUC1.CT to transcription factors that is tumors cells encoded by the phosphorylation pattern of MUC1.CT. The MUC1.CT conducts signals from the cell surface by The MUC1.CT has also been detected in the nucleus associating with and modifying the activity of transcrip- (Wen et al., 2003), and MUC1.CT colocalizes with tional activators and co-activators (Singh et al., 2007), mutant p53 and b-catenin in cell nuclei following HGF which in turn affects cellular transcriptional profiles. We and PDGF-BB stimulation, respectively (Singh et al., performed microarray analysis of mRNA expression of 2007, 2008). Though the precise mechanism of cleavage/ S2013 pancreatic tumor cells overexpressing MUC1 internalization
Load more

Recommended publications
  • Implications for Diabetic Nephropathy
    ORIGINAL ARTICLE Hyperglycemia Causes Renal Cell Damage via CCN2-Induced Activation of the Tropomyosin Receptor Kinase A, TrkA Implications for Diabetic Nephropathy Maria Fragiadaki,1 Nicola Hill,1 Reiko Hewitt,1 George Bou-Gharios,1,2 Terence Cook,1,3 Frederick W. Tam,1 Jan Domin,1,4 and Roger M. Mason1 CCN2, a secreted profibrotic protein, is highly expressed in di- biopsy specimens from patients with different stages of DN abetic nephropathy (DN) and implicated in its pathogenesis; (6). CCN2 is also induced by TGF-b, hypoxia (low oxygen), however, the actions of CCN2 in DN remain elusive. We previously and advanced glycation-end products, all of which are demonstrated that CCN2 triggers signaling via tropomyosin re- stimulants that result in kidney damage (6–9). Moreover, ceptor kinase A (TrkA). Trace expression of TrkA is found in CCN2 overexpression in transgenic mice with streptozotocin- normal kidneys, but its expression is elevated in several nephrop- induced DN led to worsening of the disease, thus indicating athies; yet its role in DN is unexplored. In this study we show de the latter may play a profibrotic role after primary injury in novo expression of TrkA in human and murine DN. We go on to the context of diabetes (10). study the molecular mechanisms leading to TrkA activation and show – More evidence that CCN2 is a profibrotic protein comes that it involves hypoxia, as demonstrated by ischemia reperfusion fi injury and in vitro experiments mimicking hypoxia, implicating from studies of genetically modi ed animals. Sonnylal et al. hypoxia as a common pathway leading to disease.
    [Show full text]
  • R&D Day for Investors and Analysts
    R&D Day for Investors and Analysts November 16, 2020 Seagen 2020 R&D Day Clay Siegall, Ph.D. Roger Dansey, M.D. Nancy Whiting, Pharm.D Megan O’Meara, M.D. Shyra Gardai, Ph.D. President & Chief Chief Medical Officer EVP, Corporate Strategy VP, Early Stage Executive Director, Executive Officer Alliances and Development Immunology Communications 2 Forward-Looking Statements Certain of the statements made in this presentation are forward looking, such as those, among others, relating to the Company’s potential to achieve the noted development and regulatory milestones in 2021 and in future periods; anticipated activities related to the Company’s planned and ongoing clinical trials; the potential for the Company’s clinical trials to support further development, regulatory submissions and potential marketing approvals in the U.S. and other countries; the opportunities for, and the therapeutic and commercial potential of ADCETRIS, PADCEV, TUKYSA, tisotumab vedotin and ladiratuzumab vedotin and the Company’s other product candidates and those of its licensees and collaborators; the potential to submit a BLA for accelerated approval of tisotumab vedotin; the potential for data from the EV-301 and EV-201 cohort 2 clinical trials to support additional regulatory approvals of PADCEV; the potential for the approval of TUKYSA by the EMA; the therapeutic potential of the Company’s SEA technology and of the Company’s early stage pipeline agents including SGN-B6A, SGN-STNV, SGN-CD228A, SEA-CD40, SEA-TGT, SEA-BCMA and SEA-CD70; as well as other statements that are not historical fact. Actual results or developments may differ materially from those projected or implied in these forward-looking statements.
    [Show full text]
  • Investigation of Hub Genes Involved in Diabetic Nephropathy Using Biological Informatics Methods
    1087 Original Article Page 1 of 11 Investigation of hub genes involved in diabetic nephropathy using biological informatics methods Zhanting Li1#, Jianxin Liu2#, Weiwei Wang3, Yunchun Zhao4, Dengfeng Yang5, Xiaodong Geng6,7^ 1Department of Nephrology, Xi'an International Medical Center Hospital, Xi’an, China; 2Physical Examination Section, Qinhuangdao Jungong Hospital, Qinhuangdao, China; 3Department of Thoracic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; 4Cadre Ward of PLA 920 Hospital, Kunming, China; 5Department of Laboratory Medicine, Mianxian Hospital, Mianxian, China; 6Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China; 7Kidney Diagnostic and Therapeutic Center of the Chinese PLA, Beidaihe Rehabilitation and Recuperation Center of the Chinese PLA, Qinhuangdao, China Contributions: (I) Conception and design: X Geng; (II) Administrative support: W Wang; (III) Provision of study materials or patients: Y Zhao, J Liu; (IV) Collection and assembly of data: J Liu, Z Li; (V) Data analysis and interpretation: Z Li, D Yang; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. #These authors contributed equally to this work. Correspondence to: Xiaodong Geng. Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China; Kidney Diagnostic and Therapeutic Center of the Chinese PLA, Beidaihe Rehabilitation and Recuperation Center of the Chinese PLA, Qinhuangdao, China. Email: [email protected]. Background: The aim of this study was to find genes with significantly aberrant expression in diabetic nephropathy (DN) and determine their underlying mechanisms. Methods: GSE30528 and GSE1009 were obtained by querying the Gene Expression Omnibus (GEO) database. The difference in target gene expression between normal renal tissues and kidney tissues in patients with DN was screened by using the GEO2R tool.
    [Show full text]
  • CAR- T Cell Immunotherapies
    CAR T Therapy Current Status Future Challenges Introduction Basics of CAR T Therapy Cytotoxic T Lymphocytes are Specific and Potent Effector Cells Ultrastructure of CTL-mediated apoptosis The CTL protrudes deeply into cytoplasm of melanoma cell 3 Peter Groscurth, and Luis Filgueira Physiology 1998;13:17-21 What is CAR T Therapy? • CAR T therapy is the name given to chimeric antigen receptor (CAR) genetically modified T cells that are designed to recognize specific antigens on tumor cells resulting in their activation and proliferation eventually resulting in significant and durable destruction of malignant cells • CAR T cells are considered “a living drug” since they tend to persist for long periods of time • CAR T cells are generally created from the patients own blood cells although this technology is evolving to develop “off the shelf” CAR T cells 4 CAR T cells: Mechanism of Action T cell Tumor cell CAR enables T cell to Expression of recognize tumor cell antigen CAR Viral DNA Insertion Antigen Tumor cell apoptosis CAR T cells multiply and release cytokines 5 Chimeric Antigen Receptors Antigen binding VH Antigen Binding Domain domain scFv Single-chain variable fragment (scFv) bypasses MHC antigen presentation, allowing direct activation of T cell by cancer cell antigens VL Hinge region Hinge region Essential for optimal antigen binding Costimulatory Domain: CD28 or 4-1BB Costimulatory Enhances proliferation, cytotoxicity and domain persistence of CAR T cells Activation Domains Signaling Domain: CD3-zeta chain CD3-zeta chain Proliferation
    [Show full text]
  • Galectin-3 Promotes Aβ Oligomerization and Aβ Toxicity in a Mouse Model of Alzheimer’S Disease
    Cell Death & Differentiation (2020) 27:192–209 https://doi.org/10.1038/s41418-019-0348-z ARTICLE Galectin-3 promotes Aβ oligomerization and Aβ toxicity in a mouse model of Alzheimer’s disease 1,2 1,3 1 1 1,2 4,5 Chih-Chieh Tao ● Kuang-Min Cheng ● Yun-Li Ma ● Wei-Lun Hsu ● Yan-Chu Chen ● Jong-Ling Fuh ● 4,6,7 3 1,2,3 Wei-Ju Lee ● Chih-Chang Chao ● Eminy H. Y. Lee Received: 1 October 2018 / Revised: 13 April 2019 / Accepted: 2 May 2019 / Published online: 24 May 2019 © ADMC Associazione Differenziamento e Morte Cellulare 2019. This article is published with open access Abstract Amyloid-β (Aβ) oligomers largely initiate the cascade underlying the pathology of Alzheimer’s disease (AD). Galectin-3 (Gal-3), which is a member of the galectin protein family, promotes inflammatory responses and enhances the homotypic aggregation of cancer cells. Here, we examined the role and action mechanism of Gal-3 in Aβ oligomerization and Aβ toxicities. Wild-type (WT) and Gal-3-knockout (KO) mice, APP/PS1;WT mice, APP/PS1;Gal-3+/− mice and brain tissues from normal subjects and AD patients were used. We found that Aβ oligomerization is reduced in Gal-3 KO mice injected with Aβ, whereas overexpression of Gal-3 enhances Aβ oligomerization in the hippocampi of Aβ-injected mice. Gal-3 expression shows an age-dependent increase that parallels endogenous Aβ oligomerization in APP/PS1 mice. Moreover, Aβ oligomerization, Iba1 expression, GFAP expression and amyloid plaque accumulation are reduced in APP/ PS1;Gal-3+/− mice compared with APP/PS1;WT mice.
    [Show full text]
  • MUC1-C Oncoprotein As a Target in Breast Cancer: Activation of Signaling Pathways and Therapeutic Approaches
    Oncogene (2013) 32, 1073–1081 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13 www.nature.com/onc REVIEW MUC1-C oncoprotein as a target in breast cancer: activation of signaling pathways and therapeutic approaches DW Kufe Mucin 1 (MUC1) is a heterodimeric protein formed by two subunits that is aberrantly overexpressed in human breast cancer and other cancers. Historically, much of the early work on MUC1 focused on the shed mucin subunit. However, more recent studies have been directed at the transmembrane MUC1-C-terminal subunit (MUC1-C) that functions as an oncoprotein. MUC1-C interacts with EGFR (epidermal growth factor receptor), ErbB2 and other receptor tyrosine kinases at the cell membrane and contributes to activation of the PI3K-AKT and mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) pathways. MUC1-C also localizes to the nucleus where it activates the Wnt/b-catenin, signal transducer and activator of transcription (STAT) and NF (nuclear factor)-kB RelA pathways. These findings and the demonstration that MUC1-C is a druggable target have provided the experimental basis for designing agents that block MUC1-C function. Notably, inhibitors of the MUC1-C subunit have been developed that directly block its oncogenic function and induce death of breast cancer cells in vitro and in xenograft models. On the basis of these findings, a first-in-class MUC1-C inhibitor has entered phase I evaluation as a potential agent for the treatment of patients with breast cancers who express this oncoprotein. Oncogene (2013) 32, 1073–1081; doi:10.1038/onc.2012.158; published online 14 May 2012 Keywords: MUC1; breast cancer; oncoprotein; signaling pathways; targeted agents INTRODUCTION In breast tumor cells with loss of apical–basal polarity, the The mucin (MUC) family of high-molecular-weight glycoproteins MUC1-N/MUC1-C complex is found over the entire cell mem- 2 8 evolved in metazoans to provide protection for epithelial cell brane.
    [Show full text]
  • Membrane-Bound Mucins: the Mechanistic Basis for Alterations in the Growth and Survival of Cancer Cells
    Oncogene (2010) 29, 2893–2904 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 $32.00 www.nature.com/onc REVIEW Membrane-bound mucins: the mechanistic basis for alterations in the growth and survival of cancer cells S Bafna1, S Kaur1 and SK Batra1,2 1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA and 2Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA Mucins (MUC) are high molecular weight O-linked tethered mucins are quite distinct from the classic glycoproteins whose primary functions are to hydrate, extracellular complex mucins forming the mucous layers protect, and lubricate the epithelial luminal surfaces of the of the gastrointestinal and respiratory tracts. These ducts within the human body. The MUC family is epithelial membrane-tethered mucins are the transmem- comprised of large secreted gel forming and transmem- brane (TM) molecules, expressed by most glandular and brane (TM) mucins. MUC1, MUC4, and MUC16 are the ductal epithelial cells (Taylor-Papadimitriou et al., well-characterized TM mucins and have been shown to be 1999). Several TM mucins (MUC1, MUC3A, MUC3B, aberrantly overexpressed in various malignancies includ- MUC4, MUC 12, MUC13, MUC15, MUC16, MUC17, ing cystic fibrosis, asthma, and cancer. Recent studies MUC20, and MUC21) (human mucins are designated have uncovered the unique roles of these mucins in the as MUC, whereas other species mucins are designated as pathogenesis of cancer. These mucins possess specific Muc) have been identified so far (Moniaux et al., 2001; domains that can make complex associations with various Chaturvedi et al., 2008a; Itoh et al., 2008).
    [Show full text]
  • (EMA) Is Preferentially Expressed by ALK Positive Anaplastic Large Cell Lymphoma, in The
    J Clin Pathol 2001;54:933–939 933 MUC1 (EMA) is preferentially expressed by ALK positive anaplastic large cell lymphoma, in the normally glycosylated or only partly J Clin Pathol: first published as on 1 December 2001. Downloaded from hypoglycosylated form R L ten Berge*, F G M Snijdewint*, S von MensdorV-Pouilly, RJJPoort-Keesom, J J Oudejans, J W R Meijer, R Willemze, J Hilgers, CJLMMeijer Abstract 30–50% of cases, a chromosomal aberration Aims—To investigate whether MUC1 such as the t(2;5)(p23;q35) translocation gives mucin, a high molecular weight trans- rise to expression of the anaplastic lymphoma membrane glycoprotein, also known as kinase (ALK) protein,2 identifying a subgroup epithelial membrane antigen (EMA), dif- of patients with systemic ALCL with excellent fers in its expression and degree of glyco- prognosis.3–6 ALK expression seems specific for sylation between anaplastic large cell systemic nodal ALCL; it is not found in classic lymphoma (ALCL) and classic Hodgkin’s Hodgkin’s disease (HD)7–11 or primary cutane- disease (HD), and whether MUC1 ous ALCL.7101213Morphologically, these lym- immunostaining can be used to diVerenti- phomas may closely resemble systemic ALCL, ate between CD30 positive large cell being also characterised by CD30 positive lymphomas. tumour cells with abundant cytoplasm, large Methods/Results—Using five diVerent irregular nuclei, and a prominent single monoclonal antibodies (E29/anti-EMA, nucleolus or multiple nucleoli.1 Clinically, DF3, 139H2, VU-4H5, and SM3) that however, classic HD and primary cutaneous distinguish between various MUC1 glyco- ALCL have a more favourable prognosis than 12 14–16 Department of forms, high MUC1 expression (50–95% of ALK negative systemic ALCL.
    [Show full text]
  • Epithelial Mucin-1 (MUCI) Expression and MA5 Anti-MUC1 Monoclonal Antibody Targeting in Multiple Myeloma I
    Vol. 5, 3065s-3072s, October 1999 (Suppl.) Clinical Cancer Research 3065s Epithelial Mucin-1 (MUCI) Expression and MA5 Anti-MUC1 Monoclonal Antibody Targeting in Multiple Myeloma I J. Burton, z D. Mishina, T. Cardillo, K. Lew, cGy/mCi of injected dose compared with 3099 cGy/mCi of A. Rubin, D. M. Goldenberg, and D. V. Gold tumor-absorbed dose delivered by nonspecific antibody. Garden State Cancer Center, Belleville, New Jersey 07109 [J. B., D. M., T. C., K. L., D. M. G., D. V. G.], and St. Joseph's Hospital and Introduction Medical Center, Paterson, New Jersey 07503 [A. R.] MM 3 is a B-cell malignancy that appears to result from the transformation and monoclonal expansion of a cell with char- acteristics of a plasma cell, i.e., a terminally differentiated B cell Abstract (1, 2). The expression by MM cells of certain non-B-cell anti- Multiple myeloma (MM) is the second most common gens also raises the possibility of the transformation of an hematological cancer in the United States. It is typically earlier, more multipotent lymphoid precursor cell. As with nor- incurable, even with myeloablative chemotherapy and stem- mal plasma cells, this degree of terminal differentiation is as- cell transplantation. The epithelial mucin-1 (MUC1) glyco- sociated with the complete or partial loss of certain B-cell- protein is expressed by normal and malignant epithelial cells associated antigens, such as surface immunoglobulin and CDs but has also been shown to be expressed by MM cells. MUC1 19-22 (CD19 is expressed on normal plasma cells; Ref. 3).
    [Show full text]
  • ETV5 Links the FGFR3 and Hippo Signalling Pathways in Bladder Cancer Received: 2 December 2016 Erica Di Martino, Olivia Alder , Carolyn D
    www.nature.com/scientificreports OPEN ETV5 links the FGFR3 and Hippo signalling pathways in bladder cancer Received: 2 December 2016 Erica di Martino, Olivia Alder , Carolyn D. Hurst & Margaret A. Knowles Accepted: 14 November 2018 Activating mutations of fbroblast growth factor receptor 3 (FGFR3) are common in urothelial Published: xx xx xxxx carcinoma of the bladder (UC). Silencing or inhibition of mutant FGFR3 in bladder cancer cell lines is associated with decreased malignant potential, confrming its important driver role in UC. However, understanding of how FGFR3 activation drives urothelial malignant transformation remains limited. We have previously shown that mutant FGFR3 alters the cell-cell and cell-matrix adhesion properties of urothelial cells, resulting in loss of contact-inhibition of proliferation. In this study, we investigate a transcription factor of the ETS-family, ETV5, as a putative efector of FGFR3 signalling in bladder cancer. We show that FGFR3 signalling induces a MAPK/ERK-mediated increase in ETV5 levels, and that this results in increased level of TAZ, a co-transcriptional regulator downstream of the Hippo signalling pathway involved in cell-contact inhibition. We also demonstrate that ETV5 is a key downstream mediator of the oncogenic efects of mutant FGFR3, as its knockdown in FGFR3-mutant bladder cancer cell lines is associated with reduced proliferation and anchorage-independent growth. Overall this study advances our understanding of the molecular alterations occurring during urothelial malignant transformation and indicates TAZ as a possible therapeutic target in FGFR3-dependent bladder tumours. Fibroblast growth factors (FGF) and their four tyrosine kinase receptors (FGFR1-4) activate multiple downstream cellular signalling pathways, such as MAPK/ERK, PLCγ1, PI3K and STATs, and regulate a variety of physiolog- ical processes, encompassing embryogenesis, angiogenesis, metabolism, and wound healing1–3.
    [Show full text]
  • Development and Validation of a Protein-Based Risk Score for Cardiovascular Outcomes Among Patients with Stable Coronary Heart Disease
    Supplementary Online Content Ganz P, Heidecker B, Hveem K, et al. Development and validation of a protein-based risk score for cardiovascular outcomes among patients with stable coronary heart disease. JAMA. doi: 10.1001/jama.2016.5951 eTable 1. List of 1130 Proteins Measured by Somalogic’s Modified Aptamer-Based Proteomic Assay eTable 2. Coefficients for Weibull Recalibration Model Applied to 9-Protein Model eFigure 1. Median Protein Levels in Derivation and Validation Cohort eTable 3. Coefficients for the Recalibration Model Applied to Refit Framingham eFigure 2. Calibration Plots for the Refit Framingham Model eTable 4. List of 200 Proteins Associated With the Risk of MI, Stroke, Heart Failure, and Death eFigure 3. Hazard Ratios of Lasso Selected Proteins for Primary End Point of MI, Stroke, Heart Failure, and Death eFigure 4. 9-Protein Prognostic Model Hazard Ratios Adjusted for Framingham Variables eFigure 5. 9-Protein Risk Scores by Event Type This supplementary material has been provided by the authors to give readers additional information about their work. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Supplemental Material Table of Contents 1 Study Design and Data Processing ......................................................................................................... 3 2 Table of 1130 Proteins Measured .......................................................................................................... 4 3 Variable Selection and Statistical Modeling ........................................................................................
    [Show full text]
  • Characterization and Function of Medium and Large Extracellular
    bioRxiv preprint doi: https://doi.org/10.1101/623553; this version posted April 30, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Characterization and function of medium and large extracellular vesicles from plasma and urine by surface antigens and Annexin V Ko Igami1, 2, 3, Takeshi Uchiumi1*, Saori Ueda1, Kazuyuki Kamioka2, 4, Daiki Setoyama1, Kazuhito Gotoh1, Masaru Akimoto1, Shinya Matsumoto1 and Dongchon Kang1 1Department of Clinical Chemistry and Laboratory Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. 2Kyushu Pro Search Limited Liability Partnership, 4-1, Kyudaishimmachi, Nishi- ku, Fukuoka, 819-0388, Japan. 3Business Management Division, Clinical Laboratory Business Segment, LSI Medience Corporation, 13-4, Uchikanda 1-chome, Chiyoda-ku, Tokyo, 101-8517, Japan. 4Medical Solutions Department, LSI Medience Corporation, 3- 30-1, Shimura, Itabashi-ku, Tokyo, 174-8555, Japan. Running title: Characterization of plasma and urine extracellular microvesicles Keywords: microvesicle, cell-derived microvesicle, peptidase, plasma, urine *Correspondence to: Takeshi Uchiumi, Department of Clinical Chemistry and Laboratory Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Tel: (+81) 92-642-5750; Fax: (+81) 92-642-5772 1 bioRxiv preprint doi: https://doi.org/10.1101/623553; this version posted April 30, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
    [Show full text]