DOCSLIB.ORG

Bone Morphogenetic Protein Antagonist Gremlin-1 Regulates Colon Cancer Progression

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Bone Morphogenetic Protein Antagonist Gremlin-1 Regulates Colon Cancer Progression Biol. Chem. 2015; 396(2): 163–183 George S. Karagiannis, Natasha Musrap, Punit Saraon, Ann Treacy, David F. Schaeffer, Richard Kirsch, Robert H. Riddell and Eleftherios P. Diamandis* Bone morphogenetic protein antagonist gremlin-1 regulates colon cancer progression Abstract: Bone morphogenetic proteins (BMP) are phylo- E-cadherin-upregulation of N-cadherin) and overexpres- genetically conserved signaling molecules of the trans- sion of Snail. Collectively, our data support that GREM1 forming growth factor-beta (TGF-beta) superfamily of promotes the loss of cancer cell differentiation at the can- proteins, involved in developmental and (patho)physi- cer invasion front, a mechanism that may facilitate tumor ological processes, including cancer. BMP signaling has progression. been regarded as tumor-suppressive in colorectal cancer (CRC) by reducing cancer cell proliferation and invasion, Keywords: angiogenesis; bone morphogenetic protein; and by impairing epithelial-to-mesenchymal transition cancer-associated fibroblasts; colorectal cancer; epithe- (EMT). Here, we mined existing proteomic repositories lial-to-mesenchymal transition; gremlin-1; stroma; tumor to explore the expression of BMPs in CRC. We found that microenvironment. the BMP antagonist gremlin-1 (GREM1) is secreted from heterotypic tumor-host cell interactions. We then sought DOI 10.1515/hsz-2014-0221 to investigate whether GREM1 is contextually and mecha- Received June 26, 2014; accepted August 1, 2014; previously nistically associated with EMT in CRC. Using immunohis- published online August 6, 2014 tochemistry, we showed that GREM1-expressing stromal cells harbor prominent features of myofibroblasts (i.e., cancer-associated fibroblasts), such as expression of α-smooth muscle actin and laminin-beta-1, and were in Introduction contextual proximity to invasion fronts with loss of the Bone morphogenetic proteins (BMPs) are a group of phylo- tight junction protein occludin and parallel nuclear accu- genetically conserved signaling molecules, which belong mulation of β-catenin, two prominent EMT hallmarks. to the transforming growth factor-β (TGF-β) superfamily Furthermore, in vitro assays demonstrated that GREM1- of proteins, and were initially shown to induce endochon- dependent suppression of BMP signaling results in EMT dral bone formation (Chen et al., 2004). During embryonic induction, characterized by cadherin switching (loss of life, BMPs are responsible for neurogenesis, hematopoie- sis, reduction of limb bud outgrowth and formation of *Corresponding author: Eleftherios P. Diamandis, Department osteoblast and chondrocyte precursors (Kishigami and of Laboratory Medicine and Pathobiology, University of Toronto, Mishina, 2005). After birth, BMPs are involved in skeletal Toronto, Ontario, Canada; Department of Pathology and Laboratory homeostasis, mainly by promoting the maintenance of Medicine, Mount Sinai Hospital, Joseph and Wolf Lebovic Ctr., 60 Murray St., Toronto M5T 3L9, Ontario, Canada; and Department of bone mass (Miyazono et al., 2005). BMP signaling is medi- Clinical Biochemistry, University Health Network, Toronto, Ontario, ated through type I and type II serine/threonine kinase Canada, e-mail: [email protected] receptors. Upon ligand binding, the type II receptor forms George S. Karagiannis, Natasha Musrap and Punit Saraon: a heterodimer with type I receptor and the constitutive Department of Laboratory Medicine and Pathobiology, University kinase of the type II receptor activates the type I receptor. of Toronto, Toronto, Ontario, Canada; and Department of Pathology Such activation may initiate signal transduction through and Laboratory Medicine, Mount Sinai Hospital, Joseph and Wolf Lebovic Ctr., 60 Murray St., Toronto M5T 3L9, Ontario, Canada phosphorylation of downstream factors [i.e., mothers Ann Treacy: MC Pathology, the Laboratory, Charlemont Clinic, against decapentaplegic (Smads)], which further causes Charlemont Mall, Dublin 2, Ireland their translocation into the nucleus, where they inhibit David F. Schaeffer: Department of Pathology and Laboratory or activate transcription of target genes (Miyazono et al., Medicine, University of British Columbia, Vancouver V5Z 1M9, 2005). British Columbia, Canada Richard Kirsch and Robert H. Riddell: Department of Pathology and In the normal colon, BMPs are primarily produced Laboratory Medicine, Mount Sinai Hospital, Joseph and Wolf Lebovic by epithelial cells to sustain epithelial phenotype and Ctr., 60 Murray St., Toronto M5T 3L9, Ontario, Canada polarity at the level of the colonic crypt (Hardwick et al., Brought to you by | Carnegie Mellon University Authenticated Download Date | 1/23/15 10:48 PM 164 G.S. Karagiannis et al.: GREM1 regulates EMT in colon cancer 2004). However, this pathway has been considered as a 2008), we had previously delineated secretome pro- major barrier to the development of intestinal cancer, files from 13 CRC cell lines (Karagiannis et al., 2014b). and various mechanisms, including genetic, epigenetic We retrieved these data, to examine in vitro secretion of and/or extracellular ones, seem to be conscientious for its BMP2, BMP4 and BMP7 in CRC. BMP2 was absent in all impairment (Hardwick et al., 2008). The most important 13 CRC secretomes, BMP4 was identified in all but the hallmark acquired from BMP-suppression seems to be the RKO secretome and BMP7 was identified in five out of disruption of the epithelial phenotype, possibly through the 13 CRC secretomes, namely the SW1116, SW480, the deployment of epithelial-to-mesenchymal transition SW620, LS174T and Colo205 ones (Figure 1A). In each (EMT) (Hardwick et al., 2004; Karagiannis et al., 2012b), case, the mean spectral counts of both BMP4 and BMP7 an event that is quite critical for the effective propaga- were higher in the SW1116 cell line, the earliest (Duke’s tion of the metastatic cascade (Kalluri, 2009; Kalluri and Stage A) stage among the 13 cell lines (Figure 1A). Notably, Weinberg, 2009; Hanahan and Weinberg, 2011). Despite BMP4 and BMP7 secretion displayed a significant reduc- an inhibitory effect of BMPs on the Wnt pathway that has tion (p < 0.025; Holms-corrected, Jonckheere-Terpstra test) been previously documented (He et al., 2004; Bertrand across the increasing Duke’s-based staging of the CRC cell et al., 2012), the exact contribution of BMPs and their lines (Figure 1B), and this occurred in a replication error antagonists in CRC progression, and especially EMT, are (RER) status-independent (p > 0.025, Holms-corrected only poorly understood. Mann-Whitney U-test) fashion (Figure 1C). Further, we Currently, high-throughput proteomics coupled to investigated BMP2, BMP4 and BMP7 gene-expression pro- mass spectrometry and bioinformatics play key roles in files in a cDNA array consisting of 24 CRC patients matched the identification, quantification and characterization with normal colonic mucosal tissue adjacent to the tumor of proteins in complex biological samples (Kulasingam (Figure S3A–C). Consistently, BMP2 showed a significant and Diamandis, 2008; Karagiannis et al., 2010), and their (p < 0.007; Holms-corrected Wilcoxon test) ∼4.5-fold down- emergence has benefited cancer research (i.e., oncopro- regulation in cancer compared to normal tissues, while teomics) with a plethora of opportunities for rationalized BMP4 and BMP7 were significantly (p < 0.007; Holms-cor- diagnosis and management (Jain, 2008; Karagiannis rected Wilcoxon test) upregulated (∼1.4-fold and ∼12-fold, et al., 2010). Using proteomics, we previously defined respectively) (Figure 1D). We verified gene-expression of protein expression signatures with potential involvement the BMP receptors type IA (BMPR1A), IB (BMPR1B) and II in tumor-host cell interactions (Karagiannis et al., 2012a), (BMPR2) in this patient array, but none of these receptors and subsequently targeted the BMP pathway as potential showed differential expression (Figure 1D; Figure S3D–F). mediator of cancer progression (Karagiannis et al., 2013; Given that BMP pathway suppression is strongly doc- Karagiannis et al., 2014c). Here, we perform meta-mining umented in sporadic CRC (Kodach et al., 2008), we consid- of these proteomic repositories to explore the expression ered that the aberrant secretion of BMPs by colon cancer levels of BMPs and their regulators and show that the BMP cells both in vitro and in patient tissues was paradoxical. antagonist gremlin-1 (GREM1) is strongly expressed in CRC Thus, we initially sought to verify in silico that progression desmoplastic invasion fronts. Further, we provide prelimi- of CRC is characterized by significant overexpression of nary evidence that GREM1 is not only contextually cor- BMPs and further examined the translational impact of related with cancer cells undergoing EMT in tissues with these expressional perturbations in advanced CRC. First, invasive colorectal carcinomas, but that it also mediates we performed gene-expression meta-analysis (Geneves- EMT by specifically disrupting the BMP7-dependent pro- tigator) and found ∼3.1-fold increase in the expression motion of epithelial phenotype in vitro. of both BMP4 and BMP7, and ∼2.2-fold decrease in the expression of BMP2 in colon adenocarcinoma/carcinoma compared to control tissues (Figure 1D). Representative heatmaps from studies showing discriminatory differences Results in BMP2, BMP4 and BMP7 gene-expression between colon cancer and healthy control tissues are shown (Figure S4). Proteomic and in silico investigations of the Second, we incorporated survival data from
Load more

Recommended publications
  • Gremlin1 Preferentially Binds to Bone Morphogenetic Protein-2 (BMP-2) and BMP-4 Over BMP-7
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Queen's University Research Portal Gremlin1 preferentially binds to Bone Morphogenetic Protein-2 (BMP-2) and BMP-4 over BMP-7 Church, R. H., Krishnakumar, A., Urbanek, A., Geschwinder, S., Meneely, J., Bianchi, A., ... Brazil, D. P. (2015). Gremlin1 preferentially binds to Bone Morphogenetic Protein-2 (BMP-2) and BMP-4 over BMP-7. Biochemical Journal, 466(1), 55-68. DOI: 10.1042/BJ20140771 Published in: Biochemical Journal Document Version: Peer reviewed version Queen's University Belfast - Research Portal: Link to publication record in Queen's University Belfast Research Portal Publisher rights The final version of record is available at http://www.biochemj.org/bj/imps/abs/BJ20140771.htm General rights Copyright for the publications made accessible via the Queen's University Belfast Research Portal is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy The Research Portal is Queen's institutional repository that provides access to Queen's research output. Every effort has been made to ensure that content in the Research Portal does not infringe any person's rights, or applicable UK laws. If you discover content in the Research Portal that you believe breaches copyright or violates any law, please contact [email protected]. Download date:15. Feb. 2017 Differential Gremlin1 binding to Bone Morphogenetic Proteins Gremlin1 preferentially binds to Bone Morphogenetic Protein-2 (BMP-2) and BMP-4 over BMP-7 Rachel H.
    [Show full text]
  • Tumor Promoting Effect of BMP Signaling in Endometrial Cancer
    International Journal of Molecular Sciences Article Tumor Promoting Effect of BMP Signaling in Endometrial Cancer Tomohiko Fukuda 1,* , Risa Fukuda 1, Kohei Miyazono 1,2,† and Carl-Henrik Heldin 1,*,† 1 Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Box 582, Uppsala University, SE-751 23 Uppsala, Sweden; [email protected] (R.F.); [email protected] (K.M.) 2 Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan * Correspondence: [email protected] (T.F.); [email protected] (C.-H.H.); Tel.: +46-18-4714738 (T.F.); +46-18-4714738 (C.-H.H.) † These authors contributed equally to this work. Abstract: The effects of bone morphogenetic proteins (BMPs), members of the transforming growth factor-β (TGF-β) family, in endometrial cancer (EC) have yet to be determined. In this study, we analyzed the TCGA and MSK-IMPACT datasets and investigated the effects of BMP2 and of TWSG1, a BMP antagonist, on Ishikawa EC cells. Frequent ACVR1 mutations and high mRNA expressions of BMP ligands and receptors were observed in EC patients of the TCGA and MSK-IMPACT datasets. Ishikawa cells secreted higher amounts of BMP2 compared with ovarian cancer cell lines. Exogenous BMP2 stimulation enhanced EC cell sphere formation via c-KIT induction. BMP2 also induced EMT of EC cells, and promoted migration by induction of SLUG. The BMP receptor kinase inhibitor LDN193189 augmented the growth inhibitory effects of carboplatin. Analyses of mRNAs of several BMP antagonists revealed that TWSG1 mRNA was abundantly expressed in Ishikawa cells.
    [Show full text]
  • The Novel Cer-Like Protein Caronte Mediates the Establishment of Embryonic Left±Right Asymmetry
    articles The novel Cer-like protein Caronte mediates the establishment of embryonic left±right asymmetry ConcepcioÂn RodrõÂguez Esteban*², Javier Capdevila*², Aris N. Economides³, Jaime Pascual§,AÂ ngel Ortiz§ & Juan Carlos IzpisuÂa Belmonte* * The Salk Institute for Biological Studies, Gene Expression Laboratory, 10010 North Torrey Pines Road, La Jolla, California 92037, USA ³ Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA § Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA ² These authors contributed equally to this work ............................................................................................................................................................................................................................................................................ In the chick embryo, left±right asymmetric patterns of gene expression in the lateral plate mesoderm are initiated by signals located in and around Hensen's node. Here we show that Caronte (Car), a secreted protein encoded by a member of the Cerberus/ Dan gene family, mediates the Sonic hedgehog (Shh)-dependent induction of left-speci®c genes in the lateral plate mesoderm. Car is induced by Shh and repressed by ®broblast growth factor-8 (FGF-8). Car activates the expression of Nodal by antagonizing a repressive activity of bone morphogenic proteins (BMPs). Our results de®ne a complex network of antagonistic molecular interactions between Activin, FGF-8, Lefty-1, Nodal, BMPs and Car that cooperate to control left±right asymmetry in the chick embryo. Many of the cellular and molecular events involved in the establish- If the initial establishment of asymmetric gene expression in the ment of left±right asymmetry in vertebrates are now understood. LPM is essential for proper development, it is equally important to Following the discovery of the ®rst genes asymmetrically expressed ensure that asymmetry is maintained throughout embryogenesis.
    [Show full text]
  • The BMP Antagonists Follistatin and Gremlin in Normal and Early Osteoarthritic Cartilage: an Immunohistochemical Study G
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Osteoarthritis and Cartilage (2009) 17, 263e270 ª 2008 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.joca.2008.06.022 International Cartilage Repair Society The BMP antagonists follistatin and gremlin in normal and early osteoarthritic cartilage: an immunohistochemical study G. Tardif Ph.D., J.-P. Pelletier M.D., C. Boileau Ph.D. and J. Martel-Pelletier Ph.D.* Osteoarthritis Research Unit, University of Montreal Hospital Centre, Notre-Dame Hospital, Montreal, Quebec, Canada Summary Objective: Bone morphogenic protein (BMP) activities are controlled in part by antagonists. In human osteoarthritic (OA) cartilage, the BMP antagonists follistatin and gremlin are increased but differentially regulated. Using the OA dog model, we determined if these BMP antagonists were produced at different stages during the disease process by comparing their in situ temporal and spatial distribution. Methods: Dogs were sacrificed at 4, 8, 10 and 12 weeks after surgery; normal dogs served as control. Cartilage was removed, differentiating fibrillated and non-fibrillated areas. Immunohistochemistry and morphometric analyses were performed for follistatin, gremlin, BMP-2/4 and IL-1b. Growth factor-induced gremlin expression was assessed in dog chondrocytes. Results: Follistatin and gremlin production were very low in normal cartilage. Gremlin was significantly up-regulated in both non-fibrillated and fibrillated areas at 4 weeks, and only slightly increased with disease progression. Follistatin showed a time-dependent increased level in the non-fibrillated areas with significance reached at 8e12 weeks; in the fibrillated areas significant high levels were seen as early as 4 weeks.
    [Show full text]
  • Transcription Activation of FLRG and Follistatin by Activin A, Through Smad Proteins, Participates in a Negative Feedback Loop to Modulate Activin a Function
    Oncogene (2002) 21, 2227 ± 2235 ã 2002 Nature Publishing Group All rights reserved 0950 ± 9232/02 $25.00 www.nature.com/onc Transcription activation of FLRG and follistatin by activin A, through Smad proteins, participates in a negative feedback loop to modulate activin A function Laurent Bartholin1,3,Ve ronique Maguer-Satta1,3, Sandrine Hayette1,2, Sylvie Martel1, MyleÁ ne Gadoux2, Laura Corbo1, Jean-Pierre Magaud1,2 and Ruth Rimokh*,1 1INSERM U453, Centre LeÂon BeÂrard, 69373 Lyon, France; 2Laboratoire de CytogeÂneÂtique MoleÂculaire, HoÃpital Edouard Herriot, 69437 Lyon, France Signaling of TGFb family members such as activin is location (Hayette et al., 1998). FLRG is a secreted tightly regulated by soluble binding proteins. Follistatin glycoprotein which is highly homologous to follistatin, binds to activin A with high anity, and prevents activin a protein known to bind to activin, a member of the binding to its own receptors, thereby blocking its transforming growth factor b (TGFb) superfamily signaling. We previously identi®ed FLRG gene from a (Nakamura et al., 1990). Activin and follistatin B-cell leukemia carrying a t(11;19)(q13;p13) transloca- proteins were originally isolated from ovarian ¯uid as tion. We and others have already shown that FLRG, a result of their ability to stimulate and inhibit, which is highly homologous to follistatin, may be respectively, the secretion of follicle-stimulating hor- involved in the regulation of the activin function through mone from the pituitary gland (Phillips and de Kretser, its binding to activin. In this study, we found that, like 1998). Further studies have revealed that activin, a follistatin, FLRG protein inhibited activin A signaling as secreted protein produced by a variety of tissues, has demonstrated by the use of a transcriptional reporter important endocrine and paracrine roles.
    [Show full text]
  • Cerberus–Nodal–Lefty–Pitx Signaling Cascade Controls Left–Right Asymmetry in Amphioxus
    Cerberus–Nodal–Lefty–Pitx signaling cascade controls left–right asymmetry in amphioxus Guang Lia,1, Xian Liua,1, Chaofan Xinga, Huayang Zhanga, Sebastian M. Shimeldb,2, and Yiquan Wanga,2 aState Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; and bDepartment of Zoology, University of Oxford, Oxford OX1 3PS, United Kingdom Edited by Marianne Bronner, California Institute of Technology, Pasadena, CA, and approved February 21, 2017 (received for review December 14, 2016) Many bilaterally symmetrical animals develop genetically pro- Several studies have sought to dissect the evolutionary history of grammed left–right asymmetries. In vertebrates, this process is un- Nodal signaling and its regulation of LR asymmetry. Notably, der the control of Nodal signaling, which is restricted to the left side asymmetric expression of Nodal and Pitx in gastropod mollusc by Nodal antagonists Cerberus and Lefty. Amphioxus, the earliest embryos plays a role in the development of LR asymmetry, in- diverging chordate lineage, has profound left–right asymmetry as cluding the coiling of the shell (5, 6). Asymmetric expression of alarva.WeshowthatCerberus, Nodal, Lefty, and their target Nodal and/or Pitx has also been reported in some other lopho- transcription factor Pitx are sequentially activated in amphioxus trochozoans, including Pitx in a brachiopod and an annelid and embryos. We then address their function by transcription activa- Nodal in a brachiopod (7, 8). These data can be interpreted to tor-like effector nucleases (TALEN)-based knockout and heat-shock suggest an ancestral role for Nodal and Pitx in regulating bilat- promoter (HSP)-driven overexpression.
    [Show full text]
  • Differential Expression of BMP Antagonists, Gremlin and Noggin In
    bioRxiv preprint doi: https://doi.org/10.1101/510602; this version posted January 3, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Differential expression of BMP antagonists, gremlin and noggin in hydra: antagonism 2 between Wnt and BMP pathways 3 4 Running title: Gremlin and noggin in hydra 5 6 Krishnapati Lakshmi Surekha1,2, Samiksha Khade1, Diptee Trimbake1, Rohan Patwardhan1, Siva 7 Kumar Nadimpalli2, Surendra Ghaskadbi1 8 9 1Developmental Biology Group, MACS-Agharkar Research Institute, Pune-411004, INDIA 10 2Laboratory for Protein Biochemistry and Glycobiology, Biochemistry Department, University 11 of Hyderabad, Hyderabad-500046, INDIA 12 13 Abstract 14 Mechanisms regulating BMP and Wnt signaling pathways have been widely studied in many 15 organisms. One of the mechanisms by which these pathways are regulated is by binding of 16 extracellular ligands. In the present study, we report studies with two BMP antagonists, gremlin 17 and noggin from Hydra vulgaris Ind-Pune and demonstrate antagonistic relationship between 18 BMP and Wnt pathways. Gremlin was ubiquitously expressed from the body column to head 19 region except in the basal disc and hypostome. During budding, gremlin was expressed 20 predominantly in the budding region suggesting a possible role in budding; this was confirmed in 21 polyps with different stages of buds. Noggin, on the other hand, was predominantly expressed in 22 the endoderm of hypostome, base of the tentacles, lower body column and at the basal disc in 23 whole polyps. During budding, noggin was expressed at the sites of emergence of tentacles 24 suggesting a role in tentacle formation.
    [Show full text]
  • Loss of a Quiescent Niche but Not Follicle Stem Cells in the Absence of Bone Morphogenetic Protein Signaling
    Loss of a quiescent niche but not follicle stem cells in the absence of bone morphogenetic protein signaling Krzysztof Kobielak, Nicole Stokes, June de la Cruz, Lisa Polak, and Elaine Fuchs* Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY 10021 Contributed by Elaine Fuchs, April 7, 2007 (sent for review March 8, 2007) During the hair cycle, follicle stem cells (SCs) residing in a special- These complexes translocate to the nucleus where they transac- ized niche called the ‘‘bulge’’ undergo bouts of quiescence and tivate their target genes (10). activation to cyclically regenerate new hairs. Developmental stud- When keratin 14 (K14)-driven Cre recombinase is used to ies have long implicated the canonical bone morphogenetic protein ablate Bmpr1a gene function in embryonic skin, the early stages (BMP) pathway in hair follicle (HF) determination and differentia- of HF morphogenesis occur, but matrix cells fail to differentiate tion, but how BMP signaling functions in the hair follicle SC niche (11, 12). Although these later differentiation steps rely on active remains unknown. Here, we use loss and gain of function studies BMP signaling, earlier steps in the lineage appear to require the to manipulate BMP signaling in the SC niche. We show that when impairment of the pathway. Noggin, an extracellular BMP the Bmpr1a gene is conditionally ablated, otherwise quiescent SCs inhibitor, is expressed by mesenchyme, where it induces follicle are activated to proliferate, causing an expansion of the niche and morphogenesis in the embryo and promotes new HF growth loss of slow-cycling cells.
    [Show full text]
  • How BMP Signaling Regulates Muscle Growth and Regeneration
    Journal of Developmental Biology Review Bu-M-P-ing Iron: How BMP Signaling Regulates Muscle Growth and Regeneration 1,2, 1,2, 1,2,3,4,5, Matthew J Borok y, Despoina Mademtzoglou y and Frederic Relaix * 1 Inserm, IMRB U955-E10, 94010 Créteil, France; [email protected] (M.J.B.); [email protected] (D.M.) 2 Faculté de santé, Université Paris Est, 94000 Creteil, France 3 Ecole Nationale Veterinaire d’Alfort, 94700 Maison Alfort, France 4 Etablissement Français du Sang, 94017 Créteil, France 5 APHP, Hopitaux Universitaires Henri Mondor, DHU Pepsy & Centre de Référence des Maladies Neuromusculaires GNMH, 94000 Créteil, France * Correspondence: [email protected]; Tel.: +33-149-813-940 These authors contributed equally to this work. y Received: 10 January 2020; Accepted: 7 February 2020; Published: 11 February 2020 Abstract: The bone morphogenetic protein (BMP) pathway is best known for its role in promoting bone formation, however it has been shown to play important roles in both development and regeneration of many different tissues. Recent work has shown that the BMP proteins have a number of functions in skeletal muscle, from embryonic to postnatal development. Furthermore, complementary studies have recently demonstrated that specific components of the pathway are required for efficient muscle regeneration. Keywords: development; regeneration; TGFβ; stem cells; satellite cells 1. Introduction As its name implies, the bone morphogenetic protein (BMP) signaling pathway was first identified as a key regulator of bone formation. Urist and colleagues isolated proteins from rabbit bone and then used them to induce bone formation in vitro or in vivo in the rat [1].
    [Show full text]
  • Fibroblasts from the Human Skin Dermo-Hypodermal Junction Are
    cells Article Fibroblasts from the Human Skin Dermo-Hypodermal Junction are Distinct from Dermal Papillary and Reticular Fibroblasts and from Mesenchymal Stem Cells and Exhibit a Specific Molecular Profile Related to Extracellular Matrix Organization and Modeling Valérie Haydont 1,*, Véronique Neiveyans 1, Philippe Perez 1, Élodie Busson 2, 2 1, 3,4,5,6, , Jean-Jacques Lataillade , Daniel Asselineau y and Nicolas O. Fortunel y * 1 Advanced Research, L’Oréal Research and Innovation, 93600 Aulnay-sous-Bois, France; [email protected] (V.N.); [email protected] (P.P.); [email protected] (D.A.) 2 Department of Medical and Surgical Assistance to the Armed Forces, French Forces Biomedical Research Institute (IRBA), 91223 CEDEX Brétigny sur Orge, France; [email protected] (É.B.); [email protected] (J.-J.L.) 3 Laboratoire de Génomique et Radiobiologie de la Kératinopoïèse, Institut de Biologie François Jacob, CEA/DRF/IRCM, 91000 Evry, France 4 INSERM U967, 92260 Fontenay-aux-Roses, France 5 Université Paris-Diderot, 75013 Paris 7, France 6 Université Paris-Saclay, 78140 Paris 11, France * Correspondence: [email protected] (V.H.); [email protected] (N.O.F.); Tel.: +33-1-48-68-96-00 (V.H.); +33-1-60-87-34-92 or +33-1-60-87-34-98 (N.O.F.) These authors contributed equally to the work. y Received: 15 December 2019; Accepted: 24 January 2020; Published: 5 February 2020 Abstract: Human skin dermis contains fibroblast subpopulations in which characterization is crucial due to their roles in extracellular matrix (ECM) biology.
    [Show full text]
  • Characterization of Tgfβ-Associated Molecular Features and Drug
    Zhang et al. BMC Gastroenterol (2021) 21:284 https://doi.org/10.1186/s12876-021-01869-4 RESEARCH Open Access Characterization of TGFβ-associated molecular features and drug responses in gastrointestinal adenocarcinoma Qiaofeng Zhang1,2,3†, Furong Liu1,2,3†, Lu Qin4, Zhibin Liao1,2,3, Jia Song1,2,3, Huifang Liang1,2,3, Xiaoping Chen1,2,3, Zhanguo Zhang1,2,3* and Bixiang Zhang1,2,3* Abstract Background: Gastrointestinal adenocarcinoma (GIAD) has caused a serious disease burden globally. Targeted ther- apy for the transforming growth factor beta (TGF-β) signaling pathway is becoming a reality. However, the molecular characterization of TGF-β associated signatures in GIAD requires further exploration. Methods: Multi-omics data were collected from TCGA and GEO database. A pivotal unsupervised clustering for TGF-β level was performed by distinguish status of TGF-β associated genes. We analyzed diferential mRNAs, miRNAs, proteins gene mutations and copy number variations in both clusters for comparison. Enrichment of pathways and gene sets were identifed in each type of GIAD. Then we performed diferential mRNA related drug response by col- lecting data from GDSC. At last, a summarized deep neural network for TGF-β status and GIADs was constracted. Results: The TGF-βhigh group had a worse prognosis in overall GIAD patients, and had a worse prognosis trend in gastric cancer and colon cancer specifcally. Signatures (including mRNA and proteins) of the TGF-βhigh group is highly correlated with EMT. According to miRNA analysis, miR-215-3p, miR-378a-5p, and miR-194-3p may block the efect of TGF-β.
    [Show full text]
  • The Effects of Transforming Growth Factor-B2 on the Expression of Follistatin and Activin a in Normal and Glaucomatous Human Trabecular Meshwork Cells and Tissues
    Biochemistry and Molecular Biology The Effects of Transforming Growth Factor-b2 on the Expression of Follistatin and Activin A in Normal and Glaucomatous Human Trabecular Meshwork Cells and Tissues Ashley M. Fitzgerald, Cecilia Benz, Abbot F. Clark, and Robert J. Wordinger PURPOSE. To compare follistatin (FST) and activin (Act) expres- in irreversible blindness and is estimated to affect more than 60 sion in normal and glaucomatous trabecular meshwork (TM) million people.2 Important risk factors for POAG include age, cells and tissues and determine if exogenous TGF-b2 regulates race, and elevated IOP. Elevated IOP results from increased the expression of FST and Act in TM cells. resistance of aqueous humor (AH) outflow through the METHODS. Total RNA was isolated from TM cell strains, and mRNA trabecular meshwork (TM) due to excess accumulation of expression for FST 317/344 isoforms and Act was determined via extracellular matrix (ECM) proteins.4–6 RT-PCR and quantitative PCR (qPCR). Western immunoblotting TGF-b2isthemostabundantTGF-b isoform in the eye.7,8 A and immunocytochemistry determined FST and Act A protein number of studies have reported elevated levels of TGF-b2(2– levels in normal TM (NTM) and glaucomatous TM (GTM) cells. 5ng/mL) in the AH of patients with POAG.7,9–11,51 Endoge- Cells were treated with recombinant human TGF-b2 protein at 0 nous TGF-b2 levels are elevated in both cultured glaucoma- to 10 ng/mL for 0 to 72 hours. qPCR, Western immunoblotting, tous TM (GTM) cell stains and GTM tissues.12,48,49 In other immunocytochemistry, and ELISA immunoassay were utilized to tissues, TGF-b signaling has been shown to mediate fibrotic determine changes in FST and Act A mRNA and protein levels.
    [Show full text]