DOCSLIB.ORG

The Roles of CCN1/CYR61 in Pulmonary Diseases

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Roles of CCN1/CYR61 in Pulmonary Diseases International Journal of Molecular Sciences Review The Roles of CCN1/CYR61 in Pulmonary Diseases Yin Zhu 1, Sultan Almuntashiri 1, Yohan Han 1, Xiaoyun Wang 2, Payaningal R. Somanath 1,3 and Duo Zhang 1,* 1 Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA; [email protected] (Y.Z.); [email protected] (S.A.); [email protected] (Y.H.); [email protected] (P.R.S.) 2 Center for Vaccines and Immunology, University of Georgia, Athens, GA 30602, USA; [email protected] 3 Department of Medicine, Augusta University, Augusta, GA 30912, USA * Correspondence: [email protected]; Tel.: +1-706-721-6491; Fax: +1-706-721-3994 Received: 21 September 2020; Accepted: 21 October 2020; Published: 22 October 2020 Abstract: CCN1 (cysteine-rich 61, connective tissue growth factor, and nephroblastoma-1), previously named CYR61 (cysteine-rich angiogenic inducer 61) belongs to the CCN family of matricellular proteins. CCN1 plays critical roles in the regulation of proliferation, differentiation, apoptosis, angiogenesis, and fibrosis. Recent studies have extensively characterized the important physiological and pathological roles of CCN1 in various tissues and organs. In this review, we summarize both basic and clinical aspects of CCN1 in pulmonary diseases, including acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), lung fibrosis, pulmonary arterial hypertension (PAH), lung infection, and lung cancer. We also emphasize the important challenges for future investigations to better understand the CCN1 and its role in physiology and pathology, as well as the questions that need to be addressed for the therapeutic development of CCN1 antagonists in various lung diseases. Keywords: lung injury; COPD; bronchopulmonary dysplasia; fibrosis; pulmonary hypertension; lung infection; lung cancer 1. Introduction The discovery of the CCN proteins started back in the 1990s, and many research groups have presented their work in regards to different CCN proteins [1]. The first found protein was named as the CCN1 or the CYR61, since the protein is recognized as a cysteine-rich protein. Then, CCN2/CTGF, CCN3/NOV, CCN4/WISP-1, CCN5/WISP-2, and CCN6/WISP-3 were introduced by researchers [1]. The CCN protein family consists of six secreted proteins with multifunction designated CCN1 to CCN6. These proteins are found to be conserved among different vertebrates, indicating their conserved roles during evolution. As shown in Figure1, most of the CCN proteins contain a similar structure consisting of four functional domains: (a) insulin-like growth factor binding protein-like module (IGFBP); (b) von Willebrand factor type C repeat module (VWC); (c) thrombospondin type I repeat module (TSP-1); and (d) cysteine-knot-containing module (CT) [2]. One of the exceptions in the CCN protein family with respect to the structure is CCN5, which is lacking the cysteine-knot-containing module (CT), while other members share the same four modules [3]. In the four different modules, receptors such as integrin αVβ3, αVβ5, and α2Bβ3 will bind to the VWC module-binding site; integrin α6β1 will binding in the TSR module. In the CT module, many molecules like heparan sulfate proteoglycans (HSPG), integrin α6β1, αVβ3, α5β1, α6β1, and αMβ2 bind to the module [4,5]. These modules with the binding molecules provide multiple functions to the CCN proteins; like most of the matricellular proteins, CCN proteins can affect cellular behaviors based on different combinations of binding molecules. Int. J. Mol. Sci. 2020, 21, 7810; doi:10.3390/ijms21217810 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 7810 2 of 16 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 15 Forhave example, several integrinsbiologicalα vactivities,β3 and heparan including sulfate cell proteoglycansadhesion, migration, have several growth, biological apoptosis, activities, and includingsenescence cell [4,6–9]. adhesion, When migration, different growth, integrins apoptosis, bind to andthe senescencefour modules, [4,6 –CCN9]. When proteins different can integrinsfunction binddifferently to the in four various modules, cell types. CCN proteins can function differently in various cell types. Figure 1. The structure of CCN protein and examples of their binding growth factors/integrins. The structure (from left to right) consists of insulin-like growth factor binding protein (IGFBP), Figure 1. The structure of CCN protein and examples of their binding growth factors/integrins. The von Willebrand factor type C repeat (vWC), thrombospondin type 1 repeat (TSP), and cysteine knot structure (from left to right) consists of insulin-like growth factor binding protein (IGFBP), von (CT). Transforming growth factor β1 (TGF-β1), fibroblast growth factor (FGF2), vascular endothelial Willebrand factor type C repeat (vWC), thrombospondin type 1 repeat (TSP), and cysteine knot (CT). growth factor (VEGF), and the integrins (αVβ5, α6β1, and αVβ3) are shown binding with each section. Transforming growth factor β1 (TGF-β1), fibroblast growth factor (FGF2), vascular endothelial Manygrowthin factor vivo (VEGF)studies,, and including the integrins animal (αVβ and5, α6 humanβ1, and α trails,Vβ3) are revealed shown thatbinding the with CCN each proteins section. might have the ability to enroll in the mediation process in human diseases. For example, the abnormal expressionMany in of vivo the CCNstudies, proteins including has animal been found and human in the trails, diabetic revealed nephropathy that the disease.CCN proteins The results might have shownthe ability that to the enroll upregulated in the mediation CCN2 is observedprocess in in human the mesangial diseases. cells, For as example, well as thethe decreasing abnormal expression of of the CCN1 CCN in proteins the podocytes has been infound the diabeticin the diabetic retina nephropathy [10–12]. In disease. atherosclerosis The results diseases, have theshown increased that the expressions upregulated of theCCN2 CCN1 is observed and CCN2 in werethe mesangial also found cells, where as well the inflammatory as the decreasing cells accumulated,expression of CCN1 practically in the around podocytes the plaques in the diabetic [13,14]. Moreover,retina [10–12]. the increasedIn atherosclerosis CCN1 level diseases, has been the seenincreased in rheumatoid expressions arthritis of the disease. CCN1 The and researchers CCN2 were who reportedalso found these where findings the suggested inflammatory a potential cells connectionaccumulated, between practically the role around of CCN1 the proteinplaques and [13,14 hyperplasia]. Moreover, in the the joint increased [15,16]. CCN1 In the cancer level has category, been CCNseen in proteins rheumatoid have beenarthritis extensively disease. investigated, The researchers especially who thereported dysregulation these findings of CCN suggested proteins ina thepotential development connection of several between types the ofro cancers.le of CCN1 Based protein on the and current hyperplasia findings, in it the has joint been [15,16]. observed In thatthe highlycancer inducedcategory, CCN1, CCN CCN2,proteins CCN3, have andbeen CCN5 extensiv wereely found investigated, in breast andespecial ovarianly the cancer dysregulation [17,18] along of withCCN theproteins downregulation in the development of CCN6 of [19 several], which types is correlated of cancers. with Based poor on prognosis the current situations. findings, In it lung has cancer,been observed there are that many highly reports induced indicating CCN1, CCN2, that the CCN3, CCN1 and and CCN5 CCN2 were are found negatively in breast correlated and ovarian with thecancer prognosis [17,18] ofalong lung with cancer, the wheredownregulation the expression of CC ofN6 CCN1 [19], andwhich CCN2 is correlated level is lower with poor compared prognosis with normalsituations. matched In lung lung cancer, tissues there [20 are,21 many]. In contrast,reports indicating there is athat significant the CCN1 induction and CCN2 of CCN4are negatively protein incorrelated the lung with carcinoma the prognosis samples of [lung20]. cancer, In colon wher cancer,e the the expression increased of CCN1, CCN1 and CCN2, CCN2 and level CCN4 is lower were consideredcompared with as an normal indicator matched for the lung tumor tissues stages [20,21]. [22,23 ].In Based contrast, on this there growing is a significant evidence, induction researchers of suggestedCCN4 protein CCN in protein the lung members carcinoma might samples serve as[20]. diagnostic In colon markers cancer, andthe increased therapeutic CCN1, targets CCN2, in human and diseases.CCN4 were As considered the investigations as an indicator summarized for the above,tumor thestages CCN [22,23]. protein Based family on this has growing shown promising evidence, potentialresearchers for suggested clinical usage. CCN In protein this review, members we focus might on the serve CCN1 as proteindiagnostic and markers its known and roles therapeutic in human lungtargets diseases. in human diseases. As the investigations summarized above, the CCN protein family has shown promising potential for clinical usage. In this review, we focus on the CCN1 protein and its 2.known CCN1 roles in human lung diseases. CCN1 protein was first identified as a matricellular protein and was cloned from mouse 3T3 2. CCN1 fibroblasts in the early 1990s [1]. Accumulated data suggested CCN1 is a multifunctional protein, whichCCN1 is essential protein for was physiological first identified processes
Load more

Recommended publications
  • Differential Expression of the CCN Family Members Cyr61, CTGF and Nov in Human Breast Cancer
    Endocrine-Related Cancer (2004) 11 781–791 Differential expression of the CCN family members Cyr61, CTGF and Nov in human breast cancer Wen G Jiang, Gareth Watkins, Oystein Fodstad 1, Anthony Douglas-Jones 2, Kefah Mokbel 3 and Robert E Mansel Metastasis & Angiogenesis Research Group, University of Wales College of Medicine, Cardiff University, Cardiff, UK 1Cancer Research Institute, University of South Alabama, Mobile, AL, USA 2Pathology, University of Wales College of Medicine, Cardiff University, Cardiff, UK 3Department of Surgery, St George Hospital, London, UK (Requests for offprints should be addressed to W G Jiang; Email: [email protected]) Abstract The CCN family members cysteine-rich 61 (Cyr61/CCN1), connective tissue growth factor (CTGF/ CCN2) and nephroblastoma over-expressed (Nov/CCN3) play diverse roles in cells, are known to regulate cell growth, adhesion, matrix production and migration and are involved in endocrine- regulated pathways in various cell types. The role of these molecules in cancer remains controversial. In a cohort of 122 human breast tumours (together with 32 normal breast tissues) we have analysed the expression of all three CCN members at the mRNA and protein levels. Significantly higher levels of Cyr61 ðP ¼ 0:02Þ, but low levels of CTGF and Nov, were seen in tumour tissues compared with normal tissues. Significantly raised levels of Cyr61 were associated with poor prognosis ðP ¼ 0:02Þ, nodal involvement ðP ¼ 0:03Þ and metastatic disease ðP ¼ 0:016Þ. Patients who died of breast cancer also had high levels of Cyr61. In contrast, CTGF in patients with poor prognosis ðP ¼ 0:021Þ, metastasis ðP ¼ 0:012Þ, local recurrence ðP ¼ 0:0024Þ and mortality ðP ¼ 0:0072Þ had markedly reduced levels.
    [Show full text]
  • Genetic Analysis of the Roles of Hh, FGF8, and Nodal Signaling During Catecholaminergic System Development in the Zebrafish Brain
    The Journal of Neuroscience, July 2, 2003 • 23(13):5507–5519 • 5507 Development/Plasticity/Repair Genetic Analysis of the Roles of Hh, FGF8, and Nodal Signaling during Catecholaminergic System Development in the Zebrafish Brain Jochen Holzschuh, Giselbert Hauptmann, and Wolfgang Driever Developmental Biology, Institute Biology 1, University of Freiburg, D-79104 Freiburg, Germany CNS catecholaminergic neurons can be distinguished by their neurotransmitters as dopaminergic or noradrenergic and form in distinct regions at characteristic embryonic stages. This raises the question of whether all catecholaminergic neurons of one transmitter type are specified by the same set of factors. Therefore, we performed genetic analyses to define signaling requirements for the specification of distinct clusters of catecholaminergic neurons in zebrafish. In mutants affecting midbrain–hindbrain boundary (MHB) organizer for- mation, the earliest ventral diencephalic dopaminergic neurons appear normal. However, after2dofdevelopment, we observed fewer cells than in wild types, which suggests that the MHB provides proliferation or survival factors rather than specifying ventral diencephalic dopaminergic clusters. In hedgehog (Hh) pathway mutants, the formation of catecholaminergic neurons is affected only in the pretectal cluster. Surprisingly, neither fibroblast growth factor 8 (FGF8) alone nor in combination with Hh signaling is required for specification of early developing dopaminergic neurons. We analyzed the formation of prosomeric territories in the forebrain of Hh and Nodal pathway mutants to determine whether the absence of specific dopaminergic clusters may be caused by early patterning defects ablating corre- sponding parts of the CNS. In Nodal pathway mutants, ventral diencephalic and pretectal catecholaminergic neurons fail to develop, whereas both anatomical structures form at least in part.
    [Show full text]
  • Epha Receptors and Ephrin-A Ligands Are Upregulated by Monocytic
    Mukai et al. BMC Cell Biology (2017) 18:28 DOI 10.1186/s12860-017-0144-x RESEARCHARTICLE Open Access EphA receptors and ephrin-A ligands are upregulated by monocytic differentiation/ maturation and promote cell adhesion and protrusion formation in HL60 monocytes Midori Mukai, Norihiko Suruga, Noritaka Saeki and Kazushige Ogawa* Abstract Background: Eph signaling is known to induce contrasting cell behaviors such as promoting and inhibiting cell adhesion/ spreading by altering F-actin organization and influencing integrin activities. We have previously demonstrated that EphA2 stimulation by ephrin-A1 promotes cell adhesion through interaction with integrins and integrin ligands in two monocyte/ macrophage cell lines. Although mature mononuclear leukocytes express several members of the EphA/ephrin-A subclass, their expression has not been examined in monocytes undergoing during differentiation and maturation. Results: Using RT-PCR, we have shown that EphA2, ephrin-A1, and ephrin-A2 expression was upregulated in murine bone marrow mononuclear cells during monocyte maturation. Moreover, EphA2 and EphA4 expression was induced, and ephrin-A4 expression was upregulated, in a human promyelocytic leukemia cell line, HL60, along with monocyte differentiation toward the classical CD14++CD16− monocyte subset. Using RT-PCR and flow cytometry, we have also shown that expression levels of αL, αM, αX, and β2 integrin subunits were upregulated in HL60 cells along with monocyte differentiation while those of α4, α5, α6, and β1 subunits were unchanged. Using a cell attachment stripe assay, we have shown that stimulation by EphA as well as ephrin-A, likely promoted adhesion to an integrin ligand- coated surface in HL60 monocytes. Moreover, EphA and ephrin-A stimulation likely promoted the formation of protrusions in HL60 monocytes.
    [Show full text]
  • Ephb3 Suppresses Non-Small-Cell Lung Cancer Metastasis Via a PP2A/RACK1/Akt Signalling Complex
    ARTICLE Received 7 Nov 2011 | Accepted 11 Jan 2012 | Published 7 Feb 2012 DOI: 10.1038/ncomms1675 EphB3 suppresses non-small-cell lung cancer metastasis via a PP2A/RACK1/Akt signalling complex Guo Li1, Xiao-Dan Ji1, Hong Gao1, Jiang-Sha Zhao1, Jun-Feng Xu1, Zhi-Jian Sun1, Yue-Zhen Deng1, Shuo Shi1, Yu-Xiong Feng1, Yin-Qiu Zhu1, Tao Wang2, Jing-Jing Li1 & Dong Xie1 Eph receptors are implicated in regulating the malignant progression of cancer. Here we find that despite overexpression of EphB3 in human non-small-cell lung cancer, as reported previously, the expression of its cognate ligands, either ephrin-B1 or ephrin-B2, is significantly downregulated, leading to reduced tyrosine phosphorylation of EphB3. Forced activation of EphB3 kinase in EphB3-overexpressing non-small-cell lung cancer cells inhibits cell migratory capability in vitro as well as metastatic seeding in vivo. Furthermore, we identify a novel EphB3-binding protein, the receptor for activated C-kinase 1, which mediates the assembly of a ternary signal complex comprising protein phosphatase 2A, Akt and itself in response to EphB3 activation, leading to reduced Akt phosphorylation and subsequent inhibition of cell migration. Our study reveals a novel tumour-suppressive signalling pathway associated with kinase-activated EphB3 in non-small-cell lung cancer, and provides a potential therapeutic strategy by activating EphB3 signalling, thus inhibiting tumour metastasis. 1 Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Graduate School of Chinese Academy of Sciences, Shanghai 200031, China. 2 The Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai 200433, China.
    [Show full text]
  • A Diverse Host Thrombospondin-Type-1
    RESEARCH ARTICLE A diverse host thrombospondin-type-1 repeat protein repertoire promotes symbiont colonization during establishment of cnidarian-dinoflagellate symbiosis Emilie-Fleur Neubauer1, Angela Z Poole2,3, Philipp Neubauer4, Olivier Detournay5, Kenneth Tan3, Simon K Davy1*, Virginia M Weis3* 1School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand; 2Department of Biology, Western Oregon University, Monmouth, United States; 3Department of Integrative Biology, Oregon State University, Corvallis, United States; 4Dragonfly Data Science, Wellington, New Zealand; 5Planktovie sas, Allauch, France Abstract The mutualistic endosymbiosis between cnidarians and dinoflagellates is mediated by complex inter-partner signaling events, where the host cnidarian innate immune system plays a crucial role in recognition and regulation of symbionts. To date, little is known about the diversity of thrombospondin-type-1 repeat (TSR) domain proteins in basal metazoans or their potential role in regulation of cnidarian-dinoflagellate mutualisms. We reveal a large and diverse repertoire of TSR proteins in seven anthozoan species, and show that in the model sea anemone Aiptasia pallida the TSR domain promotes colonization of the host by the symbiotic dinoflagellate Symbiodinium minutum. Blocking TSR domains led to decreased colonization success, while adding exogenous *For correspondence: Simon. TSRs resulted in a ‘super colonization’. Furthermore, gene expression of TSR proteins was highest [email protected] (SKD); weisv@ at early time-points during symbiosis establishment. Our work characterizes the diversity of oregonstate.edu (VMW) cnidarian TSR proteins and provides evidence that these proteins play an important role in the Competing interests: The establishment of cnidarian-dinoflagellate symbiosis. authors declare that no DOI: 10.7554/eLife.24494.001 competing interests exist.
    [Show full text]
  • Expression Profiling of KLF4
    Expression Profiling of KLF4 AJCR0000006 Supplemental Data Figure S1. Snapshot of enriched gene sets identified by GSEA in Klf4-null MEFs. Figure S2. Snapshot of enriched gene sets identified by GSEA in wild type MEFs. 98 Am J Cancer Res 2011;1(1):85-97 Table S1: Functional Annotation Clustering of Genes Up-Regulated in Klf4 -Null MEFs ILLUMINA_ID Gene Symbol Gene Name (Description) P -value Fold-Change Cell Cycle 8.00E-03 ILMN_1217331 Mcm6 MINICHROMOSOME MAINTENANCE DEFICIENT 6 40.36 ILMN_2723931 E2f6 E2F TRANSCRIPTION FACTOR 6 26.8 ILMN_2724570 Mapk12 MITOGEN-ACTIVATED PROTEIN KINASE 12 22.19 ILMN_1218470 Cdk2 CYCLIN-DEPENDENT KINASE 2 9.32 ILMN_1234909 Tipin TIMELESS INTERACTING PROTEIN 5.3 ILMN_1212692 Mapk13 SAPK/ERK/KINASE 4 4.96 ILMN_2666690 Cul7 CULLIN 7 2.23 ILMN_2681776 Mapk6 MITOGEN ACTIVATED PROTEIN KINASE 4 2.11 ILMN_2652909 Ddit3 DNA-DAMAGE INDUCIBLE TRANSCRIPT 3 2.07 ILMN_2742152 Gadd45a GROWTH ARREST AND DNA-DAMAGE-INDUCIBLE 45 ALPHA 1.92 ILMN_1212787 Pttg1 PITUITARY TUMOR-TRANSFORMING 1 1.8 ILMN_1216721 Cdk5 CYCLIN-DEPENDENT KINASE 5 1.78 ILMN_1227009 Gas2l1 GROWTH ARREST-SPECIFIC 2 LIKE 1 1.74 ILMN_2663009 Rassf5 RAS ASSOCIATION (RALGDS/AF-6) DOMAIN FAMILY 5 1.64 ILMN_1220454 Anapc13 ANAPHASE PROMOTING COMPLEX SUBUNIT 13 1.61 ILMN_1216213 Incenp INNER CENTROMERE PROTEIN 1.56 ILMN_1256301 Rcc2 REGULATOR OF CHROMOSOME CONDENSATION 2 1.53 Extracellular Matrix 5.80E-06 ILMN_2735184 Col18a1 PROCOLLAGEN, TYPE XVIII, ALPHA 1 51.5 ILMN_1223997 Crtap CARTILAGE ASSOCIATED PROTEIN 32.74 ILMN_2753809 Mmp3 MATRIX METALLOPEPTIDASE
    [Show full text]
  • Thrombospondin-1, Human (ECM002)
    Thrombospondin-1, human recombinant, expressed in HEK 293 cells suitable for cell culture Catalog Number ECM002 Storage Temperature –20 C Synonyms: THBS1, THBS, TSP1, TSP This product is supplied as a powder, lyophilized from phosphate buffered saline. It is aseptically filled. Product Description Thrombospondin-1 (TSP1) is believed to play a role in The biological activity of recombinant human cell migration and proliferation, during embryogenesis thrombospondin-1 was tested in culture by measuring and wound repair.1-2 TSP1 expression is highly the ability of immobilized DTT-treated regulated by different hormones and cytokines, and is thrombospondin-1 to support adhesion of SVEC4-10 developmentally controlled. TSP1 stimulates the growth cells. of vascular smooth muscle cells and human foreskin fibroblasts. A combination of interferon and tumor Uniprot: P07996 necrosis factor inhibits TSP1 production in these cells.3 In endothelial cells, it controls adhesion and Purity: 95% (SDS-PAGE) migration as well as proliferation. It also exhibits antiangiogenic properties and regulates immune Endotoxin level: 1.0 EU/g FN (LAL) processes.4-5 TSP1 binds to various cell surface receptors, such as integrins and integrin-associated Precautions and Disclaimer protein CD47.1 It also plays a crucial role in This product is for R&D use only, not for drug, inflammatory processes and post-inflammatory tissue household, or other uses. Please consult the Safety dynamics.6 TSP1 has been used as a potential Data Sheet for information regarding hazards and safe regulator of tumor growth and metastasis.5 It is handling practices. upregulated in rheumatoid synovial tissues and might be associated with rheumatoid arthritis.7 Variants of this Preparation Instructions gene might be linked with increased risk of autism.8 Briefly centrifuge the vial before opening.
    [Show full text]
  • Annals of Medical and Clinical Oncology Chen C, Et Al
    Annals of Medical and Clinical Oncology Chen C, et al. Ann med clin Oncol 3: 125. Short Commentary DOI: 10.29011/AMCO-125.000125 Commentary Referring to Pericyte FAK Negatively Regulates Gas6/ Axl Signalling To Suppress Tumour Angiogenesis and Tumour Growth Chen Chen, Hongyan Wang, Binfeng Wu and Jinghua Chen* Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, PR China *Corresponding author: Jinghua Chen, Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, PR China Citation: Chen C, Wang H, Wu B, Chen J (2020) Commentary Referring to Pericyte FAK Negatively Regulates Gas6/Axl Signalling To Suppress Tumour Angiogenesis and Tumour Growth. Ann med clin Oncol 3: 125. DOI: 10.29011/AMCO-125.000125 Received Date: 07 December, 2020; Accepted Date: 20 December, 2020; Published Date: 28 December, 2020 The published research article utilized multiple mouse Interestingly, knockout of FAK was specific to pericytes other models including melanoma, lung carcinoma and pancreatic B-cell than endothelial cells, mice models demonstrated that loss of insulinoma. Two hallmarks of cancer [1] such as angiogenesis and FAK from pericytes significantly promoted ɑ-SMA expression tumour growth had been evaluated. Two major molecules FAK (common metastatic biomarker) and NG-2 (typical angiogenesis (focal adhesion kinase 1) and Axl undertook the innovative roles related biomarker) in three cancer cells model. It suggested that of this elegant paper. They both belong to protein Tyrosine Kinase FAK may function as the tumour suppressive gene. However, (TK) family [2].
    [Show full text]
  • Cysteine-Rich 61 (Cyr61): a Biomarker Reflecting Disease Activity In
    Fan et al. Arthritis Research & Therapy (2019) 21:123 https://doi.org/10.1186/s13075-019-1906-y RESEARCHARTICLE Open Access Cysteine-rich 61 (Cyr61): a biomarker reflecting disease activity in rheumatoid arthritis Yong Fan†, Xinlei Yang†, Juan Zhao, Xiaoying Sun, Wenhui Xie, Yanrong Huang, Guangtao Li, Yanjie Hao and Zhuoli Zhang* Abstract Background: Numerous preclinical studies have revealed a critical role of cysteine-rich 61 (Cyr61) in the pathogenesis of rheumatoid arthritis (RA). But there is little literature discussing the clinical value of circulation Cyr61 in RA patients. The aim of our study is to investigate the serum Cyr61 level and its association with disease activity in RA patients. Methods: A training cohort was derived from consecutive RA patients who visited our clinic from Jun 2014 to Nov 2018. Serum samples were obtained at the enrollment time. To further confirm discovery, an independent validation cohort was set up based on a registered clinical trial. Paired serum samples of active RA patients were respectively collected at baseline and 12 weeks after uniformed treatment. Serum Cyr61 concentration was detected by enzyme-linked immunosorbent assay. The comparison of Cyr61 between RA patients and controls, the correlation between Cyr61 levels with disease activity, and the change of Cyr61 after treatment were analyzed by appropriate statistical analyses. Results: A total of 177 definite RA patients and 50 age- and gender-matched healthy controls were enrolled in the training cohort. Significantly elevated serum Cyr61 concentration was found in RA patients, demonstrating excellent diagnostic ability to discriminate RA from healthy controls (area under the curve (AUC) = 0.98, P < 0.001).
    [Show full text]
  • Salt-Inducible Kinases Dictate Parathyroid Hormone Receptor Action in Bone Development and Remodeling
    Salt-inducible kinases dictate parathyroid hormone receptor action in bone development and remodeling Shigeki Nishimori, … , Henry M. Kronenberg, Marc N. Wein J Clin Invest. 2019. https://doi.org/10.1172/JCI130126. Research In-Press Preview Bone Biology Endocrinology The parathyroid hormone receptor (PTH1R) mediates the biologic actions of parathyroid hormone (PTH) and parathyroid hormone related protein (PTHrP). Here, we showed that salt inducible kinases (SIKs) are key kinases that control the skeletal actions downstream of PTH1R and that this GPCR, when activated, inhibited cellular SIK activity. Sik gene deletion led to phenotypic changes that were remarkably similar to models of increased PTH1R signaling. In growth plate chondrocytes, PTHrP inhibited SIK3 and ablation of this kinase in proliferating chondrocytes rescued perinatal lethality of PTHrP-null mice. Combined deletion of Sik2/Sik3 in osteoblasts and osteocytes led to a dramatic increase in bone mass that closely resembled the skeletal and molecular phenotypes observed when these bone cells express a constitutively active PTH1R that causes Jansen’s metaphyseal chondrodysplasia. Finally, genetic evidence demonstrated that class IIa HDACs were key PTH1R-regulated SIK substrates in both chondrocytes and osteocytes. Taken together, our findings established that SIK inhibition is central to PTH1R action in bone development and remodeling. Furthermore, this work highlighted the key role of cAMP-regulated salt inducible kinases downstream of GPCR action. Find the latest version: https://jci.me/130126/pdf 1 Salt-inducible kinases dictate parathyroid hormone receptor action in bone development 2 and remodeling 3 4 Shigeki Nishimori1,2, Maureen J. O’Meara1, Christian Castro1, Hiroshi Noda1,3, Murat Cetinbas4, 5 Janaina da Silva Martins1, Ugur Ayturk5, Daniel J.
    [Show full text]
  • Fgf8b Oncogene Mediates Proliferation and Invasion of Epstein–Barr Virus-Associated Nasopharyngeal Carcinoma Cells: Implication for Viral-Mediated Fgf8b Upregulation
    Oncogene (2011) 30, 1518–1530 & 2011 Macmillan Publishers Limited All rights reserved 0950-9232/11 www.nature.com/onc ORIGINAL ARTICLE FGF8b oncogene mediates proliferation and invasion of Epstein–Barr virus-associated nasopharyngeal carcinoma cells: implication for viral-mediated FGF8b upregulation VWY Lui1,7, DM-S Yau1,7, CS-F Cheung1, SCC Wong1, AK-C Chan2, Q Zhou1, EY-L Wong1, CPY Lau1, EKY Lam1, EP Hui1, B Hong1, CWC Hui1, AS-K Chan1, PKS Ng3, Y-K Ng4, K-W Lo5, CM Tsang6, SKW Tsui3, S-W Tsao6 and ATC Chan1 1State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer, Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong; 2Department of Pathology, Queen Elizabeth Hospital, Hong Kong; 3School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong; 4Department of Surgery, Chinese University of Hong Kong, Hong Kong; 5Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong and 6Department of Anatomy, University of Hong Kong, Hong Kong The fibroblast growth factor 8b (FGF8b) oncogene is identified LMP1 as the first viral oncogene capable of known to be primarily involved in the tumorigenesis and directly inducing FGF8b (an important cellular oncogene) progression of hormone-related cancers. Its role in other expression in human cancer cells. This novel mechanism of epithelial cancers has not been investigated, except for viral-mediated FGF8 upregulation may implicate a new esophageal cancer, in which FGF8b overexpression was role of oncoviruses in human carcinogenesis. mainly found in tumor biopsies of male patients. These Oncogene (2011) 30, 1518–1530; doi:10.1038/onc.2010.529; observations were consistent with previous findings in published online 29 November 2010 these cancer types that the male sex-hormone androgen is responsible for FGF8b expression.
    [Show full text]
  • Hepatocyte Growth Factor Signaling Pathway As a Potential Target in Ductal Adenocarcinoma of the Pancreas
    JOP. J Pancreas (Online) 2017 Nov 30; 18(6):448-457. REVIEW ARTICLE Hepatocyte Growth Factor Signaling Pathway as a Potential Target in Ductal Adenocarcinoma of the Pancreas Samra Gafarli, Ming Tian, Felix Rückert Department of Surgery, Medical Faculty Mannheim, University of Heidelberg, Germany ABSTRACT Hepatocyte growth factor is an important cellular signal pathway. The pathway regulates mitogenesis, morphogenesis, cell migration, invasiveness and survival. Hepatocyte growth factor acts through activation of tyrosine kinase receptor c-Met (mesenchymal epithelial transition factor) as the only known ligand. Despite the fact that hepatocyte growth factor is secreted only by mesenchymal origin cells, the targets of this multifunctional pathway are cells of mesenchymal as well as epithelial origin. Besides its physiological role recent evidences suggest that HGF/c-Met also plays a role in tumor pathophysiology. As a “scatter factor” hepatocyte growth factor stimulates cancer cell migration, invasion and subsequently promote metastases. Hepatocyte growth factor further is involved in desmoplastic reaction and consequently indorse chemo- and radiotherapy resistance. Explicitly, this pathway seems to mediate cancer cell aggressiveness and to correlate with poor prognosis and survival rate. Pancreatic Ductal Adenocarcinoma is a carcinoma with high aggressiveness and metastases rate. Latest insights show that the HGF/c-Met signal pathway might play an important role in pancreatic ductal adenocarcinoma pathophysiology. In the present review, we highlight the role of HGF/c-Met pathway in pancreatic ductal adenocarcinoma with focus on its effect on cellular pathophysiology and discuss its role as a potential therapeutic target in pancreatic ductal adenocarcinoma. INTRODUCTION activation causes auto-phosphorylation of c-Met and subsequent activation of downstream signaling pathways Hepatocyte growth factor (HGF) is a multifunctional such as mitogen-activated protein kinases (MAPKs), gene.
    [Show full text]