CHI3L1 (YKL‐40) is expressed in human gliomas and regulates the invasion, growth and survival of glioma cells

Chitinase 3‐like 1 (CHI3L1) is a secreted glycoprotein that has pleiotropic activity in aggressive cancers. In our study, we examined the expression and function of CHI3L1 in glioma cells. CHI3L1 was highly expressed in human glioma tissue, whereas its expression in normal brain tissue was very low. CHI3L1 suppression by shRNA reduced glioma cell invasion, anchorage‐independent growth and increased cell death triggered by several anticancer drugs, including cisplatin, etoposide and doxorubicin, whereas CHI3L1 overexpression had the opposite effect in glioma cells. Because the invasive nature of glioma cells plays a critical role in the high morbidity of glioma, we have further defined the role of CHI3L1 in the process of glioma invasion. Downregulation of CHI3L1 results in decreased cell–matrix adhesion and causes a marked increase in stress fiber formation and cell size with fewer cellular processes. Furthermore, the expression and activity of matrix metalloproteinase‐2 was also decreased in glioma cells in which CHI3L1 was knocked down. Taken together, these results suggest that CHI3L1 plays an important role in the regulation of malignant transformation and local invasiveness in gliomas. Thus, targeting the CHI3L1 molecule may be a potential therapeutic molecular target for gliomas.

[1]  James E. Goldman,et al.  Cell migration in the normal and pathological postnatal mammalian brain , 2009, Progress in Neurobiology.

[2]  Erik Sahai,et al.  The actin cytoskeleton in cancer cell motility , 2009, Clinical & Experimental Metastasis.

[3]  D. Min,et al.  Overexpression of phospholipase D enhances matrix metalloproteinase-2 expression and glioma cell invasion via protein kinase C and protein kinase A/NF-kappaB/Sp1-mediated signaling pathways. , 2009, Carcinogenesis.

[4]  Christopher Beadle,et al.  The role of myosin II in glioma invasion of the brain. , 2008, Molecular biology of the cell.

[5]  S. Stylli,et al.  Invadopodia: At the cutting edge of tumour invasion , 2008, Journal of Clinical Neuroscience.

[6]  R. Kroes,et al.  Focused microarray analysis of glyco‐gene expression in human glioblastomas , 2007, Journal of neurochemistry.

[7]  K. Aldape,et al.  Aberrant FoxM1B expression increases matrix metalloproteinase-2 transcription and enhances the invasion of glioma cells , 2007, Oncogene.

[8]  I. Christensen,et al.  Changes of Biochemical Markers of Bone Turnover and YKL-40 Following Hormonal Treatment for Metastatic Prostate Cancer Are Related to Survival , 2007, Clinical Cancer Research.

[9]  A. Raz,et al.  SPARC upregulates MT1-MMP expression, MMP-2 activation, and the secretion and cleavage of galectin-3 in U87MG glioma cells , 2007, Neuroscience Letters.

[10]  D. Levine,et al.  Preoperative serum YKL-40 is a marker for detection and prognosis of endometrial cancer. , 2007, Gynecologic oncology.

[11]  M. Berens,et al.  Molecular targets of glioma invasion , 2007, Cellular and Molecular Life Sciences.

[12]  S. To,et al.  Differential effects of photofrin, 5-aminolevulinic acid and calphostin C on glioma cells. , 2006, Journal of photochemistry and photobiology. B, Biology.

[13]  Andrew D Rowan,et al.  The Mammalian Chitinase-like Lectin, YKL-40, Binds Specifically to Type I Collagen and Modulates the Rate of Type I Collagen Fibril Formation* , 2006, Journal of Biological Chemistry.

[14]  Li Zhang,et al.  Prognostic Associations of Activated Mitogen-Activated Protein Kinase and Akt Pathways in Glioblastoma , 2006, Clinical Cancer Research.

[15]  D. Figarella-Branger,et al.  Identification of genes differentially expressed in glioblastoma versus pilocytic astrocytoma using Suppression Subtractive Hybridization , 2006, Oncogene.

[16]  Thomas D. Wu,et al.  Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. , 2006, Cancer cell.

[17]  K. Aldape,et al.  YKL-40 Expression is Associated with Poorer Response to Radiation and Shorter Overall Survival in Glioblastoma , 2005, Clinical Cancer Research.

[18]  P. Kristjansen,et al.  Expression of YKL-40 by peritumoral macrophages in human small cell lung cancer. , 2005, Lung cancer.

[19]  Rebecca A Betensky,et al.  YKL-40 Is a Differential Diagnostic Marker for Histologic Subtypes of High-Grade Gliomas , 2005, Clinical Cancer Research.

[20]  P. Kristjansen,et al.  Regulation of YKL‐40 expression during genotoxic or microenvironmental stress in human glioblastoma cells , 2005, Cancer science.

[21]  K. Aldape,et al.  Integrated array-comparative genomic hybridization and expression array profiles identify clinically relevant molecular subtypes of glioblastoma. , 2005, Cancer research.

[22]  G. Borisy,et al.  Cell Migration: Integrating Signals from Front to Back , 2003, Science.

[23]  B. Jensen,et al.  High levels of serum HER-2/neu and YKL-40 independently reflect aggressiveness of metastatic breast cancer. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[24]  K. H. Kalk,et al.  Crystal Structure and Carbohydrate-binding Properties of the Human Cartilage Glycoprotein-39* , 2003, Journal of Biological Chemistry.

[25]  D. V. van Aalten,et al.  Structure and Ligand-induced Conformational Change of the 39-kDa Glycoprotein from Human Articular Chondrocytes* , 2003, Journal of Biological Chemistry.

[26]  V. Kavsan,et al.  HC gp-39 gene is upregulated in glioblastomas. , 2003, Cancer letters.

[27]  A. J. Millis,et al.  gp38k (CHI3L1) is a novel adhesion and migration factor for vascular cells. , 2003, Experimental cell research.

[28]  M. Westphal,et al.  Cost of migration: invasion of malignant gliomas and implications for treatment. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  Mark R Gilbert,et al.  Gene expression microarray analysis reveals YKL-40 to be a potential serum marker for malignant character in human glioma. , 2002, Cancer research.

[30]  H. Nielsen,et al.  High serum YKL‐40 level after surgery for colorectal carcinoma is related to short survival , 2002, Cancer.

[31]  H. Ling,et al.  The chitinase 3-like protein human cartilage glycoprotein 39 (HC-gp39) stimulates proliferation of human connective-tissue cells and activates both extracellular signal-regulated kinase- and protein kinase B-mediated signalling pathways. , 2002, The Biochemical journal.

[32]  A. Ridley.  Rho GTPases and cell migration. , 2001, Journal of cell science.

[33]  W. Broaddus,et al.  The Role of Matrix Metalloproteinase Genes in Glioma Invasion: Co-dependent and Interactive Proteolysis , 2001, Journal of Neuro-Oncology.

[34]  M. Weller,et al.  Molecular determinants of glioma cell migration and invasion. , 2001, Journal of neurosurgery.

[35]  S. Altschul,et al.  A public database for gene expression in human cancers. , 1999, Cancer research.

[36]  H. Kleinman,et al.  Gp38k, a protein synthesized by vascular smooth muscle cells, stimulates directional migration of human umbilical vein endothelial cells. , 1999, Experimental cell research.

[37]  S. Rosenfeld,et al.  Glioma migration can be blocked by nontoxic inhibitors of myosin II. , 1999, Cancer research.

[38]  Brian,et al.  Human cartilage gp-39, a major secretory product of articular chondrocytes and synovial cells, is a mammalian member of a chitinase protein family. , 1993, The Journal of biological chemistry.

[39]  Koji Yoshimoto,et al.  Distinct transcription profiles of primary and secondary glioblastoma subgroups. , 2006, Cancer research.

[40]  K. Kunishio,et al.  Matrix metalloproteinase-2 and-9 expression in astrocytic tumors , 2006, Brain Tumor Pathology.

[41]  T. Cloughesy,et al.  Upregulation of tissue inhibitor of metalloproteinases (TIMP)-2 promotes matrix metalloproteinase (MMP)-2 activation and cell invasion in a human glioblastoma cell line , 2004, Laboratory Investigation.