title: Anosmin-1 contributes to brain tumor malignancy through integrin signal pathways.
abstract: Anosmin-1, encoded by the KAL1 gene, is an extracellular matrix (ECM)-associated protein which plays essential roles in the establishment of olfactory and GNRH neurons during early brain development. Loss-of-function mutations of KAL1 results in Kallmann syndrome with delayed puberty and anosmia. There is, however, little comprehension of its role in the developed brain. As reactivation of developmental signal pathways often takes part in tumorigenesis, we investigated if anosmin-1-mediated cellular mechanisms associated with brain tumors. Our meta-analysis of gene expression profiles of patients' samples and public microarray datasets indicated that KAL1 mRNA was significantly upregulated in high-grade primary brain tumors compared with the normal brain and low-grade tumors. The tumor-promoting capacity of anosmin-1 was demonstrated in the glioblastoma cell lines, where anosmin-1 enhanced cell motility and proliferation. Notably, anosmin-1 formed a part of active β1 integrin complex, inducing downstream signaling pathways. ShRNA-mediated knockdown of anosmin-1 attenuated motility and growth of tumor cells and induced apoptosis. Anosmin-1 may also enhance the invasion of tumor cells within the ECM by modulating cell adhesion and activating extracellular proteases. In a mouse xenograft model, anosmin-1-expressing tumors grew faster, indicating the role of anosmin-1 in tumor microenvironment in vivo. Combined, these data suggest that anosmin-1 can facilitate tumor cell proliferation, migration, invasion, and survival. Therefore, although the normal function of anosmin-1 is required in the proper development of GNRH neurons, overexpression of anosmin-1 in the developed brain may be an underlying mechanism for some brain tumors.
authors.forename: Catherine T
authors.initials: CT
authors.lastname: Choy
authors.forename: Haseong
authors.initials: H
authors.lastname: Kim
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Lee
authors.forename: David M
authors.initials: DM
authors.lastname: Williams
authors.forename: David
authors.initials: D
authors.lastname: Palethorpe
authors.forename: Greg
authors.initials: G
authors.lastname: Fellows
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Wright
authors.forename: Ken
authors.initials: K
authors.lastname: Laing
authors.forename: Leslie R
authors.initials: LR
authors.lastname: Bridges
authors.forename: Franklyn A
authors.initials: FA
authors.lastname: Howe
authors.forename: Soo-Hyun
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D064593:Heterografts; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: C076266:ANOS1 protein, human; D016326:Extracellular Matrix Proteins; D019012:Integrin beta1; D009419:Nerve Tissue Proteins; D012313:RNA
keywords: Kallmann syndrome; anosmin-1; brain tumor; integrins; matrix metalloproteinases; meta-analysis; tumor microenvironment