title: p62/Sequestosome-1: Mapping Sites of Protein-Handling Stress in Canine Cutaneous Mast Cell Tumors.
abstract: Canine cutaneous mast cell tumors (MCT) are common, frequently malignant neoplasms that are currently graded histologically for provision of prognostic information. Continuing evidence of subsets of MCT within certain grades (with differing survival times) indicate the need for biomarkers that will facilitate better patient stratification and also provide further information on the biological processes involved in progression. We decided to investigate the expression of p62/sequestosome-1 (p62/SQSTM1), a stress-inducible "hub protein" found in all cell types that shuttles rapidly between the nucleus and cytoplasm and is known to play important roles in protein handling and tumorigenesis. The identity of canine p62/SQSTM1 was confirmed in silico and by validation of a commercial antibody using both Western blotting and functional (pharmaceutical-based) analyses in cell culture. Using immunohistochemistry, 3 patterns of p62 expression were identified based on the predominant intracellular localization, that is, nuclear, mixed (nuclear and cytoplasmic), and cytoplasmic. There was a highly significant association with the 2-tier (Kiupel) grade (P < .0001), with all p62-nuclear immunoreactivity being associated with low grade and most p62-cytoplasmic immunoreactivity (93%) with high grade. Most but not all mixed nuclear-cytoplasmic labeling occurred in low-grade MCT; in other (human) tumor types, this pattern has been interpreted as borderline malignant. These data indicate that there is a shift in protein-handling stress from the nucleus to the cytoplasm in association with increasing malignancy in MCT. Studies to identify the processes and drug-able targets involved in this progression are ongoing.
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom Tina.Rich@glasgow.ac.uk.
authors.forename: T
authors.initials: T
authors.lastname: Rich
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom.
authors.forename: R T G
authors.initials: RT
authors.lastname: Dean
authors.affiliation: IDEXX Laboratories, Inc, West Sacramento, CA, USA.
authors.forename: C G
authors.initials: CG
authors.lastname: Lamm
authors.affiliation: IDEXX Laboratories Ltd, Wetherby, West Yorkshire, United Kingdom.
authors.forename: F
authors.initials: F
authors.lastname: Ramiro-Ibañez
authors.affiliation: School of Veterinary Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom.
authors.forename: M L
authors.initials: ML
authors.lastname: Stevenson
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom.
authors.forename: J C
authors.initials: JC
authors.lastname: Patterson-Kane
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D063646:Carcinogenesis; D003593:Cytoplasm / Q000378:metabolism; D004283:Dog Diseases / Q000378:metabolism / Q000473:pathology*; D004285:Dogs; D007150:Immunohistochemistry / Q000662:veterinary; D008407:Mast Cells / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D016415:Sequence Alignment; D000071456:Sequestosome-1 Protein / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology / Q000662:veterinary*
chemical_list: D014408:Biomarkers, Tumor; D000071456:Sequestosome-1 Protein
keywords: canine cutaneous mast cell tumor; immunohistochemistry; p62/sequestosome-1 protein; skin neoplasms