title: Gla-rich protein is a potential new vitamin K target in cancer: evidences for a direct GRP-mineral interaction.
abstract: Gla-rich protein (GRP) was described in sturgeon as a new vitamin-K-dependent protein (VKDP) with a high density of Gla residues and associated with ectopic calcifications in humans. Although VKDPs function has been related with γ-carboxylation, the Gla status of GRP in humans is still unknown. Here, we investigated the expression of recently identified GRP spliced transcripts, the γ-carboxylation status, and its association with ectopic calcifications, in skin basal cell and breast carcinomas. GRP-F1 was identified as the predominant splice variant expressed in healthy and cancer tissues. Patterns of γ-carboxylated GRP (cGRP)/undercarboxylated GRP (ucGRP) accumulation in healthy and cancer tissues were determined by immunohistochemistry, using newly developed conformation-specific antibodies. Both GRP protein forms were found colocalized in healthy tissues, while ucGRP was the predominant form associated with tumor cells. Both cGRP and ucGRP found at sites of microcalcifications were shown to have in vitro calcium mineral-binding capacity. The decreased levels of cGRP and predominance of ucGRP in tumor cells suggest that GRP may represent a new target for the anticancer potential of vitamin K. Also, the direct interaction of cGRP and ucGRP with BCP crystals provides a possible mechanism explaining GRP association with pathological mineralization.
authors.affiliation: Centre of Marine Sciences (CCMAR), University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal ; GenoGla Diagnostics, Centre of Marine Sciences (CCMAR), University of Algarve, 8005-139 Faro, Portugal.
authors.forename: Carla S B
authors.initials: CS
authors.lastname: Viegas
authors.affiliation: VitaK, Maastricht University, 6229 EV Maastricht, The Netherlands.
authors.forename: Marjolein
authors.initials: M
authors.lastname: Herfs
authors.affiliation: Centre of Marine Sciences (CCMAR), University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal.
authors.forename: Marta S
authors.initials: MS
authors.lastname: Rafael
authors.affiliation: Algarve Medical Centre, Department of Histopathology, 8000-386 Faro, Portugal.
authors.forename: José L
authors.initials: JL
authors.lastname: Enriquez
authors.affiliation: Algarve Medical Centre, Department of Histopathology, 8000-386 Faro, Portugal.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Teixeira
authors.affiliation: Centre of Marine Sciences (CCMAR), University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal.
authors.forename: Inês M
authors.initials: IM
authors.lastname: Luís
authors.affiliation: VitaK, Maastricht University, 6229 EV Maastricht, The Netherlands.
authors.forename: Cynthia M R
authors.initials: CM
authors.lastname: van 't Hoofd
authors.affiliation: Lisbon Central Hospital-CHLC, Department of Dermatology, 1169-050 Lisbon, Portugal.
authors.forename: Alexandre
authors.initials: A
authors.lastname: João
authors.affiliation: Administração Regional de Saúde do Algarve, 8135-014 Faro, Portugal.
authors.forename: Vera L
authors.initials: VL
authors.lastname: Maria
authors.affiliation: Centre of Marine Sciences (CCMAR), University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal.
authors.forename: Sofia
authors.initials: S
authors.lastname: Cavaco
authors.affiliation: Lisbon Central Hospital-CHLC, Department of Dermatology, 1169-050 Lisbon, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Ferreira
authors.affiliation: Private Hospitals of Portugal, HPP-Santa Maria Hospital, 8000-140 Faro, Portugal.
authors.forename: Manuel
authors.initials: M
authors.lastname: Serra
authors.affiliation: VitaK, Maastricht University, 6229 EV Maastricht, The Netherlands.
authors.forename: Elke
authors.initials: E
authors.lastname: Theuwissen
authors.affiliation: VitaK, Maastricht University, 6229 EV Maastricht, The Netherlands.
authors.forename: Cees
authors.initials: C
authors.lastname: Vermeer
authors.affiliation: Centre of Marine Sciences (CCMAR), University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal ; GenoGla Diagnostics, Centre of Marine Sciences (CCMAR), University of Algarve, 8005-139 Faro, Portugal.
authors.forename: Dina C
authors.initials: DC
authors.lastname: Simes
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002114:Calcinosis; D002280:Basal Cell Carcinoma / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D009285:Naphthoquinones; D015675:Osteocalcin / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D014812:Vitamin K / Q000378:metabolism; D000519:alpha-Galactosidase / Q000378:metabolism
chemical_list: D009285:Naphthoquinones; D015675:Osteocalcin; D014812:Vitamin K; C576330:GLA protein, human; D000519:alpha-Galactosidase