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BioMed Research International
Volume 2014 (2014), Article ID 340216, 14 pages
http://dx.doi.org/10.1155/2014/340216
Research Article

Gla-Rich Protein Is a Potential New Vitamin K Target in Cancer: Evidences for a Direct GRP-Mineral Interaction

1Centre of Marine Sciences (CCMAR), University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
2GenoGla Diagnostics, Centre of Marine Sciences (CCMAR), University of Algarve, 8005-139 Faro, Portugal
3VitaK, Maastricht University, 6229 EV Maastricht, The Netherlands
4Algarve Medical Centre, Department of Histopathology, 8000-386 Faro, Portugal
5Lisbon Central Hospital-CHLC, Department of Dermatology, 1169-050 Lisbon, Portugal
6Administração Regional de Saúde do Algarve, 8135-014 Faro, Portugal
7Private Hospitals of Portugal, HPP-Santa Maria Hospital, 8000-140 Faro, Portugal

Received 24 January 2014; Accepted 8 April 2014; Published 18 May 2014

Academic Editor: Kunikazu Tsuji

Copyright © 2014 Carla S. B. Viegas et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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.