title: Liver-Specific Inactivation of the Proprotein Convertase FURIN Leads to Increased Hepatocellular Carcinoma Growth.
abstract: Proprotein convertases are subtilisin-like serine endoproteases that cleave and hence activate a variety of proproteins, including growth factors, receptors, metalloproteases, and extracellular matrix proteins. Therefore, it has been suggested that inhibition of the ubiquitously expressed proprotein convertase FURIN might be a good therapeutic strategy for several tumor types. Whether this is also the case for hepatocellular carcinoma (HCC) is currently not clear. In a mouse model for HCC expression of Furin was not altered in the tumors, while those of PC7, PC5/6, and PACE4 significantly decreased, at least at some time points. To investigate the impact of Furin inhibition on the development and progression of HCC in this model, Furin was genetically ablated in the liver. Furin inactivation resulted in an increased tumor mass after 5 weeks. This was not caused by decreased apoptosis, since no differences in the apoptosis index could be observed. However, it could at least partially be explained by increased hepatocyte proliferation at 5 weeks. The tumors of the Furin knockout mice were histologically similar to those in wild type mice. In conclusion, liver-specific Furin inhibition in HCC enhances the tumor formation and will not be a good therapeutic strategy for this tumor type.
authors.affiliation: Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Declercq
authors.affiliation: Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Bas
authors.initials: B
authors.lastname: Brouwers
authors.affiliation: Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Vincent P E G
authors.initials: VP
authors.lastname: Pruniau
authors.affiliation: Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Stijnen
authors.affiliation: Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Krizia
authors.initials: K
authors.lastname: Tuand
authors.affiliation: Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Sandra
authors.initials: S
authors.lastname: Meulemans
authors.affiliation: Laboratory of Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal, Montreal, QC, Canada H2W 1R7.
authors.forename: Annik
authors.initials: A
authors.lastname: Prat
authors.affiliation: Laboratory of Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal, Montreal, QC, Canada H2W 1R7.
authors.forename: Nabil G
authors.initials: NG
authors.lastname: Seidah
authors.affiliation: Angiogenesis Laboratory, Université Bordeaux I, 33400 Talence, France ; INSERM, UMR 1029, 33400 Talence, France.
authors.forename: Abdel-Majid
authors.initials: AM
authors.lastname: Khatib
authors.affiliation: Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: John W M
authors.initials: JW
authors.lastname: Creemers
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism; D005260:Female; D045683:Furin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D014408:Biomarkers, Tumor; D045683:Furin