title: Major Action of Endogenous Lysyl Oxidase in Clear Cell Renal Cell Carcinoma Progression and Collagen Stiffness Revealed by Primary Cell Cultures.
abstract: Human clear cell renal cell carcinoma (ccRCC) is therapy resistant; therefore, it is worthwhile studying in depth the molecular aspects of its progression. In ccRCC the biallelic inactivation of the VHL gene leads to stabilization of hypoxia-inducible factors (HIFs). Among the targets of HIF-1α transcriptional activity is the LOX gene, which codes for the inactive proenzyme (Pro-Lox) from which, after extracellular secretion and proteolysis, derives the active enzyme (Lox) and the propeptide (Lox-PP). By increasing stiffness of extracellular matrix by collagen crosslinking, Lox promotes tumor progression and metastasis. Lox and Lox-PP can reenter the cells where Lox promotes cell proliferation and invasion, whereas Lox-PP acts as tumor suppressor because of its Ras recision and apoptotic activity. Few data are available concerning LOX in ccRCC. Using an in vitro model of ccRCC primary cell cultures, we performed, for the first time in ccRCC, a detailed study of endogenous LOX and also investigated their transcriptomic profile. We found that endogenous LOX is overexpressed in ccRCC, is involved in a positive-regulative loop with HIF-1α, and has a major action on ccRCC progression through cellular adhesion, migration, and collagen matrix stiffness increment; however, the oncosuppressive action of Lox-PP was not found to prevail. These findings may suggest translational approaches for new therapeutic strategies in ccRCC.
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
authors.forename: Vitalba
authors.initials: V
authors.lastname: Di Stefano
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Torsello
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bianchi
authors.affiliation: Institute for Biomedical Technologies, National Research Council, Segrate, Italy.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Cifola
authors.affiliation: Institute for Biomedical Technologies, National Research Council, Segrate, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Mangano
authors.affiliation: Anatomo-Pathology Unit, University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bovo
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Cassina
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
authors.forename: Sofia
authors.initials: S
authors.lastname: De Marco
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Corti
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Meregalli
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bombelli
authors.affiliation: Urology Unit, Bassini ICP Hospital, Milano, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Viganò
authors.affiliation: Institute for Biomedical Technologies, National Research Council, Segrate, Italy; Department of Medical Biotechnology and Translational Medicine, University of Milano, Segrate, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Battaglia
authors.affiliation: Urology Unit, Bassini ICP Hospital, Milano, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Strada
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy. Electronic address: roberto.perego@unimib.it.
authors.forename: Roberto A
authors.initials: RA
authors.lastname: Perego
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000473:pathology*; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D003094:Collagen / Q000378:metabolism*; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000201:enzymology / Q000473:pathology*; D008297:Male; D018625:Microscopy, Atomic Force; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D061251:Primary Cell Culture; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D003094:Collagen; D008249:Protein-Lysine 6-Oxidase