title: Secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) is down regulated in aggressive prostate cancers and is prognostic for poor clinical outcome.
abstract: Prostate cancer is the second leading cause of cancer death among United States men. However, disease aggressiveness is varied, with low-grade disease often being indolent and high-grade cancer accounting for the greatest density of deaths. Outcomes are also disparate among men with high-grade prostate cancer, with upwards of 65% having disease recurrence even after primary treatment. Identification of men at risk for recurrence and elucidation of the molecular processes that drive their disease is paramount, as these men are the most likely to benefit from multimodal therapy. We previously showed that androgen-induced expression profiles in prostate development are reactivated in aggressive prostate cancers. Herein, we report the down-regulation of one such gene, Sparcl1, a secreted protein, acidic and rich in cysteine (SPARC) family matricellular protein, during invasive phases of prostate development and regeneration. We further demonstrate a parallel process in prostate cancer, with decreased expression of SPARCL1 in high-grade/metastatic prostate cancer. Mechanistically, we demonstrate that SPARCL1 loss increases the migratory and invasive properties of prostate cancer cells through Ras homolog gene family, member C (RHOC), a known mediator of metastatic progression. By using models incorporating clinicopathologic parameters to predict prostate cancer recurrence after treatment, we show that SPARCL1 loss is a significant, independent prognostic marker of disease progression. Thus, SPARCL1 is a potent regulator of cell migration/invasion and its loss is independently associated with prostate cancer recurrence.
authors.affiliation: Department of Urology, The Johns Hopkins University, Baltimore, MD 21231, USA. phurley2@jhmi.edu
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Hurley
authors.forename: Luigi
authors.initials: L
authors.lastname: Marchionni
authors.forename: Brian W
authors.initials: BW
authors.lastname: Simons
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Ross
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Peskoe
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Miller
authors.forename: Nicholas
authors.initials: N
authors.lastname: Erho
authors.forename: Ismael A
authors.initials: IA
authors.lastname: Vergara
authors.forename: Mercedeh
authors.initials: M
authors.lastname: Ghadessi
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Huang
authors.forename: Bora
authors.initials: B
authors.lastname: Gurel
authors.forename: Ben Ho
authors.initials: BH
authors.lastname: Park
authors.forename: Elai
authors.initials: E
authors.lastname: Davicioni
authors.forename: Robert B
authors.initials: RB
authors.lastname: Jenkins
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Platz
authors.forename: David M
authors.initials: DM
authors.lastname: Berman
authors.forename: Edward M
authors.initials: EM
authors.lastname: Schaeffer
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D018450:Disease Progression; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D046228:Microarray Analysis; D008954:Models, Biological; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000503:physiopathology*; D009364:Neoplasm Recurrence, Local / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013778:Tetrazolium Salts; D013844:Thiazoles; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D000075024:rhoC GTP-Binding Protein
chemical_list: D002135:Calcium-Binding Proteins; D017931:DNA Primers; D016326:Extracellular Matrix Proteins; C503126:SPARCL1 protein, human; D013778:Tetrazolium Salts; D013844:Thiazoles; C066690:RHOC protein, human; D020741:rho GTP-Binding Proteins; D000075024:rhoC GTP-Binding Protein; C022616:thiazolyl blue