title: Suppression of progranulin expression inhibits bladder cancer growth and sensitizes cancer cells to cisplatin.
abstract: We have recently demonstrated a critical role for progranulin in bladder cancer. Progranulin contributes, as an autocrine growth factor, to the transformed phenotype by modulating Akt-and MAPK-driven motility, invasion and anchorage-independent growth. Progranulin also induces F-actin remodeling by interacting with the F-actin binding protein drebrin. In addition, progranulin is overexpressed in invasive bladder cancer compared to normal tissue controls, suggesting that progranulin might play a key role in driving the transition to the invasive phenotype of urothelial cancer. However, it is not established whether targeting progranulin could have therapeutic effects on bladder cancer. In this study, we stably depleted urothelial cancer cells of endogenous progranulin by shRNA approaches and determined that progranulin depletion severely inhibited the ability of tumorigenic urothelial cancer cells to migrate, invade and grow in anchorage-independency. We further demonstrate that progranulin expression is critical for tumor growth in vivo, in both xenograft and orthotopic tumor models. Notably, progranulin levels correlated with response to cisplatin treatment and were upregulated in bladder tumors. Our data indicate that progranulin may constitute a novel target for therapeutic intervention in bladder tumors. In addition, progranulin may serve as a novel biomarker for bladder cancer.
authors.affiliation: Department of Pathology, Anatomy and Cell Biology and The Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Buraschi
authors.affiliation: Department of Urology and Biology and The Prostate Cancer Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Shi-Qiong
authors.initials: SQ
authors.lastname: Xu
authors.affiliation: Department of Urology and Biology and The Prostate Cancer Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Manuela
authors.initials: M
authors.lastname: Stefanello
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: Igor
authors.initials: I
authors.lastname: Moskalev
authors.affiliation: Department of Urology and Biology and The Prostate Cancer Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Alaide
authors.initials: A
authors.lastname: Morcavallo
authors.affiliation: Department of Urology and Biology and The Prostate Cancer Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Genua
authors.affiliation: Department of Urology and Biology and The Prostate Cancer Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Tanimoto
authors.affiliation: Department of Pathology, Anatomy and Cell Biology and The Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Birbe
authors.affiliation: Department of Pathology, Anatomy and Cell Biology and The Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Peiper
authors.affiliation: Department of Urology and Biology and The Prostate Cancer Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Leonard G
authors.initials: LG
authors.lastname: Gomella
authors.affiliation: Department of Health and Endocrinology, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Belfiore
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Black
authors.affiliation: Department of Pathology, Anatomy and Cell Biology and The Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Renato V
authors.initials: RV
authors.lastname: Iozzo
authors.affiliation: Department of Urology and Biology and The Prostate Cancer Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Morrione
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010641:Phenotype; D000077153:Progranulins; D034741:RNA, Small Interfering / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D019459:Urothelium / Q000473:pathology
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D034741:RNA, Small Interfering; D002945:Cisplatin
keywords: anchorage-independent growth; bladder cancer; motility; progranulin; tumor formation in vivo