title: Proepithelin is an autocrine growth factor for bladder cancer.
abstract: The growth factor proepithelin functions as an important regulator of proliferation and motility. Proepithelin is overexpressed in a great variety of cancer cell lines and clinical specimens of breast, ovarian and renal cancer, as well as glioblastomas. Using recombinant proepithelin on 5637 transitional cell carcinoma-derived cells, we have shown previously that proepithelin plays a critical role in bladder cancer by promoting motility of bladder cancer cells. In this study, we used the ONCOMINE database and gene microarray analysis tool to analyze proepithelin expression in several bladder cancer microarray studies. We found a statistically significant increase in proepithelin messenger RNA expression in bladder cancers vis-à-vis non-neoplastic tissues, and this was associated with pathologic and prognostic parameters. Targeted downregulation of proepithelin in T24 transitional carcinoma cells with small hairpin RNA inhibited both Akt and mitogen-activated protein kinase pathways, severely reduced the ability of T24 cells to proliferate in the absence of serum and inhibited migration, invasion and wound healing. In support of these in vitro results, we discovered that proepithelin expression was significantly upregulated in invasive bladder cancer tissues compared with normal urothelium. In addition, proepithelin was secreted in the urine, where it was detectable by immunoblotting and enzyme-linked immunosorbent assay. Collectively, these results support the hypothesis that proepithelin may play a critical role as an autocrine growth factor in the establishment and progression of bladder cancer and suggest that proepithelin may prove a novel biomarker for the diagnosis and prognosis of bladder neoplasms.
authors.affiliation: Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Lovat
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bitto
authors.forename: Shi-Qiong
authors.initials: SQ
authors.lastname: Xu
authors.forename: Matteo
authors.initials: M
authors.lastname: Fassan
authors.forename: Silvia
authors.initials: S
authors.lastname: Goldoni
authors.forename: David
authors.initials: D
authors.lastname: Metalli
authors.forename: Vera
authors.initials: V
authors.lastname: Wubah
authors.forename: Peter
authors.initials: P
authors.lastname: McCue
authors.forename: Ginette
authors.initials: G
authors.lastname: Serrero
authors.forename: Leonard G
authors.initials: LG
authors.lastname: Gomella
authors.forename: Raffaele
authors.initials: R
authors.lastname: Baffa
authors.forename: Renato V
authors.initials: RV
authors.lastname: Iozzo
authors.forename: Andrea
authors.initials: A
authors.lastname: Morrione
mesh_terms: D002295:Carcinoma, Transitional Cell / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D018450:Disease Progression; D015536:Down-Regulation; D006133:Growth Substances / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D046228:Microarray Analysis; D011379:Prognosis; D000077153:Progranulins; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology
chemical_list: C492314:GRN protein, human; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D012333:RNA, Messenger; D011994:Recombinant Proteins