Carcinogenesis Advance Access originally published online on February 23, 2009
Carcinogenesis 2009 30(5):861-868; doi:10.1093/carcin/bgp050
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Proepithelin is an autocrine growth factor for bladder cancer
1 Department of Urology
2 Department of Pathology, Anatomy and Cell Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
3 A&G Pharmaceutical Inc., Columbia, MD 21045, USA
4 Program in Oncology, Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201, USA
5 Endocrine Mechanisms and Hormone Action Program
6 Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
7 Present address: Medimmune, One Medimmune Way, Gaithersburg, MD 20878, USA
* To whom correspondence should be addressed. Department of Urology, Endocrine Mechanisms and Hormone Action Program, Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, Bluemle Life Sciences Building, Room 620, Philadelphia, PA 19107, USA. Tel: +1 215 503 4519; Fax: +1 215 923 0249; Email: andrea.morrione{at}jefferson.edu
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.
Abbreviations: CM, conditioned medium; 3D, three-dimensional; ELISA, enzyme-linked immunosorbent assay; ERK1/2, extracellular signal-regulated kinase 1/2; MAPK, mitogen-activated protein kinase; mRNA, messenger RNA; SFM, serum-free medium; shRNA, small hairpin RNA
These authors contributed equally to this work. Received December 3, 2008; revised January 28, 2009; accepted February 14, 2009.