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Carcinogenesis Advance Access published online on February 23, 2009
Carcinogenesis, doi:10.1093/carcin/bgp050
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Proepithelin is an autocrine growth factor for bladder cancer

Francesca Lovat1,{ddagger}, Alessandro Bitto1,{ddagger}, Shi-Qiong Xu1, Matteo Fassan1, Silvia Goldoni2, David Metalli1, Vera Wubah1, Peter McCue2, Ginette Serrero5,6, Leonard G. Gomella1,3, Raffaele Baffa1,§, Renato V. Iozzo2,4 and Andrea Morrione1,3,*

1 Departments of Urology
2 Pathology, Anatomy and Cell Biology
3 Endocrine Mechanisms and Hormone Action Program
4 Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107
5 A&G Pharmaceutical, Inc., Columbia, Maryland
6 Program in Oncology, Greenebaum Cancer Center, University of Maryland, Baltimore, MD

* Address correspondence to: Andrea Morrione, Department of Urology, Endocrine Mechanisms and Hormone Action Program, Kimmel Cancer Center, Thomas Jefferson University, 233 south 10th street, BLSB Room 620, Philadelphia, PA, 19107. Tel: 215 503-4519; Fax: 215 923-0249; E-Mail: Andrea.Morrione{at}jefferson.edu

The growth factor proepithelin functions as an important regulator of proliferation and motility. Proepithelin is over-expressed 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 previously shown 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 mRNA 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 shRNA inhibited both Akt and MAPK 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 to normal urothelium. In addition, proepithelin was secreted in the urine, where it was detectable by immunoblotting and ELISA assays. 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.

Key Words: Proepithelin • bladder cancer • biomarker • shRNA • migration and invasion

{ddagger} These authors contributed equally to this work.

§ Present address: Medimmune, One Medimmune Way, Gaithersburg, MD 20878

Received December 3, 2008; revised January 28, 2009; accepted February 14, 2009.


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