Suppression of progranulin expression inhibits bladder cancer growth and sensitizes cancer cells to cisplatin
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Simone Buraschi1,*, Shi-Qiong Xu2,*, Manuela Stefanello2, Igor Moskalev3, Alaide Morcavallo2, Marco Genua2, Ryuta Tanimoto2, Ruth Birbe1, Stephen C. Peiper1, Leonard G. Gomella2, Antonino Belfiore4, Peter C. Black3, Renato V. Iozzo1, Andrea Morrione2
1Department of Pathology, Anatomy and Cell Biology and The Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, PA, Philadelphia, USA
2Department of Urology and Biology and The Prostate Cancer Program, Kimmel Cancer Center, Thomas Jefferson University, PA, Philadelphia, USA
3Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
4Department of Health and Endocrinology, University Magna Graecia of Catanzaro, Catanzaro, Italy
*These authors contributed equally to this work
Andrea Morrione, email: [email protected]
Renato V. Iozzo, email: [email protected]
Keywords: progranulin, bladder cancer, motility, anchorage-independent growth, tumor formation in vivo
Received: January 21, 2016 Accepted: May 08, 2016 Published: May 23, 2016
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.
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