MP61-13 PROGRANULIN TARGETING IN UROTHELIAL CANCER CELLS INHIBITS MOTILITY, ANCHORAGE-INDEPENDENT GROWTH, TUMOR FORMATION IN VIVO AND SENSITIZES CELLS TO CISPLATIN

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology II1 Apr 2016MP61-13 PROGRANULIN TARGETING IN UROTHELIAL CANCER CELLS INHIBITS MOTILITY, ANCHORAGE-INDEPENDENT GROWTH, TUMOR FORMATION IN VIVO AND SENSITIZES CELLS TO CISPLATIN Simone Buraschi, Shi-Qiong Xu, Manuela Stefanello, Igor Moskalev, Alaide Morcavallo, Marco Genua, Ryuta Tanimoto, Thomas Neill, Stephen C Peiper, Leonard G Gomella, Peter C Black, Antonino Belfiore, Renato V Iozzo, and Andrea Morrione Simone BuraschiSimone Buraschi More articles by this author , Shi-Qiong XuShi-Qiong Xu More articles by this author , Manuela StefanelloManuela Stefanello More articles by this author , Igor MoskalevIgor Moskalev More articles by this author , Alaide MorcavalloAlaide Morcavallo More articles by this author , Marco GenuaMarco Genua More articles by this author , Ryuta TanimotoRyuta Tanimoto More articles by this author , Thomas NeillThomas Neill More articles by this author , Stephen C PeiperStephen C Peiper More articles by this author , Leonard G GomellaLeonard G Gomella More articles by this author , Peter C BlackPeter C Black More articles by this author , Antonino BelfioreAntonino Belfiore More articles by this author , Renato V IozzoRenato V Iozzo More articles by this author , and Andrea MorrioneAndrea Morrione More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.887AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Bladder cancer is a major public health problem and affects more than 74,000 Americans with more than 16,000 estimated deaths in 2015. The majority of deaths are due to metastatic spread, commonly to the lungs. Understanding the molecular mechanisms regulating bladder tumor cell invasion and progression toward metastases is essential for developing better therapies to treat bladder cancer patients. The growth factor progranulin has emerged in recent years as an important regulator of transformation in several cancer models. We have previously established a critical role for progranulin in bladder cancer as in fact progranulin acts as an autocrine growth factor and promote motility and invasion of invasive urothelial cancer cells. In addition, progranulin is upregulated in high grade bladder cancer tissues compared to normal tissue controls suggesting that progranulin might work as a novel biomarker with predictive value for bladder cancer progression. However, whether progranulin is important for anchorage-independent growth and in vivo tumor formation of urothelial cancer cells has not been previously established. METHODS Progranulin depletion was achieved by stably transfecting tumorigenic T24T, UMUC3 urothelial cancer cells with a plasmid expressing an anti-progranulin shRNA. Progranulin-depleted and control UMUC-3 and T24T cells were tested for motility, invasion and anchorage-independent growth by soft-agar assays. Tumor formation in vivo was assessed in various UMUC-3-derived cell lines by xenograft and orthotopic models. Sensitivity to cisplatin was assessed by cell survival curves. Progranulin expression levels in a bladder tissue microarray were analyzed by HIC. RESULTS Progranulin-depleted T24T and UMUC-3 cells were significantly inhibited in their ability to migrate, close a wound and invade through Matrigel compared to control cells in both serum-deprived and 1% serum media. In addition, progranulin targeting strongly reduced the ability of T24T and UMUC-3 cells to grow in anchorage-independency and form colonies in soft-agar. Significantly progranulin-depleted UMUC-3 cells were severely inhibited in tumor formation in vivo as assessed by both xenograft and orthotopic models in immunocompromised mice. Importantly, progranulin depletion sensitized UMUC-3 cells to cisplatin. Finally, progranulin levels correlated with tumor progression in bladder cancer tissues. CONCLUSIONS Our data are translationally relevant as indicate that progranulin exerts an essential functional role in the regulation of bladder cancer progression. Thus, progranulin may constitute a novel target for therapeutic intervention in bladder tumors. In addition, progranulin may serve as novel biomarker for diagnosis and prognosis of bladder cancer. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e808 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Simone Buraschi More articles by this author Shi-Qiong Xu More articles by this author Manuela Stefanello More articles by this author Igor Moskalev More articles by this author Alaide Morcavallo More articles by this author Marco Genua More articles by this author Ryuta Tanimoto More articles by this author Thomas Neill More articles by this author Stephen C Peiper More articles by this author Leonard G Gomella More articles by this author Peter C Black More articles by this author Antonino Belfiore More articles by this author Renato V Iozzo More articles by this author Andrea Morrione More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...