MP61-02 ANTI-GLI1 AND ANTI-GLI2 AS NOVEL THERAPY TO INHIBIT BLADDER CANCER PROGRESSION

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology II1 Apr 2016MP61-02 ANTI-GLI1 AND ANTI-GLI2 AS NOVEL THERAPY TO INHIBIT BLADDER CANCER PROGRESSION Peter A. Raven, Sebastian K. Frees, Betty B.H. Zhou, Claudia I. Chavez-Munoz, Michael E. Cox, and Alan I. So Peter A. RavenPeter A. Raven More articles by this author , Sebastian K. FreesSebastian K. Frees More articles by this author , Betty B.H. ZhouBetty B.H. Zhou More articles by this author , Claudia I. Chavez-MunozClaudia I. Chavez-Munoz More articles by this author , Michael E. CoxMichael E. Cox More articles by this author , and Alan I. SoAlan I. So More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.876AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The sonic hedgehog (SHH) signaling pathway regulates embryonic developmental processes such as pattern formation, differentiation, proliferation, and organogenesis. Studies have suggested that abnormal activation of the SHH pathway due to genomic alterations leads to an increase in cell survival and metastasis in cancer. High levels of hedgehog along with enhanced expression of hedgehog pathway target genes has been identified in different cancers such as bladder cancer (BC). Glioma-associated proteins (Gli), are a family of proteins which translocate to the nucleus to induce gene transcription. Expression levels of Gli have been interrelated with the expression levels of the SHH pathway, suggesting Gli transcriptional activity is a direct indicator of SHH pathway activity. Here we hypothesize that blockage of SHH pathway may be an efficacious way of stopping BC progression. METHODS SHH pathway protein expression was assessed by immunohistochemical staining in an in-house human BC tissue array comprising superficial, invasive and lymph node metastasized transitional cell carcinoma. In addition, a panel of BC cell lines was assessed for SHH pathway activation, function and responsiveness. Proliferation, cell death, migration and cell invasion were measured in response to small-molecule pathway inhibitors, and antisense oligonucleotides (ASO) targeted to Gli1 and 2. In-vitro ASO results were confirmed in an in-vivo murine non-muscle invasive BC model. RESULTS An array of human BC tissues showed SHH pathway activation through a significant upregulation of the SHH pathway proteins PTCH, SMO, and Gli1 and Gli2 in invasive BC when compared to non-invasive cancer and normal bladder tissue. Similarly, in a panel of urothelial carcinoma cells lines, Gli1 and Gli2 proteins were highly expressed in more aggressive cell lines (UM-UC3, T24) compared to less aggressive ones (RT4, SV-HUC). Inhibition of Gli1 and Gli2 signalling with ASO reduced tumor cell proliferation, migration and invasion in vitro in the more aggressive cell lines. In vivo, treatment of intravesical invasive tumors with Gli2 ASO significantly abrogated tumor growth when compared to control tumors. CONCLUSIONS Gli1 and Gli2 ASO may be a potential new therapy to stop progression and invasion of bladder cancer improving the survival of bladder cancer patients. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e803 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Peter A. Raven More articles by this author Sebastian K. Frees More articles by this author Betty B.H. Zhou More articles by this author Claudia I. Chavez-Munoz More articles by this author Michael E. Cox More articles by this author Alan I. So More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...