title: Hedgehog signaling regulates bladder cancer growth and tumorigenicity.
abstract: The role of Hedgehog (HH) signaling in bladder cancer remains controversial. The gene encoding the HH receptor and negative regulator PATCHED1 (PTCH1) resides on a region of chromosome 9q, one copy of which is frequently lost in bladder cancer. Inconsistent with PTCH1 functioning as a classic tumor suppressor gene, loss-of-function mutations in the remaining copy of PTCH1 are not commonly found. Here, we provide direct evidence for a critical role of HH signaling in bladder carcinogenesis. We show that transformed human urothelial cells and many urothelial carcinoma cell lines exhibit constitutive HH signaling, which is required for their growth and tumorigenic properties. Surprisingly, rather than originating from loss of PTCH1, the constitutive HH activity observed in urothelial carcinoma cell lines was HH ligand dependent. Consistent with this finding, increased levels of HH and the HH target gene product GLI1 were found in resected human primary bladder tumors. Furthermore, on the basis of the difference in intrinsic HH dependence of urothelial carcinoma cell lines, a gene expression signature was identified that correlated with bladder cancer progression. Our findings therefore indicate that therapeutic targeting of the HH signaling pathway may be beneficial in the clinical management of bladder cancer.
authors: Molecular Oncology Program, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, 1600 NW 10th Avenue, Miami, FL 33136, USA.
authors: Dennis Liang
authors: DL
authors: Fei
authors: Avencia
authors: A
authors: Sanchez-Mejias
authors: Zhiqiang
authors: Z
authors: Wang
authors: Colin
authors: C
authors: Flaveny
authors: Jun
authors: J
authors: Long
authors: Samer
authors: S
authors: Singh
authors: Jezabel
authors: J
authors: Rodriguez-Blanco
authors: Robert
authors: R
authors: Tokhunts
authors: Camilla
authors: C
authors: Giambelli
authors: Karoline J
authors: KJ
authors: Briegel
authors: Wolfgang A
authors: WA
authors: Schulz
authors: A Jay
authors: AJ
authors: Gandolfi
authors: Margaret
authors: M
authors: Karagas
authors: Teresa A
authors: TA
authors: Zimmers
authors: Merce
authors: M
authors: Jorda
authors: Pablo
authors: P
authors: Bejarano
authors: Anthony J
authors: AJ
authors: Capobianco
authors: David J
authors: DJ
authors: Robbins
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D015398:Signal Transduction; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism*
chemical_list: D053823:Hedgehog Proteins; D008024:Ligands