Hedgehog signaling regulates bladder cancer growth and tumorigenicity

Dennis Liang Fei, Avencia Sanchez-Mejias, Zhiqiang Wang, Colin Flaveny, Jun Long, Samer Singh, Jezabel Rodriguez-Blanco, Robert Tokhunts, Camilla Giambelli, Karoline Briegel, Wolfgang A. Schulz, A. Jay Gandolfi, Margaret Karagas, Teresa A. Zimmers, Merce Jorda, Pablo Bejarano, Anthony J Capobianco, David J Robbins

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4449-4458
Number of pages10
JournalCancer Research
Volume72
Issue number17
DOIs
StatePublished - Sep 1 2012

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Urinary Bladder Neoplasms
Growth
Carcinoma
Cell Line
Tumor Suppressor Genes
Transcriptome
Genes
Carcinogenesis
Urinary Bladder
Chromosomes
Ligands
Mutation
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Fei, D. L., Sanchez-Mejias, A., Wang, Z., Flaveny, C., Long, J., Singh, S., ... Robbins, D. J. (2012). Hedgehog signaling regulates bladder cancer growth and tumorigenicity. Cancer Research, 72(17), 4449-4458. https://doi.org/10.1158/0008-5472.CAN-11-4123

Hedgehog signaling regulates bladder cancer growth and tumorigenicity. / Fei, Dennis Liang; Sanchez-Mejias, Avencia; Wang, Zhiqiang; Flaveny, Colin; Long, Jun; Singh, Samer; Rodriguez-Blanco, Jezabel; Tokhunts, Robert; Giambelli, Camilla; Briegel, Karoline; Schulz, Wolfgang A.; Gandolfi, A. Jay; Karagas, Margaret; Zimmers, Teresa A.; Jorda, Merce; Bejarano, Pablo; Capobianco, Anthony J; Robbins, David J.

In: Cancer Research, Vol. 72, No. 17, 01.09.2012, p. 4449-4458.

Research output: Contribution to journalArticle

Fei, DL, Sanchez-Mejias, A, Wang, Z, Flaveny, C, Long, J, Singh, S, Rodriguez-Blanco, J, Tokhunts, R, Giambelli, C, Briegel, K, Schulz, WA, Gandolfi, AJ, Karagas, M, Zimmers, TA, Jorda, M, Bejarano, P, Capobianco, AJ & Robbins, DJ 2012, 'Hedgehog signaling regulates bladder cancer growth and tumorigenicity', Cancer Research, vol. 72, no. 17, pp. 4449-4458. https://doi.org/10.1158/0008-5472.CAN-11-4123
Fei DL, Sanchez-Mejias A, Wang Z, Flaveny C, Long J, Singh S et al. Hedgehog signaling regulates bladder cancer growth and tumorigenicity. Cancer Research. 2012 Sep 1;72(17):4449-4458. https://doi.org/10.1158/0008-5472.CAN-11-4123
Fei, Dennis Liang ; Sanchez-Mejias, Avencia ; Wang, Zhiqiang ; Flaveny, Colin ; Long, Jun ; Singh, Samer ; Rodriguez-Blanco, Jezabel ; Tokhunts, Robert ; Giambelli, Camilla ; Briegel, Karoline ; Schulz, Wolfgang A. ; Gandolfi, A. Jay ; Karagas, Margaret ; Zimmers, Teresa A. ; Jorda, Merce ; Bejarano, Pablo ; Capobianco, Anthony J ; Robbins, David J. / Hedgehog signaling regulates bladder cancer growth and tumorigenicity. In: Cancer Research. 2012 ; Vol. 72, No. 17. pp. 4449-4458.
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