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Hedgehog signaling is a critical mediator for urinary bladder cancer.

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Call No.	Ph.D. 2011
Author	Fei, Liang
Title	Hedgehog signaling is a critical mediator for urinary bladder cancer.
Date	2011
Abstract	The role of Hedgehog (HH) signaling in bladder cancer is controversial. 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 tumor suppressor gene, loss of function mutations in the remaining copy of PTCH1 are rarely found. Furthermore, two laboratories were unable to identify bladder cancer cell lines that were sensitive to small molecule HH antagonists, concluding that HH signaling was dispensable in bladder cancer. Here, we provide comprehensive evidence demonstrating a widespread requirement of HH signaling in bladder cancer. We show that low-level HH activation promotes urothelium proliferation in vivo. We then show that many bladder cancer cell lines harbor active Hedgehog signaling, which is required for their growth and tumorigenic properties. The constitutive HH signaling in bladder cancer cells is HH ligand-dependent, rather than originating from loss of PTCH1. Consistent with these findings, we frequently observed increased co-expression of HH ligand and the HH target gene, GLI1, in cancer cells from resected human primary bladder tumors. We further established the regulation of HH signaling by arsenic, the known bladder carcinogen. Arsenic is able to activate HH signaling in human urothelial cells and many other cell types, and this elevated HH pathway activity is critical for arsenic-mediated transformation of urothelial cells. Arsenic appears to activate Hedgehog signaling by targeting the repressor form of GLI3, a key transcription factor of the Hedgehog signaling. Furthermore, we observed a highly significant positive correlation (p = 0.0087) between the level of Hedgehog activity and patients' arsenic exposure in a large cohort of bladder cancer samples, indicating HH signaling is important for arsenic-associated bladder cancer. Overall, our results demonstrate that HH signaling is a critical regulator for bladder carcinogenesis. We also identified two novel mechanisms for HH activation in bladder cancer. Combined, these results imply that therapeutic targeting of the HH signaling pathway is beneficial in the clinical management of bladder cancer patients.
Description	1 online resource (ix, 87 leaves) : illustrations
Format	application/pdf
Advisor	DiRenzo, James ; Robbins, David ; Cole, Michael ; Dmitrovsky, Ethan ; Tevosian, Sergei
Subject	Bladder -- Cancer -- Molecular aspects. ; Cellular signal transduction. ; Transcription factors -- Pathophysiology. ; Arsenic -- Carcinogenicity. ; Urinary Bladder Neoplasms -- genetics. ; Hedgehog Proteins.
College	Dartmouth Medical School -- Department of Pharmacology and Toxicology.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D)--Dartmouth College.
Copyright	In Copyright. This material is protected by copyright and/or related rights. You are free to use this material in any way that is permitted by copyright law that applies to your use. For other uses, you need to obtain permission from the rights-holder(s). http://rightsstatements.org/page/InC/1.0/
DOI	https://doi.org/10.1349/ddlp.3080

Title	fei2011 1
Full Text	i HEDGEHOG SIGNALING IS A CRITICAL MEDIATOR FOR URINARY BLADDER CANCER A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Pharmacology and Toxicology by Liang Fei DARTMOUTH COLLEGE Hanover, New Hampshire June, 2011

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