Ultraviolet Radiation Mutagenesis of Hedgehog Pathway Genes in Basal Cell Carcinomas

Aszterbaum, Michelle; Beech, J.A.; Epstein, Ervin

doi:10.1038/sj.jidsp.5640179

Cited by 58 publications

(47 citation statements)

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“…Ptch1 +/-heterozygous knockout C57BL/6 mice were developed by deletion of exons 1 and 2 and insertion of the LacZ gene at the deletion site as described previously (15,16). We purchased male breeders (6-7 weeks old) of hemizygous ODC transgenic B6.Cg-Tg (K6-Odc)55Tgo strain (Taconic, Germantown, New York, USA).…”

Section: Methodsmentioning

confidence: 99%

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Ornithine decarboxylase is a target for chemoprevention of basal and squamous cell carcinomas in Ptch1+/– mice

et al. 2004

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Solar ultraviolet B (UVB) radiation induces cutaneous ornithine decarboxylase (ODC), the first enzyme in the polyamine-biosynthesis pathway, which drives continued proliferation and clonal expansion of initiated (mutated) cells, leading to tumorigenesis. Therefore ODC is a potentially important target for chemoprevention of basal cell carcinomas (BCCs), the majority of which have mutations in the tumor-suppressor gene known as patched (PTCH). To assess this possibility, we first overexpressed ODC in the skin of Ptch1 +/-mice using a keratin 6 (K6) promoter that directs constitutive ODC expression in the outer root sheath of the hair follicle. UVB irradiation of these mice accelerated induction of BCCs as compared with their Ptch1 +/-littermates. To further verify the role of ODC in BCC tumorigenesis, we used an antizyme (AZ) approach to inhibit ODC activity in the Ptch1 +/-mice. Ptch1 +/-mice with AZ overexpression driven by the K6 promoter were resistant to the induction of BCCs by UVB. Furthermore, oral administration of the suicidal ODC inhibitor α α-difluoromethylornithine reduced UVB-induced BCCs in Ptch1 +/-mice. These results demonstrate the crucial importance of ODC for the induction of BCCs and indicate that chemopreventive strategies directed at inhibiting this enzyme may be useful in reducing BCCs in human populations.Nonstandard abbreviations used: basal cell carcinoma (BCC); α-difluoromethylornithine (DFMO); keratin 5 (K5); nevoid basal cell carcinoma syndrome (NBCCS); ornithine decarboxylase (ODC); antizyme (AZ); outer root sheath (ORS); patched (Ptch); sonic hedgehog (SHH); squamous cell carcinoma (SCC); ultraviolet B (UVB).

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Section: Methodsmentioning

confidence: 99%

“…In the past decade, mouse models for BCCs have been developed (12). One of these is the Ptch1 +/-knockout mouse, in which exons 1 and 2 are deleted and a Lac reporter gene is inserted at the deleted site (14,15). The skin of these mice appears grossly normal.…”

Section: Introductionmentioning

confidence: 99%

Ornithine decarboxylase is a target for chemoprevention of basal and squamous cell carcinomas in Ptch1+/– mice

et al. 2004

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“…The tumor suppressor role of PTCH1 has been further shown in mice. Mice heterozygous for a Ptch1 null mutation show the essential features in basal cell nevus syndrome patients, such as tumor development such as (medulloblastomas, rhabdomyosarcomas and BCCs) and developmental defects (such as spina bifida occulta) (Goodrich et al, 1997;Hahn et al, 1998;Aszterbaum et al, 1999a). In human organotypic skin cultures, keratinocytes with heterozygous mutation of PTCH1 show high invasiveness, hyperproliferation and Hedgehog signaling in human cancer L Yang et al marked differentiation impairment in comparison with wild-type keratinocytes, arguing for PTCH1 haploinsufficiency in cancer development (Brellier et al, 2008).…”

Section: Activation Of the Hedgehog Pathway In Human Cancermentioning

confidence: 99%

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

et al. 2009

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“…18 The activation process of GLI leads to expression of HH target genes such as PTCH1, GLI1, BCL2, BMI1, and Cyclin D1 and hence to increased proliferation, survival, and self-renewal. [19][20][21] Sustained canonical HH pathway activation has been associated with cancers of the brain, 22,23 the skin, [24][25][26] the gastrointestinal tract, 27 the prostate, 28,29 the pancreas, 30,31 and the lung. 32 Noncanonical HH signaling was described in mammary gland cells, inducing direct ERK activation downstream of the PTCH1 receptor without involvement of the SMO receptor.…”

Section: Introductionmentioning

confidence: 99%

Trisomy 12 and elevated GLI1 and PTCH1 transcript levels are biomarkers for Hedgehog-inhibitor responsiveness in CLL

Decker

Zirlik

Djebatchie

et al. 2012

Blood

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Hedgehog (HH) signaling is activated in various lymphoid malignancies, but conflicting results exist about its role in chronic lymphocytic leukemia (CLL). Here, we demonstrate that the expression of essential HH pathway components like GLI1, PTCH1, and the HH ligands is highly diverse in CLL. A subset of 36.7% of 60 tested CLL samples responded to all 3 SMOOTHENED (SMO) inhibitors, whereas 40% were completely resistant. Responsiveness correlated with elevated GLI1 and PTCH1 transcript levels and the presence of trisomy 12, whereas no other karyotype correlated with responsiveness. All trisomy 12 CLLs displayed constitutive HH pathway activation driven by autocrine DESERT HH (DHH) ligand secretion, which could be blocked by the HH-blocking Ab 5E1. Cocultures with DHH-expressing BM stromal cells reduced sensitivity of CLLs to SMOinhibitor treatment by activation of noncanonical ERK phosphorylation directly downstream of the PTCH1 receptor without involvement of SMO and could be overcome by the HH-blocking Ab 5E1 or a combination of SMO and ERK inhibitors. Our results demonstrate that the HHsignaling pathway is an interesting therapeutic target for a subset of patients with CLL, characterized by high GLI1 and PTCH1 transcript levels, and all patients with trisomy 12 and indicate HH-blocking Abs to be favorable over SMO inhibitors in overcoming stroma-mediated protective effects. (Blood. 2012;119(4):997-1007) Introduction B-cell chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in Western countries and is characterized by a progressive accumulation of functionally incompetent Blymphocytes in the peripheral blood, BM, and lymphoid organs. 1,2 Several prognostic markers such as Rai and Binet staging systems, 3,4 immunoglobulin V H gene mutational status, 5 -associated protein 70 (ZAP70) expression 6,7 and cytogenetic abnormalities 8 such as trisomy 12 and del 13q14 can be used to predict the survival outcome and the need for treatment of patients with CLL. 9 Despite encouraging new therapeutic strategies 10 CLL cannot be cured by conventional therapy at present, and only hematopoietic stem cell transplantation has led to complete and ongoing remissions in some patients. 11 The exact pathogenesis of this clinically heterogenous leukemia is still unknown, 12 but it is well established that B-CLL cells are habitually interacting with stromal cells, indicating the importance of the microenvironment for survival of CLL cells. [13][14][15] In our previous work, we demonstrated that the hedgehog (HH) ligands sonic (Shh), indian (Ihh), and desert (Dhh) are produced by stromal cells in lymphoid organs and that the BM promote expansion of murine lymphomas in vitro and in vivo. 16 HH ligands activate the transmembrane receptor PATCHED (PTCH), which abrogates the suppression of the 7-transmembranehelix protein SMOOTHENED (SMO), the key player for signal transduction of the canonical HH pathway. 17 SMO activation leads to production of activating forms of the glioma-associated oncoproteins 1-3 (GLI1-3), the H...

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Ultraviolet Radiation Mutagenesis of Hedgehog Pathway Genes in Basal Cell Carcinomas

Cited by 58 publications

References 35 publications

Ornithine decarboxylase is a target for chemoprevention of basal and squamous cell carcinomas in Ptch1+/– mice

Ornithine decarboxylase is a target for chemoprevention of basal and squamous cell carcinomas in Ptch1+/– mice

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

Trisomy 12 and elevated GLI1 and PTCH1 transcript levels are biomarkers for Hedgehog-inhibitor responsiveness in CLL

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