Sonic hedgehog signaling in basal cell carcinomas

Daya–Grosjean, Leela; Couvé-Privat, Sophie

doi:10.1016/j.canlet.2004.10.003

Cited by 143 publications

(101 citation statements)

References 86 publications

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“…Activation of the hedgehog pathway has been considered to be caused by two scenarios: ligand-independent and ligand-dependent mechanisms. The former is exemplified by brain and skin tumor as seen in hereditary Gorlin syndrome (12,36), which harbors the loss of function ptch mutations. In addition, gain of function mutations of smo has been reported in sporadic basal cell carcinoma (12).…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have revealed that the activation of hedgehog signaling is implicated in the growth of various tumors, such as basal cell carcinoma of the skin (12), medulloblastoma (13,14), and tumors of the lung (15), digestive tract (16,17), and prostate (18,19). In addition, a ligandindependent, constitutive activation of hedgehog signaling due to ptch or smo gene mutations has been reported in basal cell carcinoma (12,20). However, the expression and functional involvement of hedgehog signaling molecules in endometrial tissues remain undetermined.…”

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confidence: 99%

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Overexpression of Hedgehog Signaling Molecules and Its Involvement in the Proliferation of Endometrial Carcinoma Cells

Feng

Shiozawa²,

Miyamoto³

et al. 2007

Clinical Cancer Research

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Purpose: Research has revealed abnormal activation of the hedgehog pathway in human malignancies.The present study was undertaken to examine the expression and functional involvement of the hedgehog pathway in endometrial tissues. Experimental Design: The expression of sonic hedgehog (Shh), patched (Ptch), Smoothened (Smo), and Gli1was examined in various endometrial tissues and endometrial carcinoma cell lines. The effect of hedgehog signaling on the proliferation of endometrial carcinoma cell lines was also examined. Results: The expression of Shh, Ptch, Smo, and Gli1was very weak in normal endometrium, but was increased in endometrial hyperplasia and carcinoma stepwisely with significant differences. There was no marked difference in the expression of these molecules in carcinomas according to stages and histologic grades. Treatment with cyclopamine, a specific inhibitor of the hedgehog pathway, for endometrial carcinoma Ishikawa and HHUA cells suppressed growth by 56% and 67%, respectively, compared with the control. The addition of recombinant Shh peptide to HHUA cells enhanced their proliferation by 41%. The silencing of Gli1using small interfering RNA (siGli1) resulted in the growth suppression and down-regulation of Ptch expression. In addition, the cyclopamine/siGli1-induced growth suppression was associated with the down-regulation of cyclins D1 and A and N-myc. No somatic mutations for ptch and smo genes were detected in the endometrial carcinoma cases examined. Conclusions:The abnormal activation of this pathway is involved in the proliferation of endometrial carcinoma cells possibly in an auto-/paracrine fashion, suggesting the possibility of the hedgehog pathway being a novel candidate for molecular targeting.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Overexpression of Hedgehog Signaling Molecules and Its Involvement in the Proliferation of Endometrial Carcinoma Cells

Feng

Shiozawa²,

Miyamoto³

et al. 2007

Clinical Cancer Research

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“…Oncogene (2006Oncogene ( ) 25, 7646-7649. doi:10.1038published online 12 June 2006 Keywords: basal cell carcinoma; RUNX3; b-catenin; Sonic Hedgehog Cutaneous basal cell carcinomas (BCC) comprise approximately 80% of non-melanoma skin cancers and have been reported as the most common human malignancy in the United States (Rubin et al, 2005). The molecular pathogenesis of BCC bears the distinction of being almost entirely associated to the deregulation of the Sonic Hedgehog (Shh) signalling pathway (for a recent review on this topic, see Daya-Grosjean and Couve-Privat, 2005). Originally identified as a determinant of segment polarity in Drosophila, Shh is a secreted glycoprotein that plays a major role in vertebrate development.…”

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confidence: 99%

“…SMO in turn initiates a signalling cascade that leads to the activation of the Cilike (GLI) family of transcription factors, which are the primary effectors of the Shh signal. Mutations in Shh, PTCH1, SMO and GLI have all been identified in BCC cases, with loss-of-function mutation in PTCH1 identified in 100 and 12-38% of familial and sporadic BCC cases, respectively (Dahmane et al, 1997;Unden et al, 1997;Daya-Grosjean and Couve-Privat, 2005).…”

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confidence: 99%

RUNX3 protein is overexpressed in human basal cell carcinomas

et al. 2006

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Basal cell carcinomas (BCC), which are the most common form of skin malignancy, are invariably associated with the deregulation of the Sonic Hedgehog (Shh) signalling pathway. As such, BCC represent a unique model for the study of interactions of the Shh pathway with other genes and pathways. We constructed a tissue microarray (TMA) of 75 paired BCC and normal skin and analysed the expression of b-catenin and RUNX3, nuclear effectors of the wingless-Int (Wnt) and bone morphogenetic protein/ transforming growth factor-b pathways, respectively. In line with previous reports, we observed varying subcellular expression pattern of b-catenin in BCC, with 31 cases (41%) showing nuclear accumulation. In contrast, all the BCC cases tested by the TMA showed RUNX3 protein uniformly overexpressed in the nuclei of the cancer cells. Analysis by Western blotting and DNA sequencing indicates that the overexpressed protein is normal and full-length, containing no mutation in the coding region, implicating RUNX3 as an oncogene in certain human cancers. Our results indicate that although the deregulation of Wnt signalling could contribute to the pathogenesis of a subset of BCC, RUNX3 appears to be a universal downstream mediator of a constitutively active Shh pathway in BCC.

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“…Interestingly, the majority of PTCH1 mutations identified in BCC result in premature truncation of the protein (Daya-Grosjean and Couve-Privat 2005). These findings raise the tantalizing possibility that the C-terminal half of PTCH1 is crucial for tumor suppression.…”

Section: C-terminal Domain Of Ptc1: Cell Survival Cell Cycle Progresmentioning

confidence: 99%