A role of PDGFR in basal cell carcinoma proliferation (original) (raw)
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Journal of Clinical Medicine
Basal cell carcinoma (BCC) is the most common malignant skin tumor. BCC displays a different behavior compared with other neoplasms, has a slow evolution, and metastasizes very rarely, but sometimes it causes an important local destruction. Chronic ultraviolet exposure along with genetic factors are the most important risk factors involved in BCC development. Mutations in the PTCH1 gene are associated with Gorlin syndrome, an autosomal dominant disorder characterized by the occurrence of multiple BCCs, but are also the most frequent mutations observed in sporadic BCCs. PTCH1 encodes for PTCH1 protein, the most important negative regulator of the Hedgehog (Hh) pathway. There are numerous studies confirming Hh pathway involvement in BCC pathogenesis. Although Hh pathway has been intensively investigated, it remains incompletely elucidated. Recent studies on BCC tumorigenesis have shown that in addition to Hh pathway, there are other signaling pathways involved in BCC development. In t...
Cancer research, 2003
Activation of the Sonic hedgehog signaling pathway, primarily through mutational inactivation of the PTCH1 gene, is associated with the development of basal cell carcinoma (BCC). Gli1, a member of the Gli family of transcription factors, is expressed in BCC and in transgenic mice targeted expression of Gli1 in basal keratinocytes leads to BCC development. In addition to BCC, previous studies have shown that Gli1 is expressed in the outer root sheath (ORS) of the hair follicle but is absent in interfollicular epidermis. In this study, we have characterized the expression pattern of two protein kinase C (PKC) isoforms expressed in BCC and hair follicles. We have then used reporter assays to investigate the effects of these isoforms on Gli1 transcriptional activity. We report that in BCC sections, PKC␣ but not PKC␦ was weakly expressed in the epidermis, whereas in the hair follicle, PKC␣ was expressed in the ORS and PKC␦ in the inner root sheath. In contrast, neither PKC␣ nor PKC␦ was expressed in BCC tumor islands, although both isoforms were often expressed in the surrounding stroma. In mammalian 293T cells, coexpression of constitutively active PKC␣ reduced the activity of Gli1 in a dose-dependent manner, whereas constitutively active PKC␦ increased the activity of Gli1, although this required higher expression levels. Regulation of mutant Gli1 protein localized exclusively to the nucleus was similar to that of the wild-type protein, indicating that nuclear-cytoplasmic shuttling is not a determinant of Gli1 control by either PKC isoform. Furthermore, PKC regulation of Gli1 did not involve activation of mitogen-activated protein kinase signaling. Finally, we show that exogenous Gli1 does not alter the expression of PKC␣ in human primary keratinocytes, suggesting that loss of this isoform in BCC is not via Hedgehog signaling. As BCCs have been proposed to originate from the ORS, loss of PKC␣ expression may be relevant to tumor formation; this may, in part, be because of the predicted increase in Gli1 transcriptional activity.
GLI activation by atypical protein kinase C ι/λ regulates the growth of basal cell carcinomas
Nature, 2013
Basal cell carcinoma (BCC) growth requires high levels of Hedgehog (Hh) signaling through the transcription factor Gli 1 . While inhibitors of membrane protein Smoothened (Smo) effectively suppress Hh signaling, early tumor resistance illustrates the need for additional downstream targets for therapy 1-6 . Here we identify atypical Protein Kinase C iota/lambda (aPKC) as a novel Gli regulator. aPKC and its polarity signaling partners 7 colocalize at the centrosome and form a complex with Missing-in-Metastasis (MIM), a scaffolding protein that potentiates Hh signaling 9 . Genetic or pharmacological loss of aPKC function blocks Hh signaling and proliferation of BCC cells. aPKC is a Hh target gene that forms a positive feedback loop with Gli and exhibits elevated levels in BCCs. Genome-wide transcriptional profiling shows that aPKC and Smo control the expression of similar genes in tumor cells. aPKC functions downstream of Smo to phosphorylate and activate Gli1, resulting in maximal DNA binding and transcriptional activation. Activated aPKC is upregulated in Smo-inhibitor resistant tumors and targeting aPKC suppresses signaling and growth of resistant BCC cell lines. These results demonstrate aPKC is critical for Hhdependent processes and implicates aPKC as a new, tumor-selective therapeutic target for the treatment of Smo-inhibitor resistant cancers.
Pathology International, 1999
cell carcinomas (BCC) of the skin, ovarian fibromas, and primitive neuroectodermal tumors of the central nervous system. The majority of patients with BCNS and sporadic BCC have an allele loss on chromosome 9q22, implying that the inactivation of a tumor suppressor in this region is an important step in BCC formation. 4-10 Several groups have recently identified a candidate gene responsible for BCNS in the 9q region, which is the mammalian homolog of the Drosophila segment-polarity gene, patched (ptc). 11-15 Analyses of Drosophila mutants have indicated that the ptc protein (PTC) is involved in the hedgehog (HH) signaling pathway by repressing the expression of various target genes including the wingless and decapentaplegic genes and ptc itself. Subsequent biochemical analyses strongly suggested that PTC functions as an inhibitory receptor for the HH. Another regulator involved in the HH signaling pathway is the gene, smoothened (smo). The smo gene encodes a serpentine receptor, and genetic analyses of Drosophila have indicated that SMO positively transduces the HH signal. [23] The HH signaling pathway and its transducers were recently reviewed. 26,27 A transgenic mouse that harbors the shh gene, under the control of the epidermis-specific keratin 14 promoter, exhibited abnormal skin texture supporting similar to BCC, in addition to a number of developmental defects. This study reinforced the idea that the deregulation of SHH signaling can cause malignancy of the epithelial basal cells. The expressions of SHH and PTC are detected in normal skin during development, 28,30-32 but little is known about their localization in BCC tissues or adult normal skin, or about the involvement of SMO in those tissues. In this study, the distribution patterns of smo and ptc mRNA in BCC are examined, using in situ hybridization histochemistry and reverse transcription-polymerase chain reaction (RT-PCR) analyses. We found that their patterns were characteristic and correlate with histologic subtypes. Possible functional implications of the expression patterns are discussed. International 1999; 49: 687-694 In basal cell nevus syndrome (BCNS) patients, mutations of a gene, patched (ptc), which encodes a putative signal transducer of sonic hedgehog protein (SHH), were found and are thought to be one of the major causes of BCNS. The SHH signaling pathway is an important developmental pathway, and ptc protein (PTC) is a suppressive component serving as a receptor for the secreted SHH. Another transmembrane protein, smoothened (SMO), forms a complex with PTC and regulates this signaling pathway. Recent transgenic studies have strengthened the importance of the SHH signaling system in the etiology of basal cell carcinoma (BCC). In this study, we examined the expression patterns of mRNA for ptc and smo in two different BCC subtypes and normal skin. We found that the expressions of ptc and smo mRNA were enhanced in the tumor nests of the nodular BCC, especially at the advancing portions, but were under the detectable level in the superficial BCC cases examined, indicating that ptc and smo mRNA expressions might be associated with BCC tumor progression and divide the BCC histologic types into two subtypes, superficial and nodular types. In addition, no obvious signals for ptc and smo mRNA were detected in the normal human epidermis, appendages, or seborrheic keratosis, indicating that the abnormal proliferation of follicular epithelial cells caused by ptc, smo and/or other genetic changes, which also cause ptc and smo overexpressions, might result in BCC tumor formation.
Hedgehog signaling pathway and its targets for treatment in basal cell carcinoma
Journal of Experimental Pharmacology, 2012
Basal cell carcinoma (BCC) of the skin is the most common type of cancer and accounts for up to 40% of all cancers in the US, with a growing incidence rate over recent decades in all developed countries. Surgery is curative for most patients, although it leaves unaesthetic scars, but those that develop locally advanced or metastatic BCC require different therapeutic approaches. Furthermore, patients with BCC present a high risk of developing additional tumors. The increasing economic burden and the morbidity of BCC render primary interest in the development of targeted treatments for this disease. Among the molecular signals involved in the development of BCC, the critical role of the morphogenetic Hedgehog (Hh) pathway has become evident. This pathway is found altered and activated in almost all BCCs, both sporadic and inherited. Given the centrality of the Hh pathway in the pathophysiology of BCC, the primary efforts to identify molecular targets for the topical or systemic treatment of this cancer have focused on the Hh components. Several Hh inhibitors have been so far identified-from the first identified natural cyclopamine to the recently Food and Drug Administration-approved synthetic vismodegib-most of which target the Hh receptor Smoothened (either its function or its translocation to the primary cilium). Other molecules await further characterization (bisamide compounds), while drugs currently approved for other diseases such as itraconazole (an antimicotic agent) and vitamin D3 have been tested on BCC with encouraging results. The outcomes of the numerous ongoing clinical trials are expected to expand the field in the very near future. Further research is needed to obtain drugs targeting downstream components of the Hh pathway (eg, Gli) or to exploit combinatorial therapies (eg, with phosphatidylinositol 3-kinase inhibitors or retinoids) in order to overcome potential drug resistance.
Asian Pacific Journal of Cancer Prevention
Objective: Basal cell carcinoma (BCC) is the most common malignancy in humans and represents a growing public health care problem. The major etiological factors contributing to BCC development are exposure to ultraviolet radiation and genetic alterations. BCC is primarily caused by dysregulation of sonic Hedgehog (HH) signaling pathway in basal cells of the skin. BCC can be classified into low risk non-aggressive and high risk aggressive subtypes. BCC subtypes differentiation is essential for prognosis and for better disease management and treatment strategies. The aim of this study was to assess the correlation between PTCH1 protein expression level and the aggressiveness of BCC histopathology. Methods: Archival paraffin embedded blocks containing BCC were retrieved from a cohort of 101 patients. Immunohistochemistry staining was performed to assess the expression level of PTCH1 which is a key component of Hedgehog pathway. Results: 101 paraffin embedded samples were evaluated and classified as high risk and low risk BCC subtypes by histopathological finding. High risk BCC subtypes were found in 40 samples (39.6%) and low risk subtypes were identified in 61 samples (60.4%). Nodular was the most frequent subtype which was found in (56/ 101), followed by infiltrative (22/101) and micronodular (14/ 101) subtypes. Positive PTCH1 expression was found highest in nodular subtypes (46.5%). Conclusion: In this study, the correlation between low risk or high risk BCC subtypes and PTCH1 expression level was not statistically significant (p>0.05), but the frequency of positive PTCH1 expression was found to be higher in low risk subtypes than high risk BCC subtypes.
Cancer prevention research (Philadelphia, Pa.), 2016
Patients with basal cell nevus syndrome (BCNS), also known as Gorlin syndrome, develop numerous basal cell carcinomas (BCCs) due to germline mutations in the tumor suppressor <i>PTCH1</i> and aberrant activation of Hedgehog (Hh) signaling. Therapies targeted at components of the Hh pathway, including the smoothened (SMO) inhibitor vismodegib, can ablate these tumors clinically, but tumors recur upon drug discontinuation. Using SKH1-<i>Ptch1<sup>+/-</sup></i> as a model that closely mimics the spontaneous and accelerated growth pattern of BCCs in patients with BCNS, we show that AKT1, a serine/threonine protein kinase, is intrinsically activated in keratinocytes derived from the skin of newborn <i>Ptch1<sup>+/-</sup></i> mice in the absence of carcinogenic stimuli. Introducing <i>Akt1</i> haplodeficiency in <i>Ptch1<sup>+/-</sup></i> mice…
2000
The discoveryof specific overexpressionof a gatekeepergene,ptch, in basal cell carcinoma,(BCC) led to a hypothesis,that the human,homologue of patched (PTCH) normally functions as a negative regulator of the signaling,pathway,that Is Initiated by hedgehogs,(Hils) and,activated,by the human homologue of smoothened (SMOH); however, no evidence for the involvementofsmoh and hhs has been provided.Here, we show novel evidence that smoh is also preferentially