Neuronal differentiation in basal cell carcinoma: possible relationship to Hedgehog pathway activation?
Although deregulated Hedgehog signalling and elevated Gli transcription factor expression are known to promote the development of basal cell carcinoma (BCC), little is known about molecular mechanisms driving the development of specific growth pattern subtypes. Using gene array analysis, we have previously observed that over-expression of GLI1 in human keratinocytes promotes increased expression of the neuronal differentiation markers ARC and ULK1. We asked whether neuronal differentiation is a characteristic of BCC and whether there is any correlation with BCC subtype. Using RT-PCR and immunohistochemistry, we confirmed that the neuronal markers ARC, beta-tubulin III, GAP-43 and Neurofilament are expressed in human BCC but not in normal epidermis. Moreover, we found that expression of these neuronal differentiation markers showed strong correlation to BCC subtype, with more aggressive infiltrative and morphoeic BCC showing low levels or lack of expression compared to nodular, superficial and micronodular subtypes. Primary human keratinocytes retrovirally expressing GLI1(-) and GLI2(-) showed elevated levels of beta-tubulin III and ARC but not Neurofilament or GAP-43, suggesting that beta-tubulin III and Arc may be early targets of aberrant Gli expression in BCC, whereas expression of Neurofilament and GAP-43 are either later, downstream targets or under control of alternative pathways. We propose that neuronal differentiation is a feature of BCC and that expression of these markers is in part due to aberrant Hedgehog signalling. Moreover, we suggest that correlation between loss of expression of neuronal markers in infiltrative and morphoeic BCC subtypes reflects dedifferentiation of more aggressive BCC subtypes.
Gore
Sinclair M
SM
Centre for Cutaneous Research, St. Bartholomew's and the London, Queen Mary's School of Medicine and Dentistry, London, UK.
Kasper
Maria
M
Williams
Tomos
T
Regl
Gerhard
G
Aberger
Fritz
F
Cerio
Reno
R
Neill
Graham W
GW
Philpott
Michael P
MP
D000704:Analysis of Variance; D015415:Biomarkers / Q000032:analysis; D002280:Basal Cell Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D002454:Cell Differentiation; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics; D019922:GAP-43 Protein / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D016900:Neurofilament Proteins / Q000235:genetics; D009473:Neuronal Plasticity; D009474:Neurons / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics; D014161:Transduction, Genetic; D014404:Tubulin / Q000235:genetics; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2
D015415:Biomarkers; D003598:Cytoskeletal Proteins; D019922:GAP-43 Protein; C400551:GLI1 protein, human; C082593:GLI2 protein, human; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D014404:Tubulin; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; C092069:activity regulated cytoskeletal-associated protein