Heterozygous mutations in the tumor suppressor gene PATCHED provoke basal cell carcinoma-like features in human organotypic skin cultures.
Basal cell carcinoma of the skin is the most common type of cancer in humans. The majority of these tumors displays aberrant activation of the SONIC HEDGEHOG (SHH)/PATCHED pathway, triggered by mutations in the PATCHED tumor suppressor gene, which encodes a transmembrane receptor of SHH. In this study, we took advantage of the natural genotype (PATCHED(+/-)) of healthy keratinocytes expanded from patients with the nevoid basal cell carcinoma or Gorlin syndrome to mimic heterozygous somatic mutations thought to occur in the PATCHED gene early upon basal cell carcinoma development in the general population. PATCHED(+/-) epidermis developed on a dermal equivalent containing wild-type (WT) PATCHED(+/+) fibroblasts exhibited striking invasiveness and hyperproliferation, as well as marked differentiation impairment. Deciphering the phenotype of PATCHED(+/-) keratinocytes revealed slight increases of the transcriptional activators GLI1 and GLI2-the latter known to provoke basal cell carcinoma-like tumors when overexpressed in transgenic mice. PATCHED(+/-) keratinocytes also showed a substantial increase of the cell cycle regulator cyclin D1. These data show for the first time the physiological impact of constitutive heterozygous PATCHED mutations in primary human keratinocytes and strongly argue for a yet elusive mechanism of haploinsufficiency leading to cancer proneness.
Brellier
F
F
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Bergoglio
V
V
Valin
A
A
Barnay
S
S
Chevallier-Lagente
O
O
Vielh
P
P
Spatz
A
A
Gorry
P
P
Avril
M-F
MF
Magnaldo
T
T
D001483:Base Sequence; D002280:Basal Cell Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor / Q000502:physiology; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009154:Mutation / Q000502:physiology; D009924:Organ Culture Techniques; D000072079:Patched Receptors; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D012867:Skin / Q000378:metabolism / Q000473:pathology*; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
D000072079:Patched Receptors; D011956:Receptors, Cell Surface