FOXM1 is a downstream target of Gli1 in basal cell carcinomas.

Forkhead box (FOX) proteins have been shown to play important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation, longevity, and transformation. The functional importance of this gene family in normal human skin physiology and disease processes is not well understood. Activation of Sonic Hedgehog (Shh) signaling plays a key role in the development of basal cell carcinomas (BCCs) of the skin in humans. Recent studies have established that some FOX genes are downstream targets of Shh signaling. We have investigated the role of FOX proteins in transducing Shh effects in human skin by using degenerate PCR to identify FOX genes differentially expressed in BCCs. All three known FOXM1 isoforms (a, b, and c) were detected in human skin and cultured keratinocytes, and the transcriptionally active FOXM1b isoform was found to be up-regulated in BCCs. Real-time quantitative RT-PCR showed that the increase in FOXM1 mRNA levels was specific for BCCs and not a reflection of increased cell proliferation in that no up-regulation was seen in squamous cell carcinomas or proliferating primary human keratinocyte cultures. Immunostaining studies showed intense nuclear and cytoplasmic staining throughout BCC tumor islands and not confined to the periphery regions of the tumor where proliferating Ki-67-immunopositive cells are predominantly localized. Expression of the Shh target glioma transcription factor-1 (Gli1) in primary keratinocytes and other cell lines caused a significant elevation of FOXM1 mRNA level and transcriptional activity, indicating that FOXM1 is a downstream target of Gli1. Our data provide the first evidence that activation of Shh signaling via Gli1 is an important determinant of FOXM1 expression in mammalian cells. Given the role of FOXM1 in cell proliferation, the up-regulation of FOXM1 in BCCs may be one of the mechanisms whereby Shh signaling exerts its mitogenic effect on basal keratinocytes, leading to the development of this common human cancer.

Epidermal and hair follicle progenitor cells express melanoma-associated chondroitin sulfate proteoglycan core protein.

Basal keratinocytes in the epidermis and hair follicle are biologically heterogeneous but must include a stable subpopulation of epidermal stem cells. In animal models these can be identified by their retention of radioactive label due to their slow cycle (label-retaining cells) but human studies largely depend on in vitro characterization of colony forming efficiency and clonogenicity. Differential integrin expression has been used to detect cells of increased proliferative potential but further stem cell markers are urgently required for in vivo and in vitro characterization. Using LHM2, a monoclonal antibody reacting with a high molecular weight melanoma-associated proteoglycan core protein, a subset of basal keratinocytes in both the interfollicular epidermis and the hair follicle has been identified. Coexpression of melanoma-associated chondroitin sulfate proteoglycan with keratins 15 and 19 as well as beta 1 and alpha 6 integrins has been examined in adult and fetal human skin from hair bearing, nonhair bearing, and palmoplantar regions. Although melanoma-associated chondroitin sulfate proteoglycan coexpression with a subset of beta 1 integrin bright basal keratinocytes within the epidermis suggests that melanoma-associated chondroitin sulfate proteoglycan colocalizes with epidermal stem cells, melanoma-associated chondroitin sulfate proteoglycan expression within the hair follicle was more complex and multiple subpopulations of basal outer root sheath keratinocytes are described. These data suggest that epithelial compartmentalization of the outer root sheath is more complex than interfollicular epidermis and further supports the hypothesis that more than one hair follicle stem cell compartment may exist.

Detection of a novel single nucleotide polymorphism of the human thiopurine s-methyltransferase gene in a Chinese individual.

A 62-year-old Chinese patient with recurrent pompholyx submitted his blood sample for pre-treatment thiopurine S-methyltransferase (TPMT) pharmacogenetic profiling, and it was found to harbour a novel single nucleotide polymorphism (SNP). The novel SNP, detected by mRNA sequencing, was a c.2T>C (g.11018T>C) transition in the start codon, causing a Met1Thr amino acid change. This finding was confirmed on a subsequent blood sample from the same patient by DNA sequencing. The patient was genotyped as TPMT*1/*29, sequentially named as such following the latest TPMT SNP (TPMT*1/*28) at the time of writing. The novel SNP is expected to result in complete lack of protein translation, similar to the impact exerted by TPMT*14, another start codon SNP of the TPMT gene.

Eosinophilic pustular folliculitis.

Classical eosinophilic pustular folliculitis, or Ofuji's disease, is a chronic and relapsing dermatosis that is predominantly reported in East Asian populations. Clinically, the disease typically begins as small papules, which enlarge and coalesce into a large plaque, usually on the face. The histopathology is characterized by a prominent eosinophilic infiltrate in the dermis with concentration around pilosebaceous units, often with eosinophilic microabscess formation. The differentiation of eosinophilic pustular folliculitis from other eosinophilic dermatoses is practically challenging and requires close clinicopathologic correlation. Eosinophilic pustular folliculitis may also be associated with human immunodeficiency virus infection, various drugs, and some lymphomas and could also be thought of as a nonspecific dermatopathologic pattern in such settings. The cause of classical eosinophilic pustular folliculitis is unknown, although immune processes are almost certain to play a key role in its pathogenesis.