Frequent downregulation of DMBT1 and galectin-3 in epithelial skin cancer.
DMBT1 and galectin-3 are potential interacting proteins with presumably complex roles in tumorigenesis. While at present a variety of mechanisms are discussed for DMBT1 and its participation in cancer, galectin-3 is commonly known to exert tumor-promoting effects. However, in vitro studies in a rodent system have suggested that DMBT1/galectin-3 interaction in the ECM triggers epithelial differentiation, which would point to tumor-suppressive properties. To improve the understanding of DMBT1/galectin-3 action in cancer, we carried out studies in skin cancer of different origins. Mutational analyses of DMBT1 identified a missense mutation in 1 of 13 melanoma cell lines. It led to an exchange of an evolutionary conserved proline residue for serine and located within the second CUB domain of DMBT1. Immunohistochemical analyses demonstrated absence of DMBT1/galectin-3 expression from melanocytes but induction of DMBT1 expression in 1 of 8 nevi and 1 of 11 melanomas and of galectin-3 expression in 3 of 8 nevi and 4 of 8 melanomas. These data suggest that DMBT1 and galectin-3 are unlikely to act as classical tumor suppressors in melanomas. DMBT1 and galectin-3 appear to be secreted to the ECM by epithelial cells within the epidermis and the hair follicle. Compared to the flanking normal epidermis, skin tumors of epithelial origin frequently displayed downregulation of DMBT1 (18 of 19 cases) and galectin-3 (12 of 12 cases). Thus, loss of DMBT1/galectin-3 expression may play a role in the genesis of epithelial skin cancer. This would support the view that galectin-3 can exert tumor-suppressive effects in certain scenarios, and DMBT1/galectin-3-mediated differentiation represents a candidate mechanism for this effect.
Mollenhauer
Jan
J
Department of Molecular Genome Analysis, Deutsches Krebsforschungszentrum, Heidelberg, Germany. j.mollenhauer@dfkz.de
Deichmann
Martin
M
Helmke
Burkhard
B
Müller
Hanna
H
Kollender
Gaby
G
Holmskov
Uffe
U
Ligtenberg
Toon
T
Krebs
Inge
I
Wiemann
Stefan
S
Bantel-Schaal
Ursula
U
Madsen
Jens
J
Bikker
Floris
F
Klauck
Sabine M
SM
Otto
Herwart F
HF
Moldenhauer
Gerd
G
Poustka
Annemarie
A
D000373:Agglutinins; D002135:Calcium-Binding Proteins; D002280:Basal Cell Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D037502:Galectin 3 / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D007124:Immunoenzyme Techniques; D066298:In Vitro Techniques; D019656:Loss of Heterozygosity; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018895:Microsatellite Repeats; D016133:Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D000373:Agglutinins; D002135:Calcium-Binding Proteins; C108174:DMBT1 protein, human; D017931:DNA Primers; D004268:DNA-Binding Proteins; D037502:Galectin 3; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins