Loss of syndecan-1 is associated with malignant conversion in skin carcinogenesis

• Published in: Molecular carcinogenesis 2010-04, Vol.49 (4), p.363-373
• Main Authors: Stepp, Mary Ann, Pal-Ghosh, Sonali, Tadvalkar, Gauri, Rajjoub, Lamise, Jurjus, Rosalyn A., Gerdes, Michael, Ryscavage, Andrew, Cataisson, Christophe, Shukla, Anjali, Yuspa, Stuart H.
• Format: Article
• Language: English
• Subjects: Animals; Carcinogens - toxicity; Cell Transformation, Neoplastic; Humans; Immunohistochemistry; integrin; keratinocytes; laminin 332; Mice; Mice, Inbred BALB C; Mice, Knockout; Papilloma - pathology; Phorbol Esters - toxicity; ras oncogene; skin carcinogenesis; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; syndecan-1; Syndecan-1 - genetics; Syndecan-1 - metabolism; TGFβ1; Toxicity Tests, Acute; Toxicity Tests, Chronic
• ISSN: 0899-1987; 1098-2744
• DOI: 10.1002/mc.20609

Syndecan‐1 (sdc‐1) is a cell surface proteoglycan that mediates the interaction of cells with their matrix, influencing attachment, migration, and response to growth factors. In keratinocytes, loss of sdc‐1 delays wound healing, reduces migration, and increases Transforming growth factor β (TGFβ) 1 expression. In this study we show that sdc‐1 expression is significantly reduced in basal cell, squamous cell, and metastatic human skin cancers compared to normal human skin. In experimental mouse skin tumor induction, compared to wildtype (wt) BALB/c mice, papilloma formation in sdc‐1 null mice was reduced by 50% and the percent of papillomas converting to squamous cell carcinoma (SCC) was enhanced. sdc‐1 expression on wt mouse papillomas decreased as they converted to SCC. Furthermore, papillomas forming on sdc‐1 null mice expressed suprabasal α3 and β4 integrins; suprabasal β4 integrin is a marker of a high risk for progression. While the proliferative response to phorbol‐12‐myristate‐13‐acetate (TPA) did not differ among the genotypes, sdc‐1 null mice had an enhanced inflammatory response and retained higher levels of total TGFβ1 within their skin after TPA treatment. sdc‐1 null keratinocytes, transduced in vitro by oncogenic rasHa, expressed higher levels of β4 integrin and had enhanced pSmad2 signaling and reduced senescence when compared to wt rasHa‐transduced keratinocytes. When rasHa‐transduced cells of both genotypes were grafted onto nude mice, null tumors converted to SCC with higher frequency confirming the skin painting experiments. These data indicate that sdc‐1 is important both early in the development of skin tumors and in progression of skin cancers suggesting that reduced expression of sdc‐1 could be a useful marker for progression in neoplastic skin lesions. © 2010 Wiley‐Liss, Inc.