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Loss of syndecan-1 is associated with malignant conversion in skin carcinogenesis
Mary Ann Stepp1, Sonali Pal-Ghosh, Gauri Tadvalkar
1Department of Anatomy and Regenerative Biology, The George Washington University Medical Center, Washington, District of Columbia, USA.
Abstract:
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 beta (TGFbeta) 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 alpha3 and beta4 integrins; suprabasal beta4 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 TGFbeta1 within their skin after TPA treatment. sdc-1 null keratinocytes, transduced in vitro by oncogenic ras(Ha), expressed higher levels of beta4 integrin and had enhanced pSmad2 signaling and reduced senescence when compared to wt ras(Ha)-transduced keratinocytes. When ras(Ha)-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.
Insights
Syndecan-1 (sdc-1) loss in skin cells promotes cancer progression and increases the risk of squamous cell carcinoma (SCC) development. Reduced sdc-1 expression may serve as a marker for neoplastic skin lesion progression.
Area of Science:
- Dermatology
- Cancer Biology
- Cell Biology
Background:
- Syndecan-1 (sdc-1) is a cell surface proteoglycan crucial for cell-matrix interactions, influencing keratinocyte behavior.
- Loss of sdc-1 in keratinocytes impairs wound healing, reduces migration, and elevates Transforming Growth Factor beta (TGFbeta) 1 levels.
- Reduced sdc-1 expression is observed in human skin cancers compared to normal skin.
Purpose of the Study:
- To investigate the role of syndecan-1 (sdc-1) in skin tumor development and progression.
- To determine if sdc-1 expression levels correlate with the severity of skin neoplasms.
- To explore the molecular mechanisms by which sdc-1 influences skin cancer progression.
Main Methods:
- Utilized sdc-1 null and wild-type (wt) BALB/c mice for experimental skin tumor induction via skin painting.
- Analyzed sdc-1 expression in human skin cancer biopsies.
- Investigated keratinocyte behavior in vitro using oncogenic ras(Ha) transduction and in vivo tumor grafting experiments.
- Assessed molecular markers including integrins, TGFbeta1, pSmad2 signaling, and senescence.
Main Results:
- Papilloma formation was reduced by 50% in sdc-1 null mice, but the conversion rate to squamous cell carcinoma (SCC) was enhanced.
- sDC-1 expression decreased as papillomas progressed to SCC in wt mice.
- Papillomas in sdc-1 null mice showed suprabasal alpha3 and beta4 integrin expression, with beta4 integrin indicating high progression risk.
- Sdc-1 null mice exhibited an enhanced inflammatory response and higher skin TGFbeta1 levels post-TPA treatment.
- Ras(Ha)-transduced sdc-1 null keratinocytes displayed increased beta4 integrin, enhanced pSmad2 signaling, and reduced senescence.
- Tumors derived from ras(Ha)-transduced sdc-1 null cells showed higher SCC conversion frequency when grafted onto nude mice.
Conclusions:
- Syndecan-1 (sdc-1) plays a significant role in both the early stages of skin tumor development and the progression of skin cancers.
- Reduced sdc-1 expression is associated with increased risk and progression of squamous cell carcinoma (SCC).
- Decreased sdc-1 expression may serve as a valuable biomarker for assessing the progression of neoplastic skin lesions.
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