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CYFIP1 is directly controlled by NOTCH1 and down-regulated in cutaneous squamous cell carcinoma
Piotr J Dziunycz1, Johannes Neu1, Karine Lefort2
1Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
Abstract:
Squamous cell carcinoma of the skin (SCC) represents one of the most common cancers in the general population and is associated with a substantial risk of metastasis. Previous work uncovered the functional role of CYFIP1 in epithelial tumors as an invasion inhibitor. It was down-regulated in some cancers and correlated with the metastatic properties of these malignant cells. We investigated its role and expression mechanisms in SCC. We analyzed the expression of CYFIP1 in patient derived SCC, primary keratinocytes and SCC cell lines, and correlated it to the differentiation and NOTCH1 levels. We analyzed the effects of Notch1 manipulation on CYFIP1 expression and confirmed the biding of Notch1 to the CYFIP1 promoter. CYFIP1 expression was down-regulated in SCC and correlated inversely with histological differentiation of tumors. As keratinocyte differentiation depends on Notch1 signaling, we investigated the influence of Notch1 on CYFIP1 expression. CYFIP1 mRNA was highly increased in human Notch1-overexpressing keratinocytes. Further manipulation of the Notch1 pathway in keratinocytes impacted CYFIP1 levels and chromatin immunoprecipitation assay confirmed the direct binding of Notch1 to the CYFIP1 promoter. CYFIP1 may be a link between loss of differentiation and invasive potential in malignant keratinocytes of cutaneous squamous cell carcinoma.
Insights
This study reveals that CYFIP1 is downregulated in skin squamous cell carcinoma (SCC), correlating with reduced tumor differentiation and increased invasion potential. Notch1 signaling directly regulates CYFIP1 expression, suggesting a novel therapeutic target for SCC metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Dermatology
Background:
- Squamous cell carcinoma (SCC) is a common skin cancer with significant metastatic risk.
- CYFIP1 has been identified as an invasion inhibitor in epithelial tumors, with decreased expression linked to metastatic properties.
- Understanding the regulation and role of CYFIP1 in SCC is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the expression patterns and regulatory mechanisms of CYFIP1 in cutaneous squamous cell carcinoma (SCC).
- To explore the correlation between CYFIP1 expression, tumor differentiation, and Notch1 signaling in SCC.
- To elucidate the functional link between CYFIP1, differentiation, and invasive potential in malignant keratinocytes.
Main Methods:
- Analysis of CYFIP1 expression in patient-derived SCC, primary keratinocytes, and SCC cell lines.
- Correlation of CYFIP1 levels with histological differentiation and Notch1 pathway activity.
- Investigation of Notch1's influence on CYFIP1 expression through manipulation of the Notch1 pathway.
- Chromatin immunoprecipitation assays to confirm direct binding of Notch1 to the CYFIP1 promoter.
Main Results:
- CYFIP1 expression was found to be downregulated in SCC tissues and inversely correlated with tumor histological differentiation.
- CYFIP1 mRNA levels significantly increased in keratinocytes overexpressing Notch1.
- Manipulation of the Notch1 pathway directly impacted CYFIP1 expression levels.
- Direct binding of Notch1 to the CYFIP1 promoter was confirmed via chromatin immunoprecipitation.
Conclusions:
- CYFIP1 downregulation in SCC is linked to reduced differentiation and potentially increased invasive behavior.
- Notch1 signaling directly regulates CYFIP1 expression in keratinocytes, establishing a molecular link.
- CYFIP1 may serve as a critical mediator between the loss of differentiation and the invasive potential observed in malignant keratinocytes of cutaneous squamous cell carcinoma.