SFRP1 in Skin Tumor Initiation and Cancer Stem Cell Regulation with Potential Implications in Epithelial Cancers

• Published in: Stem cell reports Vol. 14; no. 2; pp. 271 - 284
• Main Authors: Sunkara, Raghava R., Sarate, Rahul M., Setia, Priyanka, Shah, Sanket, Gupta, Sanjay, Chaturvedi, Pankaj, Gera, Poonam, Waghmare, Sanjeev K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.02.2020; Elsevier
• Subjects: Animals; cancer stem cells; Carcinogenesis - metabolism; Carcinogenesis - pathology; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; CSCs; Disease Progression; EMT; epithelial cancer; epithelial to mesenchymal transition; Epithelial-Mesenchymal Transition - genetics; Epithelium - pathology; Gene Expression Regulation, Neoplastic; head and neck squamous cell carcinoma; HNSCC; Intercellular Signaling Peptides and Proteins - metabolism; Membrane Proteins - deficiency; Membrane Proteins - metabolism; Mice; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Sfrp1 (secreted frizzled-related protein); Signal Transduction; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; skin squamous cell carcinoma; SOXB1 Transcription Factors - metabolism; tumorigenic potential; Up-Regulation - genetics; Sfrp1 (secreted frizzled-related protein); skin squamous cell carcinoma; HNSCC; epithelial cancer; epithelial to mesenchymal transition; cancer stem cells; EMT; tumorigenic potential; CSCs; head and neck squamous cell carcinoma
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2019.12.006

Wnt signaling is involved in the regulation of cancer stem cells (CSCs); however, the molecular mechanism involved is still obscure. SFRP1, a Wnt inhibitor, is downregulated in various human cancers; however, its role in tumor initiation and CSC regulation remains unexplored. Here, we used a skin carcinogenesis model, which showed early tumor initiation in Sfrp1−/− (Sfrp1 knockout) mice and increased tumorigenic potential of Sfrp1−/− CSCs. Expression profiling on Sfrp1−/− CSCs showed upregulation of genes involved in epithelial to mesenchymal transition, stemness, proliferation, and metastasis. Further, SOX-2 and SFRP1 expression was validated in human skin cutaneous squamous cell carcinoma, head and neck squamous cell carcinoma, and breast cancer. The data showed downregulation of SFRP1 and upregulation of SOX-2, establishing their inverse correlation. Importantly, we broadly uncover an inverse correlation of SFRP1 and SOX-2 in epithelial cancers that may be used as a potential prognostic marker in the management of cancer. •Loss of Sfrp1 accelerates murine skin tumor initiation and SCC progression•Sfrp1 loss enhances in vivo tumorigenic potential of murine skin CSCs•We found enhanced EMT and Sox-2 in Sfrp1−/− murine skin SCC•Sfrp1 and Sox-2 are inversely correlated in multiple human epithelial cancers Dr. Waghmare and his colleagues showed the importance of Sfrp1 in mouse skin tumor initiation and CSC regulation. Sfrp1 loss enhanced in vivo tumorigenic potential of CSCs with upregulation of EMT and stemness markers. Sfrp1 and Sox-2 showed an inverse correlation in multiple human epithelial cancers with poor overall survival. Therefore, Sfrp1 can be used as a prognostic marker in human epithelial cancers.