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

Abstract

Summary: 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. : 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. Keywords: cancer stem cells, CSCs, epithelial to mesenchymal transition, EMT, epithelial cancer, Sfrp1 (secreted frizzled-related protein), tumorigenic potential, skin squamous cell carcinoma, head and neck squamous cell carcinoma, HNSCC