The Epithelial-Mesenchymal Transcription Factor SNAI1 Represses Transcription of the Tumor Suppressor miRNA let-7 in Cancer

We aimed to determine the mechanism of epithelial-mesenchymal transition (EMT)-induced stemness in cancer cells. Cancer relapse and metastasis are caused by rare stem-like cells within tumors. Studies of stem cell reprogramming have linked repression and acquisition of stemness with the EMT factor, . The mechanisms for the loss of in cancer cells are incompletely understood. In four carcinoma cell lines from breast cancer, pancreatic cancer, and ovarian cancer and in ovarian cancer patient-derived cells, we analyzed stem cell phenotype and tumor growth via mRNA, miRNA, and protein expression, spheroid formation, and growth in patient-derived xenografts. We show that treatment with EMT-promoting growth factors or overexpression increased stemness and reduced expression, while knockdown reduced stemness and restored expression. Rescue experiments demonstrate that the pro-stemness effects of are mediated via . In vivo, nanoparticle-delivered siRNA successfully knocked down in orthotopic patient-derived xenografts, accompanied by reduced stemness and increased expression, and reduced tumor burden. Chromatin immunoprecipitation demonstrated that binds the promoters of various 7 family members, and luciferase assays revealed that represses transcription. In conclusion, the / axis is an important component of stemness pathways in cancer cells, and this study provides a rationale for future work examining this axis as a potential target for cancer stem cell-specific therapies.