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Article

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

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Division of Biochemistry, Department of Basic Sciences, Loma Linda University, Loma Linda, CA 92354, USA
2
Department of Biology, California State University San Bernardino, San Bernardino, CA 92407, USA
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Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USA
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Beckman Research Institute, City of Hope, Duarte, CA 91016, USA
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Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Loma Linda University Medical Center, Loma Linda, CA 92354, USA
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Center for Health Disparities and Molecular Medicine, Loma Linda University, Loma Linda, CA 92354, USA
*
Author to whom correspondence should be addressed.
Present address: Laboratory for Prediction of Cell Systems Dynamics, RIKEN, Osaka 565-0874, Japan.
Academic Editors: Cinzia Allegrucci and Paloma Ordóñez-Morán
Cancers 2021, 13(6), 1469; https://doi.org/10.3390/cancers13061469
Received: 25 February 2021 / Revised: 15 March 2021 / Accepted: 17 March 2021 / Published: 23 March 2021
(This article belongs to the Special Issue Stemness and Differentiation in Cancer)
When cells undergo epithelial–mesenchymal transition (EMT) they gain characteristics of stem cells. We investigated the mechanism by which the EMT transcription factor SNAI1 induces stem cell features. In these studies, we observed that SNAI1 represses a microRNA that maintains differentiation, let-7. This microRNA is lost in cancer, and its loss correlates with poor prognosis. In breast, pancreatic, and ovarian cancer cell lines the cell stemness in increased by SNAI1 overexpression and reduced by SNAI1 knockdown. We extended the ovarian cancer results to patient-derived cells, and to a mouse xenograft model. In mice, we used nanoparticles to deliver small RNAs (RNAi) targeting SNAI1, resulting in restoration of let-7 levels, inhibition of stemness, and reduced tumor burden. Our studies validate nanoparticle-delivered RNAi targeting SNAI1 as a clinically relevant approach.
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 let-7 repression and acquisition of stemness with the EMT factor, SNAI1. The mechanisms for the loss of let-7 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 SNAI1 overexpression increased stemness and reduced let-7 expression, while SNAI1 knockdown reduced stemness and restored let-7 expression. Rescue experiments demonstrate that the pro-stemness effects of SNAI1 are mediated via let-7. In vivo, nanoparticle-delivered siRNA successfully knocked down SNAI1 in orthotopic patient-derived xenografts, accompanied by reduced stemness and increased let-7 expression, and reduced tumor burden. Chromatin immunoprecipitation demonstrated that SNAI1 binds the promoters of various let-7 family members, and luciferase assays revealed that SNAI1 represses let-7 transcription. In conclusion, the SNAI1/let-7 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. View Full-Text
Keywords: epithelial–mesenchymal transition; stem cells; ovarian cancer; transcriptional regulation; miRNA; orthotopic patient-derived xenografts epithelial–mesenchymal transition; stem cells; ovarian cancer; transcriptional regulation; miRNA; orthotopic patient-derived xenografts
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MDPI and ACS Style

Wang, H.; Chirshev, E.; Hojo, N.; Suzuki, T.; Bertucci, A.; Pierce, M.; Perry, C.; Wang, R.; Zink, J.; Glackin, C.A.; Ioffe, Y.J.; Unternaehrer, J.J. The Epithelial–Mesenchymal Transcription Factor SNAI1 Represses Transcription of the Tumor Suppressor miRNA let-7 in Cancer. Cancers 2021, 13, 1469. https://doi.org/10.3390/cancers13061469

AMA Style

Wang H, Chirshev E, Hojo N, Suzuki T, Bertucci A, Pierce M, Perry C, Wang R, Zink J, Glackin CA, Ioffe YJ, Unternaehrer JJ. The Epithelial–Mesenchymal Transcription Factor SNAI1 Represses Transcription of the Tumor Suppressor miRNA let-7 in Cancer. Cancers. 2021; 13(6):1469. https://doi.org/10.3390/cancers13061469

Chicago/Turabian Style

Wang, Hanmin, Evgeny Chirshev, Nozomi Hojo, Tise Suzuki, Antonella Bertucci, Michael Pierce, Christopher Perry, Ruining Wang, Jeffrey Zink, Carlotta A. Glackin, Yevgeniya J. Ioffe, and Juli J. Unternaehrer 2021. "The Epithelial–Mesenchymal Transcription Factor SNAI1 Represses Transcription of the Tumor Suppressor miRNA let-7 in Cancer" Cancers 13, no. 6: 1469. https://doi.org/10.3390/cancers13061469

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