TY - JOUR
T1 - The epithelial–mesenchymal transcription factor snai1 represses transcription of the tumor suppressor miRNA let-7 in cancer
AU - Wang, Hanmin
AU - Chirshev, Evgeny
AU - Hojo, Nozomi
AU - Suzuki, Tise
AU - Bertucci, Antonella
AU - Pierce, Michael
AU - Perry, Christopher
AU - Wang, Ruining
AU - Zink, Jeffrey
AU - Glackin, Carlotta A.
AU - Ioffe, Yevgeniya J.
AU - Unternaehrer, Juli J.
N1 - Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/3/2
Y1 - 2021/3/2
N2 - 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.
AB - 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.
KW - Epithelial–mesenchymal transition
KW - MiRNA
KW - Orthotopic patient-derived xenografts
KW - Ovarian cancer
KW - Stem cells
KW - Transcriptional regulation
UR - http://www.scopus.com/inward/record.url?scp=85102847967&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85102847967&partnerID=8YFLogxK
U2 - 10.3390/cancers13061469
DO - 10.3390/cancers13061469
M3 - Article
SN - 2072-6694
VL - 13
SP - 1
EP - 18
JO - Cancers
JF - Cancers
IS - 6
M1 - 1469
ER -