title: Precise let-7 expression levels balance organ regeneration against tumor suppression.
abstract: The in vivo roles for even the most intensely studied microRNAs remain poorly defined. Here, analysis of mouse models revealed that let-7, a large and ancient microRNA family, performs tumor suppressive roles at the expense of regeneration. Too little or too much let-7 resulted in compromised protection against cancer or tissue damage, respectively. Modest let-7 overexpression abrogated MYC-driven liver cancer by antagonizing multiple let-7 sensitive oncogenes. However, the same level of overexpression blocked liver regeneration, while let-7 deletion enhanced it, demonstrating that distinct let-7 levels can mediate desirable phenotypes. let-7 dependent regeneration phenotypes resulted from influences on the insulin-PI3K-mTOR pathway. We found that chronic high-dose let-7 overexpression caused liver damage and degeneration, paradoxically leading to tumorigenesis. These dose-dependent roles for let-7 in tissue repair and tumorigenesis rationalize the tight regulation of this microRNA in development, and have important implications for let-7 based therapeutics.
authors.affiliation: Children's Research Institute, Departments of Pediatrics and Internal Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States.|Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.|Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Linwei
authors.initials: L
authors.lastname: Wu
authors.affiliation: Children's Research Institute, Departments of Pediatrics and Internal Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States.|Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Liem H
authors.initials: LH
authors.lastname: Nguyen
authors.affiliation: Simmons Comprehensive Cancer Center, Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Kejin
authors.initials: K
authors.lastname: Zhou
authors.affiliation: Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, United States.|Harvard Stem Cell Institute, Harvard University, Boston, United States.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.|The Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, United States.
authors.forename: T Yvanka
authors.initials: TY
authors.lastname: de Soysa
authors.affiliation: Children's Research Institute, Departments of Pediatrics and Internal Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States.|Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Simmons Comprehensive Cancer Center, Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Jason B
authors.initials: JB
authors.lastname: Miller
authors.affiliation: Department of Pathology, University of Pittsburg, Pittsburg, United States.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Tian
authors.affiliation: Department of Pathology, University of Pittsburg, Pittsburg, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Locker
authors.affiliation: Children's Research Institute, Departments of Pediatrics and Internal Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States.|Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, United States.|Harvard Stem Cell Institute, Harvard University, Boston, United States.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.|The Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, United States.
authors.forename: Gen
authors.initials: G
authors.lastname: Shinoda
authors.affiliation: Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, United States.|Harvard Stem Cell Institute, Harvard University, Boston, United States.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.|The Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, United States.
authors.forename: Marc T
authors.initials: MT
authors.lastname: Seligson
authors.affiliation: Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States.|Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Lauren R
authors.initials: LR
authors.lastname: Zeitels
authors.affiliation: Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States.|Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Asha
authors.initials: A
authors.lastname: Acharya
authors.affiliation: Children's Research Institute, Departments of Pediatrics and Internal Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States.|Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States.|Department of Surgery, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Sam C
authors.initials: SC
authors.lastname: Wang
authors.affiliation: Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States.|Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Mendell
authors.affiliation: Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Xiaoshun
authors.initials: X
authors.lastname: He
authors.affiliation: Howard Hughes Medical Institute, Children's Research Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Jinsuke
authors.initials: J
authors.lastname: Nishino
authors.affiliation: Howard Hughes Medical Institute, Children's Research Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Morrison
authors.affiliation: Simmons Comprehensive Cancer Center, Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Daniel J
authors.identifier: http://orcid.org/0000-0003-3823-1931
authors.initials: DJ
authors.lastname: Siegwart
authors.affiliation: Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, United States.|Harvard Stem Cell Institute, Harvard University, Boston, United States.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.|The Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, United States.
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
authors.affiliation: Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, United States.|Harvard Stem Cell Institute, Harvard University, Boston, United States.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.|The Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, United States.|Stem cell and Regenerative Biology, Genome Institute of Singapore, Singapore, Singapore.
authors.forename: Ng
authors.initials: N
authors.lastname: Shyh-Chang
authors.affiliation: Children's Research Institute, Departments of Pediatrics and Internal Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States.|Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhu
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis*; D009369:Neoplasms / Q000473:pathology*; D012038:Regeneration
chemical_list: D035683:MicroRNAs; C542687:mirnlet7 microRNA, mouse
keywords: MYC; cancer; cell biology; developmental biology; let-7; liver; microRNA; mouse; regeneration; stem cells