title: Cell-Cycle-Targeting MicroRNAs as Therapeutic Tools against Refractory Cancers.
abstract: Cyclins and cyclin-dependent kinases (CDKs) are hyperactivated in numerous human tumors. To identify means of interfering with cyclins/CDKs, we performed nine genome-wide screens for human microRNAs (miRNAs) directly regulating cell-cycle proteins. We uncovered a distinct class of miRNAs that target nearly all cyclins/CDKs, which are very effective in inhibiting cancer cell proliferation. By profiling the response of over 120 human cancer cell lines, we derived an expression-based algorithm that can predict the response of tumors to cell-cycle-targeting miRNAs. Using systemic administration of nanoparticle-formulated miRNAs, we inhibited tumor progression in seven mouse xenograft models, including three treatment-refractory patient-derived tumors, without affecting normal tissues. Our results highlight the utility of using cell-cycle-targeting miRNAs for treatment of refractory cancer types.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02215, USA; Department of Oncology-Pathology, Karolinska Institutet, 17176 Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Hydbring
authors.affiliation: Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, School of Life Sciences, Center for Life Sciences and Center for Statistical Science, Peking University, Beijing 100871, China.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Fassl
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Matia
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Otto
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Yoon Jong
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Katharine E
authors.initials: KE
authors.lastname: Sweeney
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Suski
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Yin
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Roman L
authors.initials: RL
authors.lastname: Bogorad
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Shom
authors.initials: S
authors.lastname: Goel
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Haluk
authors.initials: H
authors.lastname: Yuzugullu
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Kauffman
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Junghoon
authors.initials: J
authors.lastname: Yang
authors.affiliation: Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, School of Life Sciences, Center for Life Sciences and Center for Statistical Science, Peking University, Beijing 100871, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Jin
authors.affiliation: Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Yingxiang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Davide
authors.initials: D
authors.lastname: Floris
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Swanson
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Kimmie
authors.initials: K
authors.lastname: Ng
authors.affiliation: Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Ewa
authors.initials: E
authors.lastname: Sicinska
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Lars
authors.initials: L
authors.lastname: Anders
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jean J
authors.initials: JJ
authors.lastname: Zhao
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Kornelia
authors.initials: K
authors.lastname: Polyak
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Harvard-MIT Division of Health Sciences & Technology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Anderson
authors.affiliation: Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, School of Life Sciences, Center for Life Sciences and Center for Statistical Science, Peking University, Beijing 100871, China. Electronic address: cheng_li@pku.edu.cn.
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02215, USA. Electronic address: peter_sicinski@dfci.harvard.edu.
authors.forename: Piotr
authors.initials: P
authors.lastname: Sicinski
mesh_terms: D020413:3' Untranslated Regions; D000465:Algorithms; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D006801:Humans; D008815:Mice, Inbred Strains; D035683:MicroRNAs / Q000008:administration & dosage / Q000235:genetics* / Q000494:pharmacology; D009154:Mutation; D053758:Nanoparticles; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; C117307:KRAS protein, human; C546818:MIRN193 microRNA, human; D035683:MicroRNAs; D016283:Proto-Oncogene Proteins p21(ras)
keywords: cancers; cell cycle; cyclin-dependent kinases; cyclins; microRNAs