Format

Send to

Choose Destination
Cancer Cell. 2017 Apr 10;31(4):576-590.e8. doi: 10.1016/j.ccell.2017.03.004.

Cell-Cycle-Targeting MicroRNAs as Therapeutic Tools against Refractory Cancers.

Author information

1
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.
2
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.
3
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02215, USA.
4
School of Life Sciences, Tsinghua University, Beijing 100084, China.
5
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
6
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
7
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.
8
Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai 200092, China.
9
Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.
10
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
11
Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
12
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
13
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
14
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.
15
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.
16
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.

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.

KEYWORDS:

cancers; cell cycle; cyclin-dependent kinases; cyclins; microRNAs

PMID:
28399412
PMCID:
PMC5425285
DOI:
10.1016/j.ccell.2017.03.004
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center