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J. Biol. Chem. 287 (2): 1397-1405

© 2012 by The American Society for Biochemistry and Molecular Biology, Inc.

Background: Homeostatic cell competitive system between cancerous cells and non-cancerous cells is considered as the reason for tumor initiation.

Results: Exosomal tumor-suppressive microRNAs secreted by non-cancerous cells inhibit the proliferation of cancerous cells.

Conclusion: Exosomal tumor-suppressive microRNAs act as an inhibitory signal for cancer cells in a cell-competitive process.

Significance: This provides a novel insight into a tumor initiation mechanism.

Competitive Interactions of Cancer Cells and Normal Cells via Secretory MicroRNAs*Formula

Nobuyoshi Kosaka{ddagger}1, Haruhisa Iguchi{ddagger}§1, Yusuke Yoshioka{ddagger}2, Keitaro Hagiwara{ddagger}, Fumitaka Takeshita{ddagger}, , and Takahiro Ochiya{ddagger}3

From the {ddagger}Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan,
§Pharmacology Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., 1-98, Kasugadenaka 3-chome, Konohana-ku, Osaka 554-0022, Japan, and
the Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Kanagawa 226-8501, Japan

ABSTRACT Back to Top

Abstract: Normal epithelial cells regulate the secretion of autocrine and paracrine factors that prevent aberrant growth of neighboring cells, leading to healthy development and normal metabolism. One reason for tumor initiation is considered to be a failure of this homeostatic cell competitive system. Here we identify tumor-suppressive microRNAs (miRNAs) secreted by normal cells as anti-proliferative signal entities. Culture supernatant of normal epithelial prostate PNT-2 cells attenuated proliferation of PC-3M-luc cells, prostate cancer cells. Global analysis of miRNA expression signature revealed that a variety of tumor-suppressive miRNAs are released from PNT-2 cells. Of these miRNAs, secretory miR-143 could induce growth inhibition exclusively in cancer cells in vitro and in vivo. These results suggest that secretory tumor-suppressive miRNAs can act as a death signal in a cell competitive process. This study provides a novel insight into a tumor initiation mechanism.

Key Words: Cancer Biology • Cell-Cell Interaction • Exosomes • MicroRNA • Sphingomyelinase • Tumor Microenvironment • Cell Competition • Secretory MicroRNAs • Tumor-suppressive MicroRNAs • Tumor Initiation

Received for publication August 4, 2011. Revision received November 23, 2011.


1 Both authors contributed equally to this work.

2 A Research Fellow of the Japan Society for the Promotion of Science.

3 To whom correspondence should be addressed: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 1-1, Tsukiji, 5-chome, Chuo-ku, Tokyo 104-0045, Japan. Tel.: 81-3-3542-2511 (ext. 4800); Fax: 81-3-3541-2685; E-mail: tochiya{at}

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