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Secretory mechanisms and intercellular transfer of microRNAs in living cells

Nobuyoshi Kosaka1, Haruhisa Iguchi, Yusuke Yoshioka

  • 1Section for Studies on Metastasis, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.

The Journal of Biological Chemistry
|April 1, 2010
PubMed

Insights

Extracellular microRNAs (miRNAs) are released via a ceramide-dependent pathway involving neutral sphingomyelinase 2 (nSMase2). These secreted miRNAs are functional, transferable, and can inhibit recipient cell growth.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Circulating microRNAs (miRNAs) in cancer patients suggest potential as diagnostic markers.
  • The mechanisms governing the secretion and function of extracellular miRNAs are not fully understood.

Purpose of the Study:

  • To elucidate the secretory pathway of extracellular miRNAs.
  • To investigate the biological function and intercellular transfer of secreted miRNAs.

Main Methods:

  • Investigated miRNA secretion using inhibitors (GW4869) and genetic manipulation (siRNA, overexpression) of neutral sphingomyelinase 2 (nSMase2).
  • Assessed miRNA release, intercellular transfer, and gene silencing effects in recipient cells.
  • Examined the role of the endosomal sorting complex required for transport (ESCRT) system.

Main Results:

  • miRNA secretion is dependent on ceramide biosynthesis regulated by nSMase2.
  • Inhibition of nSMase2 reduced miRNA secretion, while its overexpression increased extracellular miRNA levels.
  • Secreted miRNAs were shown to be transferable, functional in recipient cells, and capable of inhibiting cell growth, independent of the ESCRT pathway.

Conclusions:

  • Identified a novel ceramide-dependent secretory pathway for miRNAs involving nSMase2.
  • Demonstrated that extracellular miRNAs are functional, transferable, and play a role in intercellular communication and gene regulation.
  • Findings provide insights into the physiological significance of secretory miRNAs in biological processes, including cancer progression.

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