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PMID: 22174421 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Homo sapiens systemic RNA interference-defective-1 transmembrane family member 1 (SIDT1) protein mediates contact-dependent small RNA transfer and microRNA-21-driven chemoresistance.

The Journal of biological chemistry ·Vol. 287 ·No. 8 ·2012-02-17 ·Pages 5267-77

Elhassan MO, Christie J, Duxbury MS

Abstract

Locally initiated RNA interference (RNAi) has the potential for spatial propagation, inducing posttranscriptional gene silencing in distant cells. In Caenorhabditis elegans, systemic RNAi requires a phylogenetically conserved transmembrane channel, SID-1. Here, we show that a human SID-1 orthologue, SIDT1, facilitates rapid, contact-dependent, bidirectional small RNA transfer between human cells, resulting in target-specific non-cell-autonomous RNAi. Intercellular small RNA transfer can be both homotypic and heterotypic. We show SIDT1-mediated intercellular transfer of microRNA-21 to be a driver of resistance to the nucleoside analog gemcitabine in human adenocarcinoma cells. Documentation of a SIDT1-dependent small RNA transfer mechanism and the associated phenotypic effects on chemoresistance in human cancer cells raises the possibility that conserved systemic RNAi pathways contribute to the acquisition of drug resistance. Mediators of non-cell-autonomous RNAi may be tractable targets for novel therapies aimed at improving the efficacy of current cytotoxic agents.

MeSH Terms
Adenocarcinoma/pathology Base Sequence Cell Adhesion/genetics Cell Line, Tumor Drug Resistance, Neoplasm/genetics Gene Expression Regulation, Neoplastic/genetics Gene Silencing HEK293 Cells Humans Intracellular Space/metabolism Membrane Transport Proteins/metabolism MicroRNAs/genetics RNA, Small Interfering/genetics,metabolism Time Factors
Chemicals
MIRN21 microRNA, human Membrane Transport Proteins MicroRNAs RNA, Small Interfering systemic RNA Interference-defective-1 transmembrane family member 1, human
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Elhassan Mohamed O
Clinical Surgery, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, Scotland, United Kingdom.
Christie Jennifer
Duxbury Mark S
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Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
1083-351X
DOI
10.1074/jbc.M111.318865
Published
2012-02-17
Epub
2011-00-15
Pages
5267-77
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC3285307
Subset
IM
Grants
Chief Scientist Office · CZB/4/693 · United Kingdom
External Links
PubMed source DOI: 10.1074/jbc.M111.318865 PMC Full Text View journal details
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