title: Homo sapiens systemic RNA interference-defective-1 transmembrane family member 1 (SIDT1) protein mediates contact-dependent small RNA transfer and microRNA-21-driven chemoresistance.
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.
authors.affiliation: Clinical Surgery, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, Scotland, United Kingdom.
authors.forename: Mohamed O
authors.initials: MO
authors.lastname: Elhassan
authors.forename: Jennifer
authors.initials: J
authors.lastname: Christie
authors.forename: Mark S
authors.initials: MS
authors.lastname: Duxbury
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology; D001483:Base Sequence; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D020868:Gene Silencing; D057809:HEK293 Cells; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: C524940:MIRN21 microRNA, human; D026901:Membrane Transport Proteins; D035683:MicroRNAs; D034741:RNA, Small Interfering; C571194:systemic RNA Interference-defective-1 transmembrane family member 1, human