Selective extracellular vesicle exclusion of miR-142-3p by oral cancer cells promotes both internal and extracellular malignant phenotypes.
Packaging of small molecular factors, including miRNAs, into small extracellular vesicles (SEVs) may contribute to malignant phenotypes and facilitate communication between cancer cells and tumor stroma. The process by which some miRNAs are enclosed in SEVs is selective rather than indiscriminate, with selection in part governed by specific miRNA sequences. Herein, we describe the selective packaging and removal via SEVs of four miRNAs (miR-142-3p, miR-150-5p, miR-451a, and miR-223-3p) in a panel of oral dysplasia and oral squamous cell carcinoma cell lines. Inhibition of exosome export protein Rab27A increased intracellular concentration of these miRNA candidates and prevented their exclusion via SEVs. Increased intracellular miR-142-3p specifically was found to target TGFBR1, causing a decrease in TGFBR1 expression in donor cells and a reduction of malignant features such as growth and colony formation. Conversely, increased excretion of miR-142-3p via donor cell SEVs and uptake by recipient endothelial cells was found to reduce TGFBR1 activity and cause tumor-promoting changes in these cells in vitro and in vivo.
Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
Christopher T D
CT
Dickman
Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
James
J
Lawson
Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
James
J
Jabalee
Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
Sara A
SA
MacLellan
Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
Nancy E
NE
LePard
Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
Kevin L
KL
Bennewith
Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC Canada.|Division of Otolaryngology, Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
Cathie
C
Garnis
D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism*; D000067128:Extracellular Vesicles / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D014408:Biomarkers, Tumor; C555159:MIRN142 microRNA, human; D035683:MicroRNAs; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse
MiRNA; TGFBR1; exosome; oral dysplasia; oral squamous cell carcinoma