Selective extracellular vesicle exclusion of miR-142-3p by oral cancer cells promotes both internal and extracellular malignant phenotypes

Abstract

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.

Loss‐of‐function of miR‐142 by hypermethylation promotes TGF‐β‐mediated tumour growth and metastasis in hepatocellular carcinoma

“…Cancers are far more complex than realized due to the genetically heterogeneity, which involve with the protean miRNA and long ated with increased vascular density in vivo. 18 We here found that miR-142 was significantly reduced during the development of HCC and TGFβ could be targeted to inhibit the cell vitality, proliferation,…”

Distinct mechanisms of microRNA sorting into cancer cell-derived extracellular vesicle subtypes

“…MiRNAs are ~22 nucleotide transcripts that modulate gene expression at the post-transcriptional level (Bartel 2004). Although the functional importance of EV-miRNAs as signaling molecules has received some support, including in immunologic response and metastatic tumor cell growth (Mittelbrunn et al 2011; Montecalvo et al 2012; Pegtel et al 2010; Fong et al 2015; Dickman et al 2017; Zhou et al 2014; Tominaga et al 2015; Hsu et al 2017), the molecular mechanisms and regulation of sorting miRNAs into EVs remain poorly understood. Both non-selective (Tosar et al 2015) and selective (Shurtleff et al 2016; Santangelo et al 2016; Villarroya-Beltri et al 2013) mechanisms of miRNA sorting into EVs have been described.…”

SVF-derived extracellular vesicles carry characteristic miRNAs in lipedema

“…The majority of single miRNAs showed higher abundance in cCM than in sEVs and only 9 of the analyzed miRNAs showed >50% signal coming from sEVs. miR-142-3p (80% sEV signal), was recently shown by another group to be selectively packaged in sEVs by a panel of oral squamous cell carcinoma cell lines, which resulted in lower intra-cellular levels and promoted malignant changes in these cells via increase of TGFBR1 expression 47 .…”