RAB27B-activated secretion of stem-like tumor exosomes delivers the biomarker microRNA-146a-5p, which promotes tumorigenesis and associates with an immunosuppressive tumor microenvironment in colorectal cancer

Int J Cancer. 2019 Oct 15;145(8):2209-2224. doi: 10.1002/ijc.32338. Epub 2019 Apr 30.

Abstract

The dynamic cell-cell communication is essential for tissue homeostasis in normal physiological circumstances and contributes to a diversified tumor microenvironment. Although exosomes are extracellular vesicles that actively participate in cell-cell interaction by shutting cellular components, impacts of tumor exosomes in the context of cancer stemness remain elusive. Here, we expand colorectal cancer stem cells (CRCSCs) as cancer spheroids and demonstrate that the β-catenin/Tcf-4-activated RAB27B expression is required for the secretion of CRCSC exosomes. In an exosomal RNA sequencing analysis, a switch of exosomal RNA species from retrotransposons to microRNAs (miRNAs) is identified upon expanding CRCSCs. miRNA-146a-5p (miR-146a) is the major miRNA in CRCSC exosomes and exosomal miR-146a promotes stem-like properties and tumorigenicity by targeting Numb in recipient CRC cells. Among 53 CRC patients, those with abundant exosomal miR-146a expression in serum exhibits higher miR-146aHigh /NumbLow CRCSC traits, an increased number of tumor-filtrating CD66(+) neutrophils and a decreased number of tumor-infiltrating CD8(+) T cells. Our study elucidates a unique mechanism of tumor exosome-mediated stemness expansion.

Keywords: cancer stem cells; exosome heterogeneity; microRNA biomarker.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers, Tumor / genetics*
  • Carcinogenesis / genetics
  • Cell Line, Tumor
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Exosomes / genetics*
  • Exosomes / metabolism
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • HT29 Cells
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • MicroRNAs / genetics*
  • Neoplastic Stem Cells / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • RNA Interference
  • Tumor Microenvironment / genetics
  • rab GTP-Binding Proteins / genetics*
  • rab GTP-Binding Proteins / metabolism

Substances

  • Biomarkers, Tumor
  • MIRN146 microRNA, human
  • Membrane Proteins
  • MicroRNAs
  • Nerve Tissue Proteins
  • Numb protein, human
  • Rab27B protein, human
  • rab GTP-Binding Proteins