Tumour YAP1 and PTEN expression correlates with tumour-associated myeloid suppressor cell expansion and reduced survival in colorectal cancer

Immunology. 2018 Oct;155(2):263-272. doi: 10.1111/imm.12949. Epub 2018 Jun 11.

Abstract

The expansion of myeloid-derived suppressor cells (MDSCs) correlates with tumorigenesis in colorectal cancer (CRC). Here, we found a significant association between CD33+ MDSC number and Yes-associated protein 1 (YAP1) and phosphatase and tensin homologue (PTEN) levels in CRC patients (P < 0·05). Moreover, the CD33+ MDSCs, YAP1 and PTEN were identified as predictors for the prognosis of CRC patients (P < 0·05). Notably, CD33+ MDSCs were an independent survival predictor for CRC patients through a Cox model analysis. In vitro data determined that the expression levels of YAP1 and PTEN in CRC-derived cell lines were associated with CRC-derived MDSC induction, and the blockade of YAP1 and PTEN decreased CRC-derived MDSC induction. A mechanistic analysis revealed that YAP1 promoted CRC-derived MDSC induction by suppressing PTEN expression to up-regulate COX-2, P-AKT and P-p65 in CRC-derived cells, leading to secretion of the cytokine granulocyte-macrophage colony-stimulating factor. Our findings establish a novel mechanism of pro-tumorigenic MDSC induction mediated by ectopic YAP1 and PTEN expression in CRC.

Keywords: colorectal cancer; myeloid-derived suppressor cell; phosphatase and tensin homologue; prognosis; yes-associated protein 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers
  • Biomarkers, Tumor*
  • Cell Proliferation
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / immunology*
  • Colorectal Neoplasms / mortality
  • Colorectal Neoplasms / pathology
  • Female
  • Gene Expression Regulation, Neoplastic
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Humans
  • Male
  • Middle Aged
  • Myeloid-Derived Suppressor Cells / immunology*
  • Myeloid-Derived Suppressor Cells / metabolism*
  • Neoplasm Grading
  • Neoplasm Staging
  • PTEN Phosphohydrolase / genetics*
  • PTEN Phosphohydrolase / metabolism
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism
  • Prognosis
  • Transcription Factors
  • Tumor Microenvironment
  • YAP-Signaling Proteins
  • Young Adult

Substances

  • Adaptor Proteins, Signal Transducing
  • Biomarkers
  • Biomarkers, Tumor
  • Phosphoproteins
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • PTEN Phosphohydrolase
  • PTEN protein, human