SKIL facilitates tumorigenesis and immune escape of NSCLC via upregulating TAZ/autophagy axis

Cell Death Dis. 2020 Dec 2;11(12):1028. doi: 10.1038/s41419-020-03200-7.

Abstract

Immune escape is an important mechanism in tumorigenesis. The aim of this study was to investigate roles of SKIL in tumorigenesis and immune escape of non-small-cell lung cancer (NSCLC). SKIL expression levels in NSCLC cell line, clinical sample, and adjacent normal tissue were measured by quantitative PCR, western blot, or immunohistochemistry. Lentivirus was used to overexpress/silence SKIL or TAZ expression. Malignant phenotypes of NSCLC cells were evaluated by colony formation, transwell, and MTT assays, and in xenograft mice model. Syngeneic mice model and flow cytometry were used to evaluate T cell infiltration. Quantitative PCR and western blot were applied to evaluate relevant mRNA and protein levels, respectively. Co-immunoprecipitation was applied to unveil the interaction between SKIL and TAZ. SKIL expression was higher in NSCLC tissue compared to adjacent normal tissue. Silencing of SKIL inhibited malignant phenotypes of NSCLC cells and promoted T cell infiltration. SKIL-knockdown inhibited autophagy and activated the STING pathway in NSCLC cells through down-regulation of TAZ. Silencing of TAZ cancelled the effects of SKIL overexpression on malignant phenotypes and autophagy of NSCLC cells. Inhibition of autophagy reversed the effects of SKIL/TAZ overexpression on the STING pathway. In conclusion, SKIL promoted tumorigenesis and immune escape of NSCLC cells through upregulation of TAZ/autophagy axis and inhibition on downstream STING pathway.

MeSH terms

  • Animals
  • Autophagy*
  • Carcinogenesis / pathology*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / immunology*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Chemokines / metabolism
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Humans
  • Immune Evasion*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / immunology*
  • Lung Neoplasms / pathology
  • Membrane Proteins / metabolism
  • Mice, Inbred BALB C
  • Mice, Nude
  • Phenotype
  • Phosphorylation
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Signal Transduction
  • T-Lymphocytes / immunology
  • Trans-Activators / metabolism*
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • Up-Regulation*

Substances

  • Chemokines
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • SKIL protein, human
  • STING1 protein, human
  • Trans-Activators
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • WWTR1 protein, human