IL-13/STAT6 signaling plays a critical role in the epithelial-mesenchymal transition of colorectal cancer cells

Oncotarget. 2016 Sep 20;7(38):61183-61198. doi: 10.18632/oncotarget.11282.

Abstract

Colorectal cancer (CRC) is one of the most common causes of cancer-related death worldwide due to the distant metastases. Compelling evidence has reported that epithelial-mesenchymal transition (EMT) is involved in promoting cancer invasion and metastasis. However, the precise molecular events that initiate this complex EMT process remain poorly understood. Here, we showed that the pleiotropic cytokine interleukin-13 (IL-13) could induce an aggressive phenotype displaying EMT by enhancing the expression of EMT-promoting factor ZEB1. Importantly, STAT6 signaling inhibitor and STAT6 knockdown significantly reversed IL-13-induced EMT and ZEB1 induction in CRC cells, whereas ectopic STAT6 expression in STAT6null CRC cell line markedly promoted EMT in the present of IL-13. ChIP-PCR and Luciferase assays revealed that activated STAT6 directly bound to the promoter of ZEB1. Otherwise, we found IL-13 also up-regulated the stem cell markers (nanog, CD44, CD133 and CD166) and promoted cell migration and invasion through STAT6 pathway. We also found that siRNA-mediated knockdown of IL-13Rα1 could reverse IL-13-induced ZEB1 and EMT changes by preventing STAT6 signaling. Finally, we demonstrated positive correlation between IL-13Rα1 and ZEB1 at mRNA levels in human CRC samples. Taken together, our findings first demonstrated that IL-13/IL-13Rα1/STAT6/ZEB1 pathway plays a critical role in promoting EMT and aggressiveness of CRC.

Keywords: EMT; STAT6; ZEB1; colorectal cancer; interleukin-13.

MeSH terms

  • Caco-2 Cells
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Epithelial-Mesenchymal Transition*
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Interleukin-13 / metabolism*
  • Neoplasm Invasiveness
  • Phosphorylation
  • Promoter Regions, Genetic
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Receptors, Interleukin-13 / metabolism*
  • STAT6 Transcription Factor / metabolism*
  • Signal Transduction
  • Stem Cells / metabolism
  • Zinc Finger E-box-Binding Homeobox 1 / metabolism*

Substances

  • Interleukin-13
  • RNA, Small Interfering
  • Receptors, Interleukin-13
  • STAT6 Transcription Factor
  • STAT6 protein, human
  • ZEB1 protein, human
  • Zinc Finger E-box-Binding Homeobox 1
  • interleukin-13 receptor, human