IL-4, a direct target of miR-340/429, is involved in radiation-induced aggressive tumor behavior in human carcinoma cells

Oncotarget. 2016 Dec 27;7(52):86836-86856. doi: 10.18632/oncotarget.13561.


Radiotherapy induces the production of cytokines, thereby increasing aggressive tumor behavior. This radiation effect results in the failure of radiotherapy and increases the mortality rate in patients. We found that interleukin-4 (IL-4) and IL-4Rα (IL-4 receptor) are highly expressed in various human cancer cells subsequent to radiation treatment. In addition, IL-4 is highly overexpressed in metastatic carcinoma tissues compared with infiltrating carcinoma tissues. High expression of IL-4 in patients with cancer is strongly correlated with poor survival. The results of this study suggest that radiation-induced IL-4 contributes to tumor progression and metastasis. Radiation-induced IL-4 was associated with tumorigenicity and metastasis. IL-4 expression was downregulated by miR-340 and miR-429, which were decreased by ionizing radiation (IR). Radiation-regulated miR-340/429-IL4 signaling increased tumorigenesis and metastasis by inducing the production of Sox2, Vimentin, VEGF, Ang2, and MMP-2/9 via activating JAK, JNK, β-catenin, and Stat6 in vitro and in vivo. Our study presents a conceptual advance in our understanding of the modification of tumor microenvironment by radiation and suggests that combining radiotherapy with genetic therapy to inhibit IL-4 may be a promising strategy for preventing post-radiation recurrence and metastasis in patients.

Keywords: interleukin-4; metastasis; miR-340/429; radiation; tumorigenicity.

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / radiotherapy*
  • Cell Line, Tumor
  • Cells, Cultured
  • Female
  • Gene Expression Regulation, Neoplastic / radiation effects*
  • HEK293 Cells
  • Humans
  • Interleukin-4 / genetics*
  • Interleukin-4 / metabolism
  • Interleukin-4 Receptor alpha Subunit / genetics
  • Interleukin-4 Receptor alpha Subunit / metabolism
  • MCF-7 Cells
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / genetics*
  • RNA Interference
  • Signal Transduction / genetics
  • Signal Transduction / radiation effects
  • Xenograft Model Antitumor Assays / methods
  • beta Catenin / genetics
  • beta Catenin / metabolism


  • IL4 protein, human
  • IL4R protein, human
  • Interleukin-4 Receptor alpha Subunit
  • MIRN340 microRNA, human
  • MIRN429 microRNA, human
  • MicroRNAs
  • beta Catenin
  • Interleukin-4