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

// Eun Sook Kim 1, * , Young Eun Choi 1, * , Su Jin Hwang 1 , Young-Hoon Han 1 , Myung-Jin Park 1 , In Hwa Bae 1 1 Division of Basic Radiation Bioscience, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea * These authors have contributed equally to this work Correspondence to: In Hwa Bae, email: ihbae@kirams.re.kr Keywords: radiation, interleukin-4, miR-340/429, tumorigenicity, metastasis Received: August 10, 2016      Accepted: November 07, 2016      Published: November 24, 2016 ABSTRACT 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.