title: IL-4, a direct target of miR-340/429, is involved in radiation-induced aggressive tumor behavior in human carcinoma cells.
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.
authors.affiliation: Division of Basic Radiation Bioscience, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea.
authors.forename: Eun Sook
authors.initials: ES
authors.lastname: Kim
authors.affiliation: Division of Basic Radiation Bioscience, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea.
authors.forename: Young Eun
authors.initials: YE
authors.lastname: Choi
authors.affiliation: Division of Basic Radiation Bioscience, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea.
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Hwang
authors.affiliation: Division of Basic Radiation Bioscience, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea.
authors.forename: Young-Hoon
authors.initials: YH
authors.lastname: Han
authors.affiliation: Division of Basic Radiation Bioscience, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea.
authors.forename: Myung-Jin
authors.initials: MJ
authors.lastname: Park
authors.affiliation: Division of Basic Radiation Bioscience, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea.
authors.forename: In Hwa
authors.initials: IH
authors.lastname: Bae
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects*; D057809:HEK293 Cells; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics* / Q000378:metabolism; D053662:Interleukin-4 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C508598:IL4 protein, human; C504000:IL4R protein, human; D053662:Interleukin-4 Receptor alpha Subunit; C570046:MIRN340 microRNA, human; C546363:MIRN429 microRNA, human; D035683:MicroRNAs; D051176:beta Catenin; D015847:Interleukin-4
keywords: interleukin-4; metastasis; miR-340/429; radiation; tumorigenicity