Tumor growth suppressive effect of IL-4 through p21-mediated activation of STAT6 in IL-4Rα overexpressed melanoma models
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Hye Lim Lee1,*, Mi Hee Park1,*, Ju Kyoung Song1, Yu Yeon Jung1, Youngsoo Kim1, Kyung Bo Kim2, Dae Yeon Hwang3, Do Young Yoon4, Min Jong Song5, Sang Bae Han1, Jin Tae Hong1
1College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, 361-951, Republic of Korea
2Department of Pharmaceutical Science, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536, USA
3Department of Biomaterial Science, Pusan National University, Miryang, Kyungnam, 627-706, Republic of Korea
4Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Gwangjin-gu, Seoul, 143-701, Republic of Korea
5Department of Obstetrics and Gynecology, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Jung-gu, Daejeon, 301-723, Republic of Korea
*These authors contributed equally to this work
Jin Tae Hong, e-mail: firstname.lastname@example.org
Sang Bae Han, e-mail: email@example.com
Keywords: IL-4, STAT6, p21, melanoma, tumor growth
Received: August 30, 2015 Accepted: February 28, 2016 Published: March 16, 2016
To evaluate the significance of interleukin 4 (IL-4) in tumor development, we compared B16F10 melanoma growth in IL-4-overespressing transgenic mice (IL-4 mice) and non-transgenic mice. In IL-4 mice, reduced tumor volume and weight were observed when compared with those of non-transgenic mice. Significant activation of DNA binding activity of STAT6, phosphorylation of STAT6 as well as IL-4, IL-4Rα and p21 expression were found in the tumor tissues of IL-4 mice compared to non-transgenic mice. Higher expression of IL-4, STAT6 and p21 in human melanoma tissue compared to normal human skin tissue was also found. Higher expression of apoptotic protein such as cleaved caspase-3, cleaved caspase-8, cleaved caspase-9, Bax, p53 and p21, but lower expression levels of survival protein such as Bcl-2 were found in the tumor of IL-4 mice. In vitro study, we found that overexpression of IL-4 significantly inhibited SK-MEL-28 human melanoma cell and B16F10 murine melanoma cell growth via p21-mediated activation of STAT6 pathway as well as increased expression of apoptotic cell death proteins. Moreover, p21 knockdown with siRNA abolished IL-4 induced activation of STAT6 and expression of p53 and p21 accompanied with reduced IL-4 expression as well as melanoma cell growth inhibition. Therefore, these results showed that IL-4 overexpression suppressed tumor development through p21-mediated activation of STAT6 pathways in melanoma models.
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