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Expression of ADAM33 Is a Novel Regulatory Mechanism in IL-18-Secreted Process in Gastric Cancer¹

Kyung-Eun Kim^*, Hyunkeun Song, Candace Hahm, Sun Young Yoon^*, Sunyoung Park^*, Ha-reum Lee^*, Dae Young Hur, Taesung Kim, Cherl-hyun Kim^¶, Sa Ik Bang^||, Jung-Wook Bang^#, Hyunjeong Park^2,** and Dae-Ho Cho^2,*

^* Department of Life Science, Sookmyung Women’s University, Seoul, Republic of Korea; Department of Anatomy, Inje University College of Medicine, Pusan, Republic of Korea; Middlesex School, Concord, MA 01742; School of Life Science and Technology, Korea University Graduate School, Seoul, Republic of Korea; ^¶ Department of Animal Resource and Sciences, Dankook University, Cheonan; Republic of Korea; ^|| Department of Plastic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; ^# Faculty of Medicine, Imperial College London, London, United Kingdom; and ^** Department of Dermatology, St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

IL-18 has recently been reported to play a critical role in tumor migration, invasion, and metastasis. Because IL-18 has various biological activities after its secretion as an 18 kDa mature form, the regulation of the IL-18 secretion process is an important step in tumor progression. This study investigated the implication of IL-18 in vascular endothelial growth factor (VEGF)-D-regulated migration, along with the role of the IL-18 secretion process. VEGF-D enhanced cell migration, which was then blocked by inhibiting IL-18. VEGF-D increased IL-18 expression and secretion, suggesting that IL-18 is a critical mediator for VEGF-D-enhanced migration. VEGF-D induced a disintegrin and metalloprotease 33 (ADAM33) expression, which has a metalloproteinase domain. VEGF-D-enhanced IL-18 secretion and cell migration were inhibited by ADAM33 knock-down. Moreover, cell proliferation was considerably reduced in ADAM33 small interfering RNA transfectants. In conclusion, ADAM33 has a key role in gastric cancer pathogenesis by up-regulating IL-18 secretion process, resulting in increased cell migration and proliferation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant of the Korea Health 21 Research and Development Project, Ministry of Health and Welfare, Republic of Korea (A050569) and the Korea Science and Engineering Foundation (KOSEF) through the Research Center for Women’s Disease (RCWD) at Sookmyung Women’s University, and through the Tumor Immunity Medical Research Center (TIMRC) at Seoul National University College of Medicine.

² Address correspondence and reprint requests to Dr. H. Park, Department of Dermatology, St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea and Dr. D.-H. Cho, Department of Life Science, Sookmyung Women’s University, Chungpa-Dong 2-Ga, Yongsan-Gu Seoul, Republic of Korea. E-mail addresses: hjpark{at}catholic.ac.kr and cdhkor{at}sookmyung.ac.kr

³ Abbreviations used in this paper: VEGF, vascular endothelial growth factor; ADAM, a disintegrin and metalloprotease. siRNA, small interfering RNA.