Interleukin-18 enhances breast cancer cell migration via down-regulation of claudin-12 and induction of the p38 MAPK pathway.
Interleukin-18 (IL-18) was recently reported to have a pro-tumor effect in various cancers. Increased IL-18 levels in the serum of cancer patients correlated with malignancy, and IL-18 acts a crucial factor for cell migration in gastric cancer and melanoma. Claudins, which are the most important tight junction proteins, are also linked with cancer progression and metastasis. However, the relationship between claudins and IL-18 is not well-understood. Here, we show that the migratory ability of MCF-7 cells was reduced when endogenous IL-18 expression was inhibited with IL-18 siRNA. Moreover, exogenous IL-18 enhanced breast cancer cell migration and suppressed the expression of the tight junction proteins claudin-1, claudin-3, claudin-4, and claudin-12 in MCF-7 cells. Knockdown of claudin-3, claudin-4, and claudin-12, but not claudin-1, increased breast cancer migration with maximal effects observed in claudin-12 siRNA-transfected cells. To investigate whether the mitogen-activated protein kinase (MAPK) signaling pathway is involved in IL-18-induced cell migration and claudin-12 expression, cells were pretreated with SB203580 (an inhibitor of p38 MAPK) or PD98059 (an inhibitor of ERK1/2) prior to the addition of IL-18. Although pretreatment of MCF-7 cells with SB203580 blocked both the enhanced cell migration and the decreased claudin-12 expression, PD98059 only blocked cell migration and did not affect claudin-12 expression. In addition, exogenous IL-18 induced rapid phosphorylation of p38 MAPK. These results suggest that IL-18 is an important factor inducing breast cancer cell migration through down-regulation of claudin-12 and activation of the p38 MAPK pathway.
Department of Plastic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Yoolhee
Y
Yang
Department of Life Science, Sookmyung Women's University, Seoul, Republic of Korea.
Soyoung
S
Cheon
Department of Life Science, Sookmyung Women's University, Seoul, Republic of Korea.
Min Kyung
MK
Jung
Department of Life Science, Sookmyung Women's University, Seoul, Republic of Korea.
Seok Bean
SB
Song
Department of Anatomy, College of Medicine, Chung Ang University, Seoul, Republic of Korea.
Daejin
D
Kim
Department of Dermatology, St Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea.
Hee Jung
HJ
Kim
Department of Dermatology, St Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea.
Hyunjeong
H
Park
Department of Plastic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Electronic address: si55.bang@samsung.com.
Sa Ik
SI
Bang
Department of Life Science, Sookmyung Women's University, Seoul, Republic of Korea. Electronic address: cdhkor@sookmyung.ac.kr.
Daeho
D
Cho
D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D062445:Claudin-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D062465:Claudin-3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D062506:Claudin-4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D057167:Claudins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D061986:MCF-7 Cells; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D019108:Tight Junctions / Q000187:drug effects / Q000502:physiology
C568108:CLDN1 protein, human; C522352:CLDN12 protein, human; C568122:CLDN3 protein, human; C568157:CLDN4 protein, human; D062445:Claudin-1; D062465:Claudin-3; D062506:Claudin-4; D057167:Claudins; D005419:Flavonoids; D007093:Imidazoles; D020382:Interleukin-18; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
Breast cancer; Claudin-12; Interleukin-18 (IL-18); Migration; Tight junction