Interleukin-18 increases metastasis and immune escape of stomach cancer via the downregulation of CD70 and maintenance of CD44.
Cancer cells metastasize to the other site after escaping from the immune system and CD70, CD44 and vascular endothelial growth factor (VEGF) play important roles in this process. It is recently reported that interleukin (IL)-18 is closely related with the pathogenesis of skin tumor. Therefore, we investigated the role of endogenous IL-18 from stomach cancer on the immune escape mechanism and metastasis via the regulation of CD70, CD44 and VEGF expression. IL-18 and IL-18R expressions were not only investigated on tumor tissues (n = 10), and sera (n = 20) from stomach cancer patients, but also on human stomach cancer cell lines. IL-18 and IL-18R expressions were found on stomach cancer cell lines and tumor tissues. In addition, IL-18 levels were elevated in sera from cancer patients (P < 0.05), compared with sera from normal individuals. Changes in CD70, CD44 and VEGF expression by flow cytometry, immunoblotting and enzyme-linked immunosorbent assay and immune susceptibility by (51)Cr-release assay were investigated, after silencing or neutralization of endogenous IL-18. CD70 expression was increased and it increases immune susceptibility of cancer cells. In contrast, CD44 and VEGF expression was decreased and it suppresses neovascularization and the metastasis of stomach cancer. After inoculation of IL-18 small interfering RNA (siRNA)-transfected stomach cancer cells into Balb/C (nu/nu) mice, regression of tumor mass was determined by measuring of tumor size. And the number and location of metastatic lesions were investigated by hematoxylin and eosin staining. The regression of tumor mass and the suppression of metastasis were observed in the mice, which are injected with IL-18 siRNA-transfected cell lines. Our data suggest that endogenous IL-18 might facilitate stomach cancer cell immune escape by suppressing CD70 and increasing metastatic ability by upregulating CD44 and VEGF.
Kang
Jae Seung
JS
Department of Anatomy and Tumor Immunity Medical Research Center, Seoul National University College of Medicine, Yongon-dong, Chongno-gu, Seoul 110-799, Republic of Korea.
Bae
Seyeon Y
SY
Kim
Hangrae R
HR
Kim
Yeong Seok
YS
Kim
Daejin J
DJ
Cho
Byung Joo
BJ
Yang
Han-Kwang
HK
Hwang
Young-Il
YI
Kim
Kyungjae J
KJ
Park
Hong Suk
HS
Hwang
Doukho H
DH
Cho
Daeho J
DJ
Lee
Wang Jae
WJ
D000818:Animals; D053282:CD27 Ligand / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis*; D007107:Immune System; D020382:Interleukin-18 / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D034741:RNA, Small Interfering / Q000378:metabolism; D013274:Stomach Neoplasms / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D053282:CD27 Ligand; D018960:Hyaluronan Receptors; D020382:Interleukin-18; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A