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Enhanced spontaneous metastasis in bikunin‐deficient mice
Author(s) -
Yagyu Tatsuo,
Kobayashi Hiroshi,
Matsuzaki Hidenori,
Wakahara Kiyoshi,
Kondo Toshiharu,
Kurita Noriyuki,
Sekino Hideo,
Inagaki Kiyokazu
Publication year - 2005
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21293
Subject(s) - downregulation and upregulation , metastasis , cancer research , phosphorylation , plasminogen activator , chemistry , biology , endocrinology , cancer , medicine , microbiology and biotechnology , biochemistry , gene
Previously, we showed that bikunin, a Kunitz‐type protease inhibitor, inhibits invasion and metastasis in several types of cancer cells possibly through suppression of upregulation of urokinase‐type plasminogen activator (uPA) expression. Bikunin corresponds to a light chain of the inter‐alpha inhibitor. To explore critical role of endogenous bikunin, we used bikunin knockout (Bik−/−) mice. Here, we show that 1) higher frequency of spontaneous 3LL lung metastasis was observed in Bik−/− mice compared to Bik+/+ mice, suggesting that bikunin deficiency increases the sensitivity of mice to lung metastasis; 2) administration of exogenous bikunin caused a significant reduction of lung metastasis in Bik−/− and Bik+/+ mice; 3) primary and metastatic tumors significantly upregulated uPA and PAI‐1 expression in Bik−/− mice relative to Bik+/+ mice at least through phosphorylation of ERK1/2 and 4) exogenous bikunin suppressed phosphorylation of ERK1/2 and upregulation of uPA and PAI‐1 expression in 3LL cells in response to G‐CSF. These data allow us to conclude that the increased sensitivity of Bik−/− mice to lung metastasis in vivo is due to a lack of circulating proteins of the inter‐alpha inhibitor family, especially bikunin. © 2005 Wiley‐Liss, Inc.