Enhanced spontaneous metastasis in bikunin-deficient mice

✍ Scribed by Tatsuo Yagyu; Hiroshi Kobayashi; Hidenori Matsuzaki; Kiyoshi Wakahara; Toshiharu Kondo; Noriyuki Kurita; Hideo Sekino; Kiyokazu Inagaki

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: French
• Weight: 209 KB
• Volume: 118
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.21293

✦ Synopsis

Abstract

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.