Enhanced spontaneous metastasis in bikunin-deficient mice.
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.
Yagyu
Tatsuo
T
NetForce Co., Ltd., Nakamura, Nagoya, Aichi, Japan.
Kobayashi
Hiroshi
H
Matsuzaki
Hidenori
H
Wakahara
Kiyoshi
K
Kondo
Toshiharu
T
Kurita
Noriyuki
N
Sekino
Hideo
H
Inagaki
Kiyokazu
K
D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000473:pathology*; D020022:Genetic Predisposition to Disease; D008175:Lung Neoplasms / Q000235:genetics / Q000503:physiopathology* / Q000556:secondary*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis; D014360:Trypsin Inhibitor, Kunitz Soybean / Q000235:genetics*; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis
D008562:Membrane Glycoproteins; D017395:Plasminogen Activator Inhibitor 1; C109148:SPINT2 protein, human; D014360:Trypsin Inhibitor, Kunitz Soybean; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D014568:Urokinase-Type Plasminogen Activator