Enhanced spontaneous metastasis in bikunin-deficient mice

Area of Science:

• Biochemistry
• Oncology
• Molecular Biology

Background:

• Bikunin, a Kunitz-type protease inhibitor and light chain of inter-alpha inhibitor, previously demonstrated inhibition of cancer cell invasion and metastasis.
• The precise role of endogenous bikunin in metastasis remains to be fully elucidated.

Purpose of the Study:

• To investigate the critical role of endogenous bikunin in lung metastasis using a bikunin knockout mouse model.
• To explore the molecular mechanisms underlying bikunin's effect on metastasis, focusing on urokinase-type plasminogen activator (uPA) and PAI-1 expression.

Main Methods:

• Utilized bikunin knockout (Bik-/-) and wild-type (Bik+/+) mice for spontaneous metastasis studies.
• Administered exogenous bikunin to assess its therapeutic potential in reducing lung metastasis.
• Analyzed the expression of uPA and PAI-1, and phosphorylation of ERK1/2 in tumor tissues and 3LL cells.

Main Results:

• Bikunin deficiency (Bik-/- mice) significantly increased the frequency of spontaneous 3LL lung metastasis compared to wild-type mice.
• Exogenous bikunin administration markedly reduced lung metastasis in both Bik-/- and Bik+/+ mice.
• Tumors in Bik-/- mice exhibited upregulated uPA and PAI-1 expression, linked to ERK1/2 phosphorylation.
• Exogenous bikunin suppressed ERK1/2 phosphorylation and the upregulation of uPA and PAI-1 in 3LL cells.

Conclusions:

• Endogenous bikunin, particularly circulating inter-alpha inhibitor proteins, plays a crucial role in suppressing lung metastasis.
• Bikunin deficiency enhances susceptibility to lung metastasis, likely through dysregulation of uPA and PAI-1 expression via the ERK1/2 pathway.
• Bikunin represents a potential therapeutic target for inhibiting cancer metastasis.