Open AccessActivation of MMP ‐9 by membrane type‐1 MMP / MMP ‐2 axis stimulates tumor metastasis
Author(s) -
Li Zichen,
Takino Takahisa,
Endo Yoshio,
Sato Hiroshi
Publication year - 2017
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13134
Subject(s) - matrix metalloproteinase , transfection , microbiology and biotechnology , gene knockdown , metalloproteinase , chemistry , receptor , cell culture , biology , biochemistry , genetics
An artificial receptor for pro MMP ‐9 was created by fusing tissue inhibitor of MMP ‐1 ( TIMP ‐1) with type II transmembrane mosaic serine protease ( MSP ‐T1). Expression of MSP ‐T1 in 293T cells induced binding of pro MMP ‐9, which was processed by MMP ‐2 activated by membrane type 1 MMP ( MT 1‐ MMP ). HT 1080 cells transfected with the MSP ‐T1 gene produced activated MMP ‐9 in collagen gel, and addition of pro MMP ‐2 to the culture augmented it, which resulted in intensive collagen digestion. These cells metastasized into chick embryonic liver more than control cells. Treatment of HT 1080 cells with concanavalin A in the presence of exogenous pro MMP ‐2 induced activation of not only pro MMP ‐2 but also pro MMP ‐9. Knockdown of MT 1‐ MMP or TIMP ‐2 expression with si RNA suppressed activation of both pro MMP ‐2 and pro MMP ‐9. Transfection of TIMP ‐1 si RNA suppressed cell binding and activation of pro MMP ‐9, but not pro MMP ‐2 activation. Knockdown of a disintegrin and metalloproteinase 10 ( ADAM 10) expression reduced cell binding and processing of pro MMP ‐9. These results suggest that pro MMP ‐9, which binds to a receptor complex containing TIMP ‐1 and ADAM 10, is activated by the MT 1‐ MMP / MMP ‐2 axis, and MMP ‐9 thus activated stimulates cellular proteolysis and metastasis.