TGF-β1 facilitates MT1-MMP-mediated proMMP-9 activation and invasion in oral squamous cell carcinoma cells

Hirari Yamahana; Minoru Terashima; Risa Takatsuka; Chikako Asada; Takeshi Suzuki; Yoshihiro Uto; Takahisa Takino

doi:10.1016/j.bbrep.2021.101072

TGF-β1 facilitates MT1-MMP-mediated proMMP-9 activation and invasion in oral squamous cell carcinoma cells

Biochem Biophys Rep. 2021 Jul 27:27:101072. doi: 10.1016/j.bbrep.2021.101072. eCollection 2021 Sep.

Authors

Hirari Yamahana¹, Minoru Terashima², Risa Takatsuka², Chikako Asada¹, Takeshi Suzuki², Yoshihiro Uto¹, Takahisa Takino³

Affiliations

¹ Graduate School of Technology, Industrial and Social Science, Tokushima University, Tokushima 770-8506, Japan.
² Division of Functional Genomics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
³ Division of Education for Global Standard, Institute of Liberal Arts and Science, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.

Abstract

Matrix metalloproteinase (MMP)-2 and MMP-9, also known as gelatinases or type IV collagenases, are recognized as major contributors to the proteolytic degradation of extracellular matrix during tumor invasion. Latent MMP-2 (proMMP-2) is activated by membrane type 1 MMP (MT1-MMP) on the cell surface of tumor cells. We previously reported that cell-bound proMMP-9 is activated by the MT1-MMP/MMP-2 axis in HT1080 cells treated with concanavalin A in the presence of exogenous proMMP-2. However, the regulatory mechanism of proMMP-9 activation remains largely unknown. Transforming growth factor (TGF)-β1 is frequently overexpressed in tumor tissues and is associated with tumor aggressiveness and poor prognosis. In this study, we examined the role of TGF-β1 on MT1-MMP-mediated proMMP-9 activation using human oral squamous cell carcinoma cells. TGF-β1 significantly increased the expression of MMP-9. By adding exogenous proMMP-2, TGF-β1-induced proMMP-9 was activated during collagen gel culture, which was suppressed by the inhibition of TGF-β1 signaling or MT1-MMP activity. This MT1-MMP-mediated proMMP-9 activation was needed to facilitate TGF-β1-induced cell invasion into collagen gel. Thus, TGF-β1 may facilitate MT1-MMP-mediated MMP-9 activation and thereby stimulate invasion of tumor cells in collaboration with MT1-MMP and MMP-2.

Keywords: ADAM, a disintegrin and metalloproteinase; Con A, concanavalin A; DMEM, Dulbecco's modified Eagle's medium; ECM; ECM, extracellular matrix; FBS, fetal bovine serum; Invasion; MAPK, mitogen-activated protein kinase; MMP; MMP, matrix metalloproteinase; MT1-MMP, membrane type-1 MMP; OSCC, oral squamous cell carcinoma; Oral cancer; PBS, phosphate-buffered saline; TGF, transforming growth factor; TGF-β1; TIMP, tissue inhibitor of MMP.