Squamous cell carcinoma antigen (SCCA) is clinically used as a
tumor marker for patients with
squamous cell carcinoma of various organs. SCCA1 and its highly homologous molecule, SCCA2, belong to the
serine proteinase inhibitors (
serpins) family, suggesting that these
proteins may be involved in the malignant behavior of
squamous cell carcinoma cells. The aim of this study is to functionally characterize these
tumor-associated
serpins regarding the potential to influence the production of
matrix metalloproteinases (
MMPs), which play a key role in
tumor cell invasion and
metastasis. Cervical
squamous cell carcinoma cell lines, CaSki cells and SKG-IIIa cells were incubated with SCCA1 or SCCA2 and
MMP production was analyzed by
gelatin zymography. Both SCCA1 and SCCA2 significantly increased production of
proMMP-9, but not
proMMP-2. These stimulatory effects were still observed when cells were treated with SCCA mutants lacking the
proteinase inhibitory activity of
serpins. Furthermore, treatments with various forms of SCCAs, which are generated by interacting with their target
proteinases, diminished the stimulatory effect of SCCAs, implying the importance of the conformational structure of SCCAs in the stimulatory effects of SCCAs on
proMMP-9 production. In addition, in vitro invasion assay showed that SCCA1 and SCCA2 significantly promoted the activity of cell invasion. It is concluded that SCCAs can alter the invasive phenotype of cervical
squamous cell carcinoma cells, probably by stimulating
proMMP-9 production, and that intact conformational structure of SCCAs, but not
proteinase inhibitory activity of
serpins, is required for its stimulatory activity on
proMMP-9 production.