期刊
ONCOGENESIS
卷 10, 期 5, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41389-021-00334-x
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资金
- Academy of Finland [308363]
- Cancer Society of Finland
- Sigrid Juselius Foundation
- Oulu University Hospital
- NSERC Discovery Grant [DGECR-2019-00112]
- CIHR Foundation [FDN148408]
- Canada Research Chair in Protease Proteomics and Systems Biology
- Academy of Finland (AKA) [308363, 308363] Funding Source: Academy of Finland (AKA)
In this study, we identified FXYD5 as a novel substrate of MMP8, which when cleaved by MMP8 or silenced with siRNA, leads to increased cell adhesion and reduced motility in HSC-3 and SCC-25 tongue cancer cells. The findings suggest that targeting FXYD5, a known prognostic factor in OTSCC, may have therapeutic potential in cancer treatment.
Matrix metalloproteinases (MMPs) modify bioactive factors via selective processing or degradation resulting in tumour-promoting or tumour-suppressive effects, such as those by MMP8 in various cancers. We mapped the substrates of MMP8 to elucidate its previously shown tumour-protective role in oral tongue squamous cell carcinoma (OTSCC). MMP8 overexpressing (+) HSC-3 cells, previously demonstrated to have reduced migration and invasion, showed enhanced cell-cell adhesion. By analysing the secretomes of MMP8 + and control cells with terminal amine isotopic labelling of substrates (TAILS) coupled with liquid chromatography and tandem mass spectrometry (LC-MS/MS), we identified 36 potential substrates of MMP8, including FXYD domain-containing ion transport regulator 5 (FXYD5). An anti-adhesive glycoprotein FXYD5 has been previously shown to predict poor survival in OTSCC. Cleavage of FXYD5 by MMP8 was confirmed using recombinant proteins. Furthermore, we detected a loss of FXYD5 levels on cell membrane of MMP8 + cells, which was rescued by inhibition of the proteolytic activity of MMP8. Silencing (si) FXYD5 increased the cell-cell adhesion of control but not that of MMP8 + cells. siFXYD5 diminished the viability and motility of HSC-3 cells independent of MMP8 and similar effects were seen in another tongue cancer cell line, SCC-25. FXYD5 is a novel substrate of MMP8 and reducing FXYD5 levels either with siRNA or cleavage by MMP8 increases cell adhesion leading to reduced motility. FXYD5 being a known prognostic factor in OTSCC, our findings strengthen its potential as a therapeutic target.
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