Juurikka, K., Dufour, A., Pehkonen, K. et al. MMP8 increases tongue carcinoma cell–cell adhesion and diminishes migration via cleavage of anti-adhesive FXYD5. Oncogenesis 10, 44 (2021). https://doi.org/10.1038/s41389-021-00334-x
MMP8 increases tongue carcinoma cell–cell adhesion and diminishes migration via cleavage of anti-adhesive FXYD5
|Author:||Juurikka, K.1,2; Dufour, A.3,4; Pehkonen, K.1,2;|
1Cancer and Translational Medicine Research Unit, Faculty of Medicine, University of Oulu, Oulu, Finland
2Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
3Department of Physiology & Pharmacology, University of Calgary, Calgary, Canada
4Department of Oral Biological and Medical Sciences, Faculty of Dentistry, Centre for Blood Research, and Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada
5Biobank Borealis of Northern Finland, Oulu University Hospital, Oulu, Finland
6Department of Oral and Maxillofacial Diseases, Faculty of Medicine, University of Helsinki, Helsinki, Finland
7Helsinki University Hospital, Helsinki, Finland
8Translational Immunology Research Program (TRIMM), University of Helsinki, Helsinki, Finland
9Research Unit of Biomedicine, Faculty of Medicine, University of Oulu, Oulu, Finland
|Online Access:||PDF Full Text (PDF, 2.9 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2021062339865
|Publish Date:|| 2021-06-23
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.
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
This study received funding from the Academy of Finland (P.Å. #308363), Cancer Society of Finland (T.S.), Sigrid Juselius Foundation (T.S., P.Å.), and Oulu University Hospital (T.S., P.N.). AD and BM were supported by an NSERC Discovery Grant (DGECR-2019-00112). C.M.O. is supported by a CIHR Foundation Grant [FDN148408] and a Canada Research Chair in Protease Proteomics and Systems Biology.
|Academy of Finland Grant Number:||
308363 (Academy of Finland Funding decision)
© The Author(s) 2021. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.