Inhibition of matrix metalloproteinase-2 modulates malignant behaviour of oral squamous cell carcinoma cells

Antonio Celentano; Tami Yap; Rita Paolini; Callisthenis Yiannis; Michiko Mirams; Kendrick Koo; Michael McCullough; Nicola Cirillo

doi:10.1111/jop.12992

Inhibition of matrix metalloproteinase-2 modulates malignant behaviour of oral squamous cell carcinoma cells

J Oral Pathol Med. 2021 Mar;50(3):323-332. doi: 10.1111/jop.12992. Epub 2020 Jan 27.

Authors

Antonio Celentano¹, Tami Yap¹, Rita Paolini¹, Callisthenis Yiannis¹, Michiko Mirams², Kendrick Koo³, Michael McCullough¹, Nicola Cirillo¹

Affiliations

¹ Melbourne Dental School, The University of Melbourne, Melbourne, VIC, Australia.
² School of BioSciences, Faculty of Science, The University of Melbourne, Melbourne, VIC, Australia.
³ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.

PMID: 31925966
DOI: 10.1111/jop.12992

Abstract

Background: Matrix metalloproteinases (MMPs) play a crucial role in the malignant phenotype of cancer cells. In particular, active levels of MMP2 in cancer cells have been associated with invasion and metastasis through the degradation of basement membrane extracellular matrix proteins. However, little is known about the role of this potential biomarker in oral cancer. Our aim was to investigate the effect of MMP2 inhibition on OSCC activity in vitro, as well as to assess MMP2 dysregulation in oral cancer samples.

Methods: Human OSCC cell lines H357 and H400 were tested with the selective MMP2 inhibitor ARP101 and the MMP2 neutralising monoclonal antibody MA5-13590 to assess cell proliferation in vitro using MTS assay. Cell migration at 12/24 h was assessed using a Transwell migration assay. Cell invasion was assessed at 24 h using a Corning Matrigel invasion assay. MMP2 expression was assessed in 208 tissue samples (related to 60 OSCC cases and nine normal control) using tissue microarray (TMA) and further analysed via TCGA.

Results: Both ARP101 and MA5-13590 monoclonal antibody reduced cell proliferation in both the cell lines tested. Treatment with 4μg/mL of MMP2 monoclonal antibody showed a significant decrease in cell migration at 24 hours. The administration of ARP101 and monoclonal antibody to H357 and H400 cell lines induced a drastic reduction in cell invasion at 24 h compared to the control. In patients, TCGA analysis demonstrated that oral cancer tissues express significantly higher levels of MMP2 mRNA compared to normal oral tissues. Further, IHC analysis on TMA showed significant difference in MMP2 protein expression between low and high histopathological grade OSCC.

Conclusions: We have demonstrated, for the first time, that MMP2 inhibition affects oral cancer cells ability to survive, migrate and invade in vitro. Differences between MMP2 expression in normal and malignant tissues varied. Further research on the role of MMP2 in OSCC and novel mechanisms to inhibit MMP2-dependent pathways should be encouraged.

Keywords: MMP2; keratinocytes; matrix metalloproteinases; oral cancer.

MeSH terms

Carcinoma, Squamous Cell*
Cell Line, Tumor
Cell Movement
Head and Neck Neoplasms*
Humans
Matrix Metalloproteinase 2
Mouth Neoplasms*
Squamous Cell Carcinoma of Head and Neck

Substances

Matrix Metalloproteinase 2