Abstract Purpose: Matrix metalloproteinase-9 (MMP-9), a Zn-dependent endopeptidase is known to play a central role in oral cancer pathogenesis. Recently we observed differential function of MMP-9 and reversion-inducing cysteine-rich protein with Kazal motifs (RECK) respectively in OSCC invasion. We hypothesize that the downregulation of MMP-9 via RECK promotes human oral cancer progression and invasion. Experimental procedure: The mRNA expression, protein expression and activity of MMP-9/2, expression of transcription factors like Snail, c-Myc, β-catenin and protein-protein interaction of TIMP1/RECK with MMP9 and promoter methylation of RECK gene were assessed by using RT-PCR, immunohistochemistry (IHC), Western blotting, co-immunoprecipitation, gelatin zymography, and bisulphate modification-PCR analyses. Wnt5a and LPA mediated MMP-9 regulation as well as the MMP-9 regulation by the exogenously expression of RECK, GSK3β (WT) or non phosphoryable active GSK3β (S9A) was also performed in oral tongue SCC derived SCC-9 cells. Summary: We observed up-regulation/activation of MMP-9 was associated with decreased expression of RECK and progression and invasion of OSCC. MMP-9 expression/ activity was positively correlated with inactivation of GSK3β signaling. Conversely, a link between inactivation of GSK3 signaling and the progressive silencing of RECK gene through promoter hypermethylation was observed. Finally, Wnt5a and LPA mediated increased MMP-9 and decreased RECK expressions were observed. Conclusion: Taken together, these results demonstrated the influence of a novel signaling axis GSK3β-RECK-MMP-9 to drive OSCC progression and invasion. Thus, targeting this pathway may be exploited for treating OSCC. Citation Format: Kamdeo Kumar Pramanik, Basabi Rana, Ajay Rana, Rajakishore Mishra. Expression and regulation of MMP9 and RECK in human oral squamous cell carcinoma progression and invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 103.