Disruption of CADM1-dependent cell-cell adhesion in human oral squamous cell carcinoma cells results in tumor progression, possibly through an increase of MMP-2 and MMP-9 expression

Abstract

Objectives: This study aimed to clarify the molecular mechanism underlying the higher invasion and metastasis abilities of LMF4 cells than those of HSC-3 cells by comparing the expression levels of the tumor suppressor factor, cell adhesion molecule 1 (CADM1).

Methods: We explored 1) whether CADM1 expression level was downregulated in LMF4 cells compared with HSC-3 cells, 2) whether CADM1 expression knockdown increased the expression levels of matrix metalloproteinases (MMPs), 3) the exact cellular signaling pathways responsible for increased MMP expression after knockdown of CADM1 expression, and 4) whether disruption of CADM1-dependent HSC-3 cell adhesion increased the migratory and invasive activities of HSC-3 cells.

Results: CADM1 expression was lower in the LMF4 than in the HSC-3 cells. The knockdown of CADM1 increased the expression of MMP-2 and MMP-9 in HSC-3 cells. In addition, the upregulation of MMP-2 expression after CADM1 knockdown was abrogated by the mitogen-activated protein (MAP)/extracellular signal-regulated kinase kinase (MEK) inhibitor U0126 and the phosphoinositide 3-kinase (PI3K) inhibitor LY294002. The upregulation of MMP-9 expression after the knockdown of CADM1 was abrogated by the c-Jun N-terminal kinase (JNK) inhibitor SP600125 and the p38 MAP kinase (MAPK) inhibitor SB203580 and LY294002. Anti-CADM1 neutralizing antibody evoked migratory and invasive abilities of HSC-3 cells.

Conclusion: The disruption of CADM1-dependent cell-cell adhesion in human oral squamous cell carcinoma cells resulted in tumor progression, possibly through an increase in MMP-2 expression in a MEK/PI3K-dependent manner and an increase in MMP-9 expression in a JNK/p38 MAPK/PI3K-dependent manner.

Keywords: Cell adhesion; Cell adhesion molecule 1; Invasion; Matrix metalloproteinase; Oral squamous cell carcinoma.