Introduction
Tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), a regulator of matrix metalloproteinases and inducer of cell behavior signaling pathways, has been identified as a poor prognostic biomarker in various cancers, however its role in head and neck squamous cell carcinoma (HNSCC) remains understudied. Binding of TIMP-1 to its main cell surface receptor, CD63, activates several downstream cellular signaling pathways involved in cell survival, growth, proliferation, and migration. The aim of our study was to further evaluate the prognostic value of TIMP-1 and CD63 expression in HNSCC and evaluate potential mechanisms of this pathway.
Methods
We evaluated associations with survival and clinical variables using RNAseq normalized mRNA expression data from 519 HNSCC primary tumors and 43 matched adjacent normal tissue samples from TCGA. A gene set enrichment analysis was performed across high and low expression groups for these genes.
Results
High expression of TIMP-1 and CD63 are associated with decreased OS and PFI, both independently and through a TIMP1-CD63 interaction, by Kaplan-Meier survival analysis. In evaluating risk of metastatic disease, nodal status was significantly associated with high TIMP-1 and CD63 expression [odds ratio (OR)=1.77, p=0.004; OR=1.65, p=0.01, respectively], and perineural invasion was significantly associated with high CD63 expression (OR=1.68, p=0.01). TIMP-1 mRNA is overexpressed in HNSCC tumors relative to normal tissue with TIMP-1 and CD63 expression having significant positive correlation in HNSCC (r=0.68, p<0.0001). TIMP-1 and CD63 expression are significantly associated with expression of epithelial-mesenchymal transition (EMT) markers and PI3K-AKT pathway genes. Amongst EMT genes, there is significantly positive co-expression with a more mesenchymal state and negative co-expression with a more epithelial state. In the PI3K-AKT pathway, AKT3 and its downstream mediators are significantly co-expressed, raising the possibility of an anti-apoptotic mechanism. While EMT pathway genes were significantly enriched in tumors with high TIMP-1 and high CD63, PI3K pathway genes were not.
Tables & Figures
Figure 1. Kaplan-Meier Survival curves based on (A) TIMP1 and (B) CD63 expression
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