Identity of MMP1 and its effects on tumor progression in head and neck squamous cell carcinoma.

Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignant tumor worldwide with high morbidity and mortality. However, the diagnosis and molecular mechanisms of HNSCC remains poor.

Methods: Robust rank aggregation method was performed to excavate the differentially expressed genes (DEGs) in five datasets (GSE6631, GSE13601, GSE23036, GSE30784, GSE107591) from the Gene Expression Omnibus. Search Tool for the Retrieval of Interacting Genes (STRING) database extracted hub genes from the protein-protein interaction network. The expression of the hub genes was validated using expression profile from The Cancer Genome Atlas and Oncomine database. The module analysis and disease-free survival analysis of the hub genes were analyzed by Cytoscape and the Kaplan-Meier curve, respectively. The expression of hub genes was verified in clinical specimens. The functions of MMP1 which is most important in hub genes were explored in vitro and in vivo.

Results: Totally, 235 DEGs were identified in the present study which consists of 103 up-regulated and 132 down-regulated genes which were significantly enriched in the molecular function of calcium ion binding followed in the biological process of skin development. The mainly enriched pathways were ECM (extracellular matrix)-receptor interaction (hsa04512) and protein digestion and absorption (hsa04974). Six hub genes were screened out which showed dramatically increased expression in HNSCC samples compared with normal samples, including COL4A1, MMP1, PLAU, RBP1, SEMA3C, and COL4A2. These hub genes all showed worse disease-free survival with higher expression and were up-regulated in HNSCC clinical samples. MMP1 was proved to promote cell growth, migration, and phosphorylation of AKT in vitro and to promote liver metastasis in vivo.

Conclusion: Bioinformatics analysis identified six key genes in HNSCC. Of these, MMP1 is the most likely biomarker. It activates the AKT pathway and promotes tumor progression.