Abstract
Plasminogen activator, urokinase (uPA) is a secreted serine protease whose Dysregulation is often accompanied by various cancers. However, the biological functions and potential mechanisms of PLAU in head and neck squamous cell carcinoma (HNSCC) remain undetermined. Here, the expression, prognosis, function, and coexpression genetic networks of PLAU in HNSCC were investigated by a series of public bioinformatics tools. A Higher PLAU level predicted a poorer clinical outcome. Meanwhile, functional network analysis implied that PLAU and associated genes mainly regulated cell-substrate adhesion, tissue migration, and extracellular matrix binding. The top 4 significantly associated genes are C10orf55, ITGA5, SERPINE1, and TNFRSF12A. Pathway enrichment analysis indicated that PLAU might activate the epithelial-to-mesenchymal transition (EMT) process, which could explain the poor prognosis in HNSCC. Besides, genes associated with PLAU were also enriched in EMT pathways. We further validated the bioinformatics analysis results by in vivo and in vitro experiments. Then, we found that much more PLAU was detected in HNSCC tissues, and the silencing of PLAU inhibit the proliferation, migration, and EMT process of CAL27 cell lines. Notably, the downregulation of PLAU decreased the expression of TNFRSF12A. Moreover, knockdown TNFRSF12A also inhibits cell proliferation and migration. In vivo experiment results indicated that PLAU inhibition could suppress tumor growth. Collectively, PLAU is necessary for tumor progression and can be a diagnostic and prognostic biomarker in HNSCC.
Highlights
Head and neck cancer derives from the oral cavity, pharynx, and other upper aerodigestive tracts, in which head and neck squamous cell carcinoma (HNSCC) is the most common one (Mehanna et al, 2010)
PLAU Is Upregulated in Head and Neck Squamous Cell Carcinoma
The four associated genes identified in this study, TNFRSF12A was validated to be regulated by PLAU and TNFRSF12A downregulation restrains proliferation and migration of CAL-27 cells
Summary
Head and neck cancer derives from the oral cavity, pharynx, and other upper aerodigestive tracts, in which HNSCC is the most common one (Mehanna et al, 2010). Carcinogenic factors of HNSCC contain smoking and alcohol as well as human papillomavirus (HPV) infection (Chow, 2020). Due to the high incidence of HNSCC and most HNCSS patients present a tendency of recurrence or distant metastasis, the prognosis of HNSCC patients is poor (Argiris et al, 2008). PLAU Is a Prognostic Biomarker of HNSCC. Certain mechanisms and pathways for tumor formation have been identified for targeted drug development, such as EGFR inhibitors. The benefit of existing drugs is dissatisfactory (Sacco and Cohen, 2015). The identification of new drug targets for the therapy and prognosis of HNSCC seems urgent
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