Small Molecule Inhibition in HPV-Positive Oral Squamous Cell Carcinoma

Objectives: Oral cancer is the 6th most common cancer worldwide, with over 49,000 new cases expected in 2017 in the United States alone. Head and neck squamous cell carcinoma (HNSCC) results in approximately 9700 deaths each year, with only a 50-60% five-year survival rate. Despite an overall decrease in the incidence of oral cancer, there is an increasing trend of human papillomavirus (HPV)-associated HNSCC. Tumor biology is an extremely complex process, and oral carcinogenesis involves a series of concerted steps, including precancerous lesions, invasion, and metastasis. New therapies targeted at tumor spread represent a potential strategy to lessen morbidity and mortality for those affected by HNSCC. We used two HPV-positive cell lines to examine the effect of a small molecule in the production of matrix metalloproteinases (MMPs) and its potential effect in reducing invasion and metastasis.
Methods: Cal-27 (HPV 16 -, control) and UM-SCC-104 cells (HPV 16+) and SCC25 (HPV 16+) were incubated with varying concentrations of Compound C (0-100mM), a polyphenolic compound derived from tannic acid, to evaluate MMP expression and STAT3 phosphorylation. We also measured the expression of TIMPs to assess the effect of Compound C on the expression of endogenous inhibitors.
Results: Compound C decreased the expression of MMP-2, MMP-3, and MMP-9 by up to 50% in the HNSCC cell lines and moderately increased TIMP-1 expression in a dose-dependent manner. This effect was mediated through a decrease in Stat3 phosphorylation.
Conclusions: Novel small molecules may present as promising therapeutics in reducing the expression of MMPs known to propagate cellular invasiveness of squamous cell carcinoma lines Cal-27, SCC2-25, and UM-SCC-104. With interest in HPV status beginning to dominate the oral oncology landscape, recognizing and controlling the expression of molecules responsible for metastasis may present therapeutic adjuncts for this subset of patients.