Head and neck squamous cell carcinoma (HNSCC) is a highly invasive cancer, with a five-year survival rate of around 50%. Our goal is to improve patient outcome through understanding the mechanisms determining HNSCC invasiveness. Our research group identified miR-375 as the most consistently down-regulated miRNA in tumor samples when compared to paired normal samples. Patients in the lowest quartile of miR-375 expression had significantly decreased disease-specific survival, increase incidence of loco-regional recurrence and distant metastasis. The highly significant association of lower miR-375 expression in patients with poor prognosis and distant metastasis led us to investigate the mechanism by which miR-375 expression causes alterations to the invasive properties of HNSCC. Stable transductant cell lines with increased expression of miR-375 have been generated from two oral cavity cell lines, UMSCC1 and UMSCC47, utilizing lentiviral constructs driving expression of the miR-375 precursor. We have not seen a significant change in proliferation rate for either of the miR-375 expressing lines compared to the empty vector control expressing lines. We have observed diminished invasion properties in vitro correlates with increased miR-375 expression. We have also identified that miR-375 expression in HNSCC result in impaired chemotactic migration properties and suppressed matrix degradation properties. To identify proteins regulated by miR-375, we are utilizing stable isotope labeling of cells in cell culture (SILAC) to identify candidate miRNA target proteins to identify differentially expressed proteins in control and miR-375 over-expressing lines. Candidate target proteins will be validated as targets of miR-375 and tested for involvement in the diminished invasive properties of HNSCC as a result of miR-375 expression. In conclusion, miR-375 represents a potential prognostic marker of poor outcome and metastasis in HNSCC and may function by suppressing the expression of genes and proteins which are involved in the invasive properties of HNSCC.
Citation Format: Lizandra Jimenez, Thomas Harris, Nicole Kawachi, Thomas Belbin, Nicolas Schlecht, Jihyeon Lim, Ruth Angeletti, Michael B. Prystowsky, Geoffrey Childs, Jeffrey Segall. MicroRNA-375 regulates tumor invasion and metastasis phenotypes and is associated with poor outcome in head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4939. doi:10.1158/1538-7445.AM2013-4939