Abstract LB-354: Dysregulation of microRNA-34a expression in head and neck squamous cell carcinoma promotes tumor growth and tumor angiogenesis

Abstract

Abstract Objectives of the study: Head and Neck squamous cell carcinoma (HNSCC) results from deregulation of multiple signaling pathways leading to tumor cells acquiring proliferative, invasive, angiogenic and metastatic properties. Interactions between neoplastic cells and the surrounding microenvironment also play a major role in tumor progression. Recent studies have demonstrated that microRNA's (miRs) play a critical role in cancer development where they can act as oncogenes or as onco-suppressors. A microRNA array analysis of a panel often HNSCC cell lines reveled that miR-34a is significantly downregulated in all these cell lines as compared to normal human oral keratinocyes (HOK). In addition, miR-34a expression was also downregulated in highly angiogenic endothelial cells (endothelial cells overexpressing Bcl-2; EC-Bcl-2) as compared to normal human endothelial cells. However, little is known about the role of miR-34a in HNSCC tumor growth and tumor angiogenesis. In this study, we examined if dysregulation of miR-34a in HNSCC promotes tumor growth and tumor angiogenesis. Methodology: The study was performed using a panel of established human head & neck cancer cell lines. miRs expression in tumor and endothelial cells was examined by miR-arrays and further validated by real time PCR. Lipofectamine-2000 was used to transfect miR-34a in 2 HNSCC cell lines (UM-SCC-74A and UM-SCC-47) and human endothelial cells. Cell-proliferation assay was performed by MTT and colony formation assay. Tumor cell and endothelial cell motility was assessed by scratch assay. Expression of miR-34a downstream mediators was measured by Western blot. Results: Ectopic expression of miR34a significantly inhibited cell proliferation of UM-SCC-74A cells (52% and 58% on days 2 and 4) and UM-SCC-47 cells (43% and 47% on days 2 and 4). In addition, enhanced expression of miR34a in UM-SCC-74A and UM-SCC-47 cells significantly inhibited tumor cell colony formation and tumor cell migration. Similar to tumor cells, miR-34a significantly inhibited EC-Bcl-2 proliferation and migration by down regulating c-met, Bcl-2 expression and upregulating phospho p38 MAPK expression. Conclusion: These findings indicate that dysregulation of miR-34a expression is common in HNSCC and modulation of miR34a activity might represent a novel therapeutic strategy for the treatment of head and neck cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-354.