Abstract 137: Molecular networks regulated by tumor suppressive microRNA-375 in head and neck squamous cell carcinoma

Abstract

Abstract BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. In spite of considerable advances in multimodality therapy including surgery, radiotherapy and chemotherapy, the overall five-year survival rate for patients with HNSCC is around 40%. Understanding of the molecular oncogenic pathway underlying HNSCC could significantly improve diagnosis, therapy, and disease prevention. Our microRNA (miRNA) expression signatures of hypopharyngeal squamous cell carcinoma (SCC), maxillary sinus SCC and esophageal SCC revealed that the expression of microRNA-375 (miR-375) was significantly reduced in cancer tissues. In this study, we investigated the functional significance of miR-375 and explored novel molecular networks regulated by miR-375 in HNSCC. METHODS: Cell proliferation assay was performed to investigate the functional significance of miR-375 and its target genes in HNSCC cell lines. Genome-wide gene expression analysis was performed to identify the molecular networks of miR-375 by microarray technique. The expression levels of miR-375 target genes were verified using quantitative real-time RT-PCR in HNSCC clinical specimens. A luciferase reporter assay was used to identify the actual binding site between miR-375 and its candidate target genes. RESULTS: Restoration of miR-375 significantly inhibited cancer cell proliferation in HNSCC cells. Genome-wide molecular targets search and TargetScan database indicated that homocysteine-inducible, endoplasmic reticulum stress-inducible, ubiquitin-like domain member 1 (HERPUD1), lactate dehydrogenase B (LDHB), PC4 and SFRS1 interacting protein 1 (PSIP1), metadherin (MTDH) and solute-carrier family 7, member 11 (SLC7A11) were the candidate genes of miR-375 target. Among them, the expression levels of LDHB and MTDH were significantly up-regulated in clinical HNSCC tumor specimens compared with adjacent normal epithelium. Luciferase reporter assay showed that LDHB and MTDH were directly regulated by miR-375. Silencing of these genes studies demonstrated significant inhibition of cell proliferation in HNSCC cells. CONCLUSIONS: miR-375 functions as a tumor suppressor in HNSCC. LDHB and MTDH are directly regulated by miR-375. These genes may function as oncogenes and contributed to cell proliferation in HNSCC. Tumor suppressive miR-375 and its target oncogenes may provide new insights into the molecular networks of HNSCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 137. doi:1538-7445.AM2012-137