Abstract 2094: MicroRNA expression signatures in hypopharyngeal squamous cell carcinoma (HSCC): miR-489 inhibits cell proliferation by targeting PTPN11

Abstract

Abstract Head and neck squamous cell carcinoma (HNSCC) affects the oral cavity, oropharynx, larynx, and hypopharynx, and is the sixth most common cancer accounting for over 500,000 new cases annually, worldwide. Hypopharyngeal squamous cell carcinomas (HSCC) are an aggressive malignancy associated with one of the worst prognoses within HNSCC. Survival rates of patients with HSCC have not improved despite recent advances in various treatment modalities, including surgery, radiotherapy and chemotherapy. Understanding of the molecular oncogenic pathways underlying HSCC would be helpful to improve diagnosis, therapy, and prevention of the disease. MicroRNAs (miRNA) are a class of naturally occurring, small, non-coding RNA that can control gene expression by targeting mRNA molecules for translational repression or cleavage. Mature miRNAs originate from pre-miRNAs that consist of 70- to 100-nucleotide hairpins. The precursors are cleaved by cytoplasmic RNase III Dicer to give around 22-nucleotide miRNA duplexes. One strand of the short-lived duplex is then degraded, whereas the other strand serves as mature miRNA. Mature miRNAs bind through partial sequence homology to the 3’-untranslated regions (3’-UTR) of target messenger RNAs, and block either translation or mRNA degradation. In cancer research, miRNAs have recently been found to be aberrantly expressed in several types of human cancer, and it appears that some miRNAs can function as oncogenes or tumor suppressors. Dysregulated miRNAs may play a role in carcinogenesis or tumor progression by altering normal gene expression patterns. The aim of this study was to identify tumor suppressive miRNAs based on miRNA expression signatures of HSCC tissues and to predict biological target genes. Expression levels of 365 human mature miRNAs were screened using the stem-loop real-time quantitative PCR method. We identified 11 up-regulated and 31 down-regulated mature miRNAs based on miRNA expression signatures. Gain-of-function analysis of down-regulated miRNAs revealed that five miRNAs (miR-489, miR-126, miR-195, miR-1 and miR-497) inhibited cell growth in cancer cell lines, with miR-489 inhibiting cell growth in all cancer cell lines examined. We identified PTPN11, a cytoplasmic protein tyrosine phosphatase that contains two Scr homology domains, as a miR-489 target gene using genome-wide gene expression analysis. miR-489-transfected cells showed reduced PTPN11 protein and mRNA expression levels. In addition, knockdown of PTPN11 expression inhibited cell growth, which suggested that PTPN11 functioned as an oncogene. Tumor suppressive miRNAs and target oncogenes may provide new insights into the mechanisms in cancer. Our findings have therapeutic implications and may be exploited for future HSCC treatments. 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 2094.