Deep Sequencing-Based Microrna Expression Signature In Head And Neck Squamous Cell Carcinoma: Dual Strand Of Microrna-150 Acts As Tumor Suppressors

Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world and ~500 000 cases are diagnosed every year. In spite of considerable advances in multimodality therapy, including surgery, radiotherapy and chemotherapy, the overall survival rate for patients with HNSCC is ~50%. Patients with HNSCC are usually diagnosed at a late stage and local tumor recurrence and distant metastasis occur after conventional therapies. Application of genomic approaches might elucidate novel molecular pathways underlying HNSCC and thereby improve therapeutic approaches to the disease. The discovery of noncoding RNAs (ncRNAs) in the human genome was an important conceptual breakthrough for cancer research in the post-genome sequencing era. Among ncRNAs, the microRNAs (miRNAs) are small ncRNA molecules (18-25 nucleotides in length) that regulate the expression of protein-coding/non-protein-coding genes by repressing translation or cleaving RNA transcripts in a sequence-specific manner. Accumulating evidence has demonstrated pivotal roles for miRNAs in human cancer pathogenesis. To seek out differentially expressed miRNAs in HNSCC cells, we newly constructed the deep-sequencing based miRNA expression signature by using laryngeal and hypopharyngeal clinical specimens. Our present data showed that a total of 160 miRNAs (44 upregulated and 116 downregulated) were identified as aberrantly expressed miRNAs in cancer tissues. Based on the signature, we focused on the dual strand of pre-miR-150, miR-150-5p and miR-150-3p in HNSCC signature because of these miRNAs significantly reduced in cancer tissues, suggesting these miRNAs act as antitumor miRNAs in this disease. However, the role of these miRNAs on HNSCC cells is still ambiguous. In miRNA biogenesis, it is the general consensus that processing of the pre-miRNA through Dicer1 generates a miRNA duplex (a passenger strand and a guide strand), and that the passenger strand has degradation and no regulatory activity and disintegrates in cells. Our present data showed that both miRNAs, miR-150-5p and miR-150-3p significantly suppressed cancer cell migration and invasion. Moreover, gene expression data and in silico database analysis showed that Integrin A3 (ITGA3), Integrin A6 (ITGA6) and Tenascin C (TNC) were direct regulation of both antitumor miRNAs. A large number of cohort study by TCGA showed that overall survival of high expression of ITGA3, ITGA6 and TNC groups were significantly shorter than that of low expression of these expression groups (p = 0.0177, p = 0.0237 and p = 0.026, respectively). These target genes acted as oncogenes and deeply contributed to HNSCC pathogenesis. Dual strand of miR-150 functioned as tumor suppressors based on the miRNA expression signature of HNSCC. Identification of miRNA-mediated cancer networks may provide novel molecular pathogenesis of the disease. Citation Format: Keiichi Koshizuka, Nijiro Nohata, Toyoyuki Hanazawa, Naoko Kikkawa, Ichiro Fukumoto, Takayuki Arai, Atsushi Okato, Yoshitaka Okamoto, Naohiko Seki. Deep sequencing-based microRNA expression signature in head and neck squamous cell carcinoma: dual strand of microRNA-150 acts as tumor suppressors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3430. doi:10.1158/1538-7445.AM2017-3430