Abstract
Recent our microRNA (miRNA) expression signature revealed that expression of microRNA-218 (miR-218) was reduced in cancer tissues, suggesting a candidate of tumor suppressor in head and neck squamous cell carcinoma (HNSCC). The aim of this study was to investigate the functional significance of miR-218 and its mediated moleculer pathways in HNSCC. Restoration of miR-218 in cancer cells led to significant inhibition of cell migration and invasion activities in HNSCC cell lines (FaDu and SAS). Genome-wide gene expression analysis of miR-218 transfectants and in silico database analysis showed that focal adhesion pathway was a promising candidate of miR-218 target pathways. The laminins are an important and biologically active part of the basal lamina, the function of that are various such as influencing cell differentiation, migration and adhesion as well as proliferation and cell survival. Interestingly, all components of laminin-332 (LAMA3, LAMB3 and LAMC2) are listed on the candidate genes in focal adhesion pathway. Furthermore, we focused on LAMB3 which has a miR-218 target site and gene expression studies and luciferase reporter assays showed that LAMB3 was directly regulated by miR-218. Silencing study of LAMB3 demonstrated significant inhibition of cell migration and invasion. In clinical specimens with HNSCC, the expression levels of laminin-332 were significantly upregulated in cancer tissues compared to adjacent non-cancerous tissues. Our analysis data showed that tumor suppressive miR-218 contributes to cancer cell migration and invasion through regulating focal adhesion pathway, especially laminin-332. Tumor suppressive miRNA-mediated novel cancer pathways provide new insights into the potential mechanisms of HNSCC oncogenesis.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and approximately 650,000 new cases occur and 350,000 patients dying from head and neck squamous cell carcinoma (HNSCC) annually [1]
We focused on LAMB3 which has a miR-218 target site and gene expression studies and luciferase reporter assays showed that LAMB3 was directly regulated by miR-218
We focused on the focal adhesion pathway because this pathway can be implicated in cancer cell migration and invasion and can be a promising candidate of miR218 target pathway
Summary
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and approximately 650,000 new cases occur and 350,000 patients dying from HNSCC annually [1]. Despite of considerable advances in multimodality therapy including surgery, radiation therapy, and chemotherapy, the overall survival rate for patients with this type of cancer is among the lowest of all major cancer types and has not improved during recent decades [2]. Local tumor recurrence and distant metastasis after conventional therapy appear to be major contributing factors for restricted survival of HNSCC patients [2]. The discovery of non-coding RNA in human www.impactjournals.com/oncotarget. The reconstructing of the genome-wide study, including noncoding RNA is necessary for cancer research at present. MicroRNAs (miRNAs) are most characterized among noncoding RNAs. miRNAs are a class of small non-coding RNA molecules consisting of 19–22 nucleotides that play important roles in a variety of biological processes, including development, differentiation, apoptosis and cell proliferation [4] The reconstructing of the genome-wide study, including noncoding RNA is necessary for cancer research at present. microRNAs (miRNAs) are most characterized among noncoding RNAs. miRNAs are a class of small non-coding RNA molecules consisting of 19–22 nucleotides that play important roles in a variety of biological processes, including development, differentiation, apoptosis and cell proliferation [4]
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