Abstract
Abstract BACKGROUNDS: Cervical cancer is the second most common cause of cancer death in women worldwide, and approximately 500,000 new cases of cervical cancer are diagnosed each year, with 280,000 deaths. Cervical squamous cell carcinoma (SCC) is the most frequent type of cervical cancer and the most important risk factor for cervical-SCC is persistent human papilloma virus (HPV) infection. However, the molecular mechanisms of cervical SCC initiation, development, and metastasis have not yet been fully elucidated. Our recent studies of microRNA (miRNA) expression signatures have indicated that miRNA-29a (miR-29a) was significantly downregulated in several types of human cancers, suggesting that miR-29a may be a putative tumor-suppressive miRNA in human cancers. The aim of this study was to investigate the functional significance of miR-29a in cervical squamous cell carcinoma (SCC) and to identify novel miR-29a-regulated cancer pathways and target genes involved in cervical SCC oncogenesis and metastasis. METHODS: The expression levels of miR-29a were validated using real-time RT-PCR using cervical SCC clinical specimens and cell lines (CaSKi, HeLa, ME180, and YUMOTO). Cell proliferation, migration and invasion assays were performed to investigate the functional significance of miR-29a and its target gene, heat-shock protein 47 (HSP47) in cell lines. Cells were transfected with mature miR-29a or si-HSP47 by reverse transfection methods. Genome-wide gene expression data and in silico analysis were used to identify the molecular pathways and putative targets regulated by miR-29a. The luciferase reporter assay was applied to identify the actual binding site of miR-29a in target gene. The expression of HSP47 was investigated by immunohistochemistry. RESULTS: Restoration of miR-29a in cervical cancer cell lines revealed that this miRNA significantly inhibited cancer cell migration and invasion. Gene expression data and in silico analysis demonstrated that HSP47 was a potential target of miR-29a regulation. Luciferase reporter assays showed that miR-29a directly regulated HSP47. Moreover, silencing of the HSP47 gene significantly inhibited cell migration and invasion in cancer cells, and the expression of HSP47 was upregulated in cancer tissues and cervical intraepithelial neoplasia (CIN), as demonstrated by immunostaining. CONCLUSIONS: Downregulation of miR-29a was a frequent event in cervical SCC, and miR-29a acted as a tumor suppressor by directly targeting HSP47. Recognition of tumor-suppressive miRNA-regulated molecular targets provides new insights into the potential mechanisms of cervical SCC oncogenesis and metastasis and suggests novel therapeutic strategies for treatment of this disease. Citation Format: Noriko Yamamoto, Takashi Kinoshita, Nijiro Nohata, Akira Mitsuhashi, Hirokazu Usui, Hirofumi Yoshino, Toshihiko Itesako, Hideki Enokida, Masayuki Nakagawa, Makio Shozu, Naohiko Seki. Tumor-suppressive microRNA-29a inhibits cancer cell migration and invasion via targeting HSP47 in cervical squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4350. doi:10.1158/1538-7445.AM2014-4350
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