The role of microRNA in human cancer angiogenesis and invasion

• Main Authors: Shih-Ting Cha, 查詩婷
• Other Authors: Min-Liang Kuo
• Format: Others
• Language: en_US
• Published: 2011
• Online Access: http://ndltd.ncl.edu.tw/handle/99193667085002724778

博士 === 國立臺灣大學 === 毒理學研究所 === 99 === 英文摘要 MicroRNAs (miRNAs) are a new class of endogenous, small evolutionarily conserved non-coding RNAs of 18-25 nucleotides in length that act as post-transcriptional repressors of gene expression involved in fundamental cell processes, such as development, differentiation, proliferation, survival and death ranging from plants to human. A wide spread role for miRNAs in diverse molecular processes driving the initiation and progression of various tumor types has recently been described. Here, we discuss the role of mir-519c and mir-211 in tumor angiogenesis and invasion/ migration, which define as tumor suppressor. In first chapter of this thesis, we have identified miR-519c as a hypoxia independent regulator of HIF-1α, acting through direct binding to HIF-1α 3’UTR and leading to reduced tumor angiogenesis. In consistence with the over-expression of miR-519c in cancer patients with better prognosis, mice injected with miR-519c over-expressing cells exhibited dramatically reduced HIF-1α level, followed by suppressed tumor angiogenesis, growth, and metastasis. In addition, we found that hepatocyte growth factor (HGF), a known HIF-1α inducer, reduced the miR-519c levels through an Akt-dependent pathway. This regulation was post-transcriptional and may be mediated by suppression of miR-519c maturation. Taken together, our findings provide the first evidence that miR-519c is a pivotal regulator of tumor angiogenesis and, moreover, micro environmental HGF contributes to regulating miR-519c biogenesis in cancer cells. In addition, we also found a significant down-regulate 5 miRNAs (miR-211, miR-107, miR-141, miR-187 and miR-514) in metastatic melanomas comparing 6 pairs of metastatic and primary melanomas from six patients. Further results suggested that miR-211 could regulate melanoma metastasis by inhibiting migration/invasion abilities of melanoma cells. Specifically, compared with expression levels in melanocytes, levels of miR-211 were consistently reduced in all eight non-pigmented melanoma cell lines we examined; they were also reduced in 21 out of 30 distinct melanoma samples from patients, classified as primary in situ, regional metastatic, distant metastatic, and nodal metastatic. Transfection of anti-miR-211 oligonucleotides (200 pmole) enhances the migration and invasion abilities of MeWo and B16F0 cells. In vivo model shows that over-expression of miR-211 in A375 melanoma cells attenuates its lymph node metastatic ability (n=12 for each group; lymph node meta rate: A3-211 vs. A3-VEC= 3/12 vs. 12/12). The aim of this study is to investigate the roles and molecular mechanisms of miR-211 in melanoma metastasis, which may improve the development of prognostic markers and novel treatments for melanoma.