Significance of Plk1 regulation by miR-100 in human nasopharyngeal cancer
Publication in refereed journal



摘要Polo-like kinase 1 (Plkl) is a critical regulator of many stages of mitosis; increasing evidence indicates that Plk1 overexpression correlates with poor clinical outcome, yet its mechanism of regulation remains unknown. Hence, a detailed evaluation was undertaken of Plk1 expression in human nasopharyngeal cancer (NPC), the cellular effects of targeting Plk1 using siRNA in combination with ionizing radiation (RD and potential upstream microRNAs (miRs) that might regulate Plk1 expression. Using immunohistochemistry, Plk1 was observed to be overexpressed in 28 of 40 (70%) primary NPC biopsies, which in turn was associated with a higher likelihood of recurrence (p = 0.018). SiPlk1 significantly inhibited Plkl mRNA and protein expression, and decreased Cdc25c levels in NPC cell lines. This depletion resulted in cytotoxicity of C666-1 cells, enhanced by the addition of RI, mediated by G2/M arrest, increased DNA double-strand breaks, apoptosis, and caspase activation. Immunolluorescence demonstrated that the G2/M arrest was associated with aberrant spindle formation, leading to mitotic arrest. In vivo, transfection of C666-1 cells and systemic delivery of siPlk1 decreased tumour growth. MicroRNA-100 (miR-100) was predicted to target Plk1 mRNA, which was indeed underexpressed in C666-1 cells, inversely correlating with Plkl expression. Using luciferase constructs containing the 3'-UTR of Plkl sequence, we document that miR-100 can directly target Plkl. Hence, our data demonstrate for the first time that underexpressed miR-100 leads to Plkl overexpression, which in turn contributes to NPC progression. Targeting Plk1 will cause mitotic catastrophe, with significant cytotoxicity both in vitro and in vivo, underscoring the important therapeutic opportunity of Plkl in NPC.
著者Shi W, Alajez NM, Bastianutto C, Hui ABY, Mocanu JD, Ito E, Busson P, Lo KW, Ng R, Waldron J, O'Sullivan B, Liu FF
期刊名稱International Journal of Cancer
頁次2036 - 2048
關鍵詞human nasopharyngeal carcinoma; ionizing radiation; microRNAs; Plk1
Web of Science 學科類別Oncology; ONCOLOGY

上次更新時間 2021-25-02 於 23:55