Li Zongyu, Huang Xin, Xu Jinkai, Su Qinghua, Zhao Jun, Ma Jiancang
Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Department of General Surgery, The Xi'an Central Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Int J Oncol. 2016 Oct;49(4):1629-1637. doi: 10.3892/ijo.2016.3659. Epub 2016 Aug 18.
Papillary thyroid carcinoma (PTC) is the most common thyroid cancer and represent approximately 80% of all thyroid cancers. The present study is aimed to investigate the role of microRNA (miR)-449 in the progression of PTC. Our results revealed that miR-449 was underexpressed in the collected PTC specimens compared with non-cancerous PTC tissues. Overexpression of miR-449 induced a cell cycle arrest at G0/G1 phase and inhibited PTC cell growth in vitro. Further studies revealed that RET proto-oncogene (RET) is a novel miR-449 target, due to miR-449 bound directly to its 3'-untranslated region and miR-449 mimic reduced the protein expression of RET. Similar to the effects of miR-449 overexpression, RET downregulation inhibited cell growth, whereas RET overexpression reversed the inhibitive effect of miR-449 mimic. Furthermore, miR-449 overexpression inhibited the nuclear translocation of β-catenin and reduced the expression of several downstream genes, including c-Myc, cyclin D1, T cell-specific transcription factor (TCF) and lymphoid enhancer-binding factor 1 (LEF-1), and inactivated the β-catenin pathway in TPC-1 cells. Moreover, overexpression of β-catenin prevented miR-449-reduced cell cycle arrest and cell viability. In xenograft animal experiments, miR-449 overexpression effectively suppressed the tumor growth of PTC. Taken together, our research indicated that miR-449 functions as an anti-oncogene by targeting RET, and that miR-449 overexpression inhibited the growth of PTC by inactivating the β-catenin pathway. Thus, miR-449 may serve as a potential therapeutic strategy for the treatment of PTC.
乳头状甲状腺癌（PTC）是最常见的甲状腺癌，约占所有甲状腺癌的80%。本研究旨在探讨微小RNA（miR）-449在PTC进展中的作用。我们的结果显示，与癌旁PTC组织相比，收集的PTC标本中miR-449表达下调。miR-449过表达诱导细胞周期停滞于G0/G1期，并在体外抑制PTC细胞生长。进一步研究表明，RET原癌基因（RET）是miR-449的一个新靶点，因为miR-449直接与其3'-非翻译区结合，且miR-449模拟物降低了RET的蛋白表达。与miR-449过表达的作用相似，RET下调抑制细胞生长，而RET过表达逆转了miR-449模拟物的抑制作用。此外，miR-449过表达抑制β-连环蛋白的核转位，并降低包括c-Myc、细胞周期蛋白D1、T细胞特异性转录因子（TCF）和淋巴细胞增强因子结合因子1（LEF-1）在内的几个下游基因的表达，并使TPC-1细胞中的β-连环蛋白通路失活。此外，β-连环蛋白的过表达阻止了miR-449诱导的细胞周期停滞和细胞活力。在异种移植动物实验中，miR-449过表达有效抑制了PTC的肿瘤生长。综上所述，我们的研究表明，miR-449通过靶向RET发挥抑癌基因的作用，且miR-449过表达通过使β-连环蛋白通路失活抑制PTC生长。因此，miR-449可能成为治疗PTC的一种潜在治疗策略。
