He Xing-Xing, Guo An-Yuan, Xu Chuan-Rui, Chang Ying, Xiang Guang-Ya, Gong Jing, Dan Zi-Li, Tian De-An, Liao Jia-Zhi, Lin Ju-Sheng
Institute of Liver Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.
Hubei Bioinformatics and Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P.R. China.
Oncol Rep. 2014 Sep;32(3):1200-10. doi: 10.3892/or.2014.3306. Epub 2014 Jul 3.
Hepatocellular carcinoma (HCC) is a worldwide malignancy; however, there is a lack of effective targeted therapies. We and others have found that miR-221 is one of the most consistently overexpressed miRNAs in liver cancer. However, the roles of miR-221 in hepatocellular carcinogenesis are still not fully elucidated. In the present study, we used bioinformatics tools, gain- and loss-of-function methods to determine the roles of miR-221 in HCC. Bioinformatics analysis showed that miR-221 is a core miRNA which targets a large number of HCC-related genes and has formed many feed-forward regulatory loops combining transcription factors (TFs) to regulate HCC-related genes. Inhibition of miR-221 in liver cancer cells decreased cell proliferation, clonogenicity, migration/invasion and also induced G1 arrest and apoptosis. In addition, we demonstrated that miR-221 bound directly to the 3'-untranslated region of BMF, BBC3 and ANGPTL2, and inhibited the expression of BMF, BBC3 and ANGPTL2. In a mouse model, lentivirus‑mediated miR-221 silencing could significantly suppress the growth of hepatoma xenografts in nude mice. In conclusion, we showed that miR-221 is a critical modulator in the HCC signaling pathway, and miR-221 silencing inhibits liver cancer malignant properties in vitro and in vivo, which may benefit the treatment for patients with unresectable HCC.
肝细胞癌（HCC）是一种全球性的恶性肿瘤；然而，目前缺乏有效的靶向治疗方法。我们和其他研究人员发现，miR-221是肝癌中最常持续过度表达的miRNA之一。然而，miR-221在肝细胞癌发生过程中的作用仍未完全阐明。在本研究中，我们使用生物信息学工具、功能获得和功能丧失方法来确定miR-221在HCC中的作用。生物信息学分析表明，miR-221是一个核心miRNA，它靶向大量与HCC相关的基因，并形成了许多与转录因子（TFs）相结合的前馈调节环，以调控与HCC相关的基因。抑制肝癌细胞中的miR-221可降低细胞增殖、克隆形成能力、迁移/侵袭能力，还可诱导G1期阻滞和细胞凋亡。此外，我们证明miR-221直接与BMF、BBC3和ANGPTL2的3'-非翻译区结合，并抑制BMF、BBC3和ANGPTL2的表达。在小鼠模型中，慢病毒介导的miR-221沉默可显著抑制裸鼠体内肝癌异种移植瘤的生长。总之，我们表明miR-221是HCC信号通路中的关键调节因子，miR-221沉默在体外和体内均可抑制肝癌的恶性特性，这可能有利于不可切除HCC患者的治疗。
