Yang Nan, Chen Jinqiu, Zhang Hui, Wang Xiaman, Yao Huan, Peng Yue, Zhang Wanggang
Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, West Five Road, NO.157, Xi'an, China.
Cell Death Dis. 2017 Aug 10;8(8):e2975. doi: 10.1038/cddis.2017.358.
Numerous studies confirmed that aberrant miRNAs expression contributes to multiple myeloma (MM) development and progression. However, the roles of specific miRNAs in MM remain to be investigated. In present study, we demonstrated that miR-410 expression was increased in MM newly diagnosed and relapsed tissues and cell lines. Clinical analysis revealed that miR-410 was positively correlated with advanced ISS stage. Moreover, high miR-410 expression in MM patients showed an obvious shorter overall survival and progression-free survival. Gain- and loss-of function experiments indicated that miR-410 promoted cell proliferation, cell cycle progression and apoptosis inhibition both in vitro and in vivo. Moreover, KLF10 was identified as a direct downstream target of miR-410 in MM cells, and mediated the functional influence of miR-410 in MM, resulting in PTEN/AKT activation. In clinical samples of MM, miR-410 inversely correlated with KLF10. Alteration of KLF10 expression or AKT inhibitor at least partially abolished the biological effects of miR-410 on MM cells. Furthermore, downregulated expression of lncRNA OIP5-AS1 was inversely correlated with miR-410 expression in MM tissues. LncRNA OIP5-AS1 could modulate the miR-410 expression and regulate its target KLF10/PTEN/AKT-mediated cellular behaviors. Taken together, this research supports the first evidence that lncRNA OIP5-AS1 loss-induced miR-410 accumulation facilitates cell proliferation, cycle progression and apoptosis inhibition by targeting KLF10 via activating PTEN/PI3K/AKT pathway in MM.
众多研究证实，异常的微小RNA（miRNA）表达促成了多发性骨髓瘤（MM）的发生和发展。然而，特定miRNA在MM中的作用仍有待研究。在本研究中，我们证明miR-410在新诊断和复发的MM组织及细胞系中表达增加。临床分析显示，miR-410与国际分期系统（ISS）晚期呈正相关。此外，MM患者中miR-410高表达显示总体生存期和无进展生存期明显缩短。功能获得和功能丧失实验表明，miR-410在体外和体内均促进细胞增殖、细胞周期进程并抑制细胞凋亡。此外，KLF10被确定为MM细胞中miR-410的直接下游靶点，并介导miR-410在MM中的功能影响，导致PTEN/AKT激活。在MM临床样本中，miR-410与KLF10呈负相关。KLF10表达改变或使用AKT抑制剂至少部分消除了miR-410对MM细胞的生物学效应。此外，长链非编码RNA（lncRNA）OIP5-AS1在MM组织中的表达下调与miR-410表达呈负相关。LncRNA OIP5-AS1可调节miR-410的表达，并调节其靶向KLF10/PTEN/AKT介导的细胞行为。综上所述，本研究首次证明lncRNA OIP5-AS1缺失诱导的miR-410积累通过激活PTEN/PI3K/AKT通路靶向KLF10，促进MM细胞增殖、周期进程和凋亡抑制。
