LncRNA OIP5-AS1 loss-induced microRNA-410 accumulation regulates cell proliferation and apoptosis by targeting KLF10 via activating PTEN/PI3K/AKT pathway in multiple myeloma.
LncRNA OIP5-AS1 loss-induced microRNA-410 accumulation regulates cell proliferation and apoptosis by targeting KLF10 via activating PTEN/PI3K/AKT pathway in multiple myeloma.
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DOI：
10.1038/cddis.2017.358
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发表时间：
2017-08-10
影响因子：
9
通讯作者：
Zhang W
中科院分区：
文献类型：
--
作者：
Yang N;Chen J;Zhang H;Wang X;Yao H;Peng Y;Zhang W
大量研究证实，miRNAs的异常表达与多发性骨髓瘤（MM）的发生、发展密切相关。然而，特定的miRNAs在MM中的作用仍有待研究。在本研究中，我们证明了miR-410在MM新诊断和复发组织和细胞系中的表达增加。临床分析显示，miR-410与ISS晚期呈正相关。此外，MM患者中miR-410的高表达显示出明显较短的总生存期和无进展生存期。功能获得和丧失实验表明，miR-410在体外和体内均促进细胞增殖、细胞周期进展和凋亡抑制。此外，KLF 10被鉴定为MM细胞中miR-410的直接下游靶标，并介导miR-410在MM中的功能影响，导致PTEN/AKT活化。在MM临床样本中，miR-410与KLF 10呈负相关。KLF 10表达的改变或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，在MM组织中，lncRNA OIP 5-AS 1的下调表达与miR-410的表达呈负相关。LncRNA OIP 5-AS 1可调控miR-410的表达，并调节其靶点KLF 10/PTEN/AKT介导的细胞行为。综上所述，本研究支持了第一个证据，即lncRNA OIP 5-AS 1缺失诱导的miR-410积累通过激活MM中的PTEN/PI 3 K/AKT通路靶向KLF 10促进细胞增殖、周期进展和凋亡抑制。
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.
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