Musashi 2 contributes to the sternness and chemoresistance of liver cancer stern cells via LIN28A activation
Musashi 2 contributes to the sternness and chemoresistance of liver cancer stern cells via LIN28A activation
复制标题
Musashi 2通过LIN28A激活促进肝癌干细胞的干性和化疗耐药性
DOI：
10.1016/j.canlet.2016.10.007
复制
发表时间：
2017-01-01
期刊：
影响因子：
9.7
通讯作者：
Wang, Hongyang
中科院分区：
文献类型：
--
作者：
Fang, Tian;Lv, Hongwei;Wang, Hongyang
越来越多的证据表明，癌症干细胞（CSCs），一个小的癌细胞亚群，负责肿瘤的发生，进展，复发和转移。Musashi 2（MSI2）是一种RNA结合蛋白，被认为是一种在髓系白血病和胃肠道恶性肿瘤中起关键作用的癌基因。然而，MSI2如何调节HCC中的干细胞特征仍然难以捉摸。在此，我们证明了MSI2在肝CSC中高度表达。MSI2的过表达或敲低改变了HCC细胞系中CSC相关基因的表达、自我更新以及对化疗的抗性。在小鼠异种移植模型中，MSI2可显著增强致瘤性。在机制上，MSI2的过表达导致Lin28A的上调。Lin28A基因敲低可显著降低MSI2过表达诱导的皮肤僵硬度和化疗药物耐药性。此外，MSI2和LIN28A水平与HCC患者的临床严重程度和预后呈正相关。因此，MSI2可能通过LIN28A依赖的方式在HCC中维持肝CSC5的干性和化疗耐药性中起关键作用。我们的研究结果表明，MSI2和Lin28A可能被用作根除肝CSC 5的潜在治疗靶点。(C)由Elsevier爱尔兰Ltd.出版
Accumulating evidence suggests that cancer stem cells (CSCs), a small subset of cancer cells, are responsible for tumor initiation, progression, relapse and metastasis. Musashi 2 (MSI2), a RNA-binding protein, was proposed to be a potent oncogene playing key roles in myeloid leukemia and gastrointestinal malignancies. However, it remains elusive how MSI2 regulates stem cell features in HCC. Herein, we demonstrated that MSI2 was highly expressed in liver CSCs. Overexpression or knockdown of MSI2 altered CSC-related gene expression, self-renewal as well as resistance to chemotherapy in HCC cell lines. In mouse xenograft models, MSI2 could markedly enhance tumorigenicity. Mechanistically, over expression of MSI2 resulted in the upregulation of Lin28A. Sternness and chemotherapeutic drug resistance induced by MSI2 overexpression were dramatically reduced by Lin28A knockdown. Moreover, MSI2 and LIN28A levels positively correlated with the clinical severity and prognosis in HCC patients. In conclusion, MSI2 might play a crucial role in sustaining sternness and chemoresistance of liver CSC5 via LIN28A-dependent manner in HCC. Our findings revealed that MSI2 and Lin28A might be used as potential therapeutic targets for eradicating liver CSC5. (C) 2016 Published by Elsevier Ireland Ltd.