SF3B4 is regulated by microRNA-133b and promotes cell proliferation and metastasis in hepatocellular carcinoma
SF3B4 is regulated by microRNA-133b and promotes cell proliferation and metastasis in hepatocellular carcinoma
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SF3B4受microRNA-133b调控促进肝细胞癌细胞增殖和转移
DOI：
10.1016/j.ebiom.2018.10.067
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发表时间：
2018-12-01
期刊：
影响因子：
11.1
通讯作者：
Liu, Shanrong
中科院分区：
文献类型：
--
作者：
Liu, Zhiyong;Li, Wei;Liu, Shanrong
背景：剪接因子3b亚单位4(SF3B4)是肝细胞癌中的一种剪接因子和潜在癌基因，但其调控机制尚不清楚。我们的目的是确定SF3B4在肝癌中的作用及其潜在的机制。方法：利用TargetScan筛选可能的miRNAs，以研究选择性剪接事件与miRNAs之间的关联。根据公开的基因组数据和临床样本确定SF3B4和miRNAs的表达水平和预后信息。然后，我们研究了SF3B4和miRNA-133b在肝癌细胞和异种移植小鼠模型中的可能作用。皮尔逊相关性分析和体外实验证实了SF3B4是miRNA-133b的靶标。用免疫印迹法检测SF3B4信号通路关键靶点的蛋白水平。结果：SF3B4在肝癌组织和细胞系中表达上调，而miRNA-133b表达下调。MiRNA-133b负性调控SF3B4的表达。SF3B4的过度表达可被miRNA-133b模拟物部分消除，证实SF3B4是miRNA-133b的靶标。此外，与SF3B4相关的分子，包括KLF4、KIP1和SNAI2，也受到miRNA-133b的调控。解释：SF3B4在肝细胞癌中起关键作用，并受到miRNA-133b的负调控。MiRNA-133b/SF3B4轴可能成为治疗肝癌的新靶点。基金：国家杰出青年科学家基金(81425019号)、中国国家自然科学基金重点项目(81730076号)、上海市科委计划(18XD1405300号)和上海市特聘教授基金(2015009号)。中国国家自然科学基金(81672899号)。(C)2018年作者。爱思唯尔出版公司(Elsevier B.V.)
Background: Splicing factor 3b subunit 4 (SF3B4) is a splicing factor and potential oncogene in hepatocellular carcinoma (HCC); however, its regulatory mechanism is yet unclear. We aimed to determine the role of SF3B4 in HCC and the underlying mechanism.Methods: To investigate the association between alternative splicing events and miRNAs, putative miRNAs were screened using TargetScan. Expression levels of and prognostic information for SF3B4 and miRNAs were determined based on public genomic data and clinical samples. Then, we examined the possible roles of SF3B4 and miRNA-133b in HCC cells and a xenograft mouse model. Pearson correlation analysis and in vitro experiments verified SF3B4 as a miRNA-133b target. Protein levels of key targets from the SF3B4 signaling pathway were estimated using western blotting.Findings: The expression of SF3B4 was upregulated in HCC tissues and cell lines whereas, the expression of miRNA-133b was downregulated. MiRNA-133b negatively regulated the expression of SF3B4. Effects of SF3B4 overexpression were partially abolished by miRNA-133b mimics, confirming that SF3B4 is a target of miRNA-133b. Moreover, molecules associated with SF3B4, including KLF4, KIP1, and SNAI2, were also modulated by miRNA-133b.Interpretation: SF3B4 plays a crucial role in HCC and is negatively regulated by miRNA-133b. The miRNA-133b/SF3B4 axis may serve as a new therapeutic target for HCC treatment.Fund: ChinaNational Funds for Distinguished Young Scientists (No. 81425019), the State Key Programof National Natural Science Foundation of China (No. 81730076), Shanghai Science and Technology Committee Program (No. 18XD1405300) and Specially-Appointed Professor Fund of Shanghai (GZ2015009). China National Funds for National Natural Science Fund (No. 81672899). (c) 2018 The Authors. Published by Elsevier B.V.