Molecular Pathogenesis of Gene Regulation by the miR-150 Duplex: miR-150-3p Regulates TNS4 in Lung Adenocarcinoma
Molecular Pathogenesis of Gene Regulation by the miR-150 Duplex: miR-150-3p Regulates TNS4 in Lung Adenocarcinoma
复制标题
DOI：
10.3390/cancers11050601
复制
发表时间：
2019-05-01
期刊：
影响因子：
5.2
通讯作者：
Inoue, Hiromasa
中科院分区：
文献类型：
--
作者：
Misono, Shunsuke;Seki, Naohiko;Inoue, Hiromasa
基于我们的miRNA表达特征，我们以miR-150-5p(引导链)和miR-150-3p(客体链)为研究对象，探讨它们在肺腺癌中的功能意义。在LUAD临床标本中证实miR-150双链表达下调。体外实验表明，miR-150-5p和miR-150-3p的异位表达抑制了癌细胞的恶性程度。我们进行了全基因组基因表达分析和电子数据库搜索，以确定它们在LUAD细胞中的致癌靶点。共有41个基因和26个基因分别被鉴定为miR-150-5p和miR-150-3p靶点，它们与LUAD的发病密切相关。在这些靶点中，我们研究了紧张素4(TnS4)的致癌作用，因为TnS4的高表达与LUAD患者较差的预后密切相关(无病生存率：P=0.0213，总生存率：P=0.0003)。在LUAD细胞中，miR-150-3p直接调控TNS4的表达。在LUAD临床标本中检测到TNS4的异常表达，其异常表达增加了LUAD细胞的侵袭性。此外，我们还鉴定了TNS4下游与基因组稳定性的关键调节因子相关的基因。我们的方法(发现LUAD的抗肿瘤miRNAs及其靶向RNAs)将有助于阐明LUAD恶变过程中涉及的分子网络。
Based on our miRNA expression signatures, we focused on miR-150-5p (the guide strand) and miR-150-3p (the passenger strand) to investigate their functional significance in lung adenocarcinoma (LUAD). Downregulation of miR-150 duplex was confirmed in LUAD clinical specimens. In vitro assays revealed that ectopic expression of miR-150-5p and miR-150-3p inhibited cancer cell malignancy. We performed genome-wide gene expression analyses and in silico database searches to identify their oncogenic targets in LUAD cells. A total of 41 and 26 genes were identified as miR-150-5p and miR-150-3p targets, respectively, and they were closely involved in LUAD pathogenesis. Among the targets, we investigated the oncogenic roles of tensin 4 (TNS4) because high expression of TNS4 was strongly related to poorer prognosis of LUAD patients (disease-free survival: p = 0.0213 and overall survival: p = 0.0003). Expression of TNS4 was directly regulated by miR-150-3p in LUAD cells. Aberrant expression of TNS4 was detected in LUAD clinical specimens and its aberrant expression increased the aggressiveness of LUAD cells. Furthermore, we identified genes downstream from TNS4 that were associated with critical regulators of genomic stability. Our approach (discovery of anti-tumor miRNAs and their target RNAs for LUAD) will contribute to the elucidation of molecular networks involved in the malignant transformation of LUAD.