miR-145, miR-133a and miR-133b: tumor-suppressive miRNAs target FSCN1 in esophageal squamous cell carcinoma
miR-145, miR-133a and miR-133b: tumor-suppressive miRNAs target FSCN1 in esophageal squamous cell carcinoma
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DOI：
10.1002/ijc.25284
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发表时间：
2010-12-15
影响因子：
6.4
通讯作者：
Matsubara, Hisahiro
中科院分区：
文献类型：
--
作者：
Kano, Masayuki;Seki, Naohiko;Matsubara, Hisahiro
MicroRNA（miRNAs）是一类长度为21-25个核苷酸的非编码RNA，主要在转录后水平调控基因表达。越来越多的证据表明，miRNA在许多人类癌症中异常表达，并且它们在癌症发生和癌症进展中起重要作用。使用从食管鳞状细胞癌（ESCC）临床标本中获得的miRNA表达特征，进行了在ESCC中具有肿瘤抑制功能的miRNA的搜索。15个miRNAs的亚组在ESCC中显著下调。比较ESCC和我们先前的报告中的miRNA特征，发现了4种共同下调的miRNA（miR-145，miR-30 a-3 p，miR-133 a和miR-133 b），表明这些miRNA是候选的肿瘤抑制因子。功能获得性分析显示3种转染子（miR-145、miR-133 a和miR-133 b）抑制ESCC细胞的增殖和细胞侵袭。这些在FSCN 1（肌动蛋白结合蛋白，Fascin同系物1）的3 'UTR中具有保守序列的miRNA（miR-145、miR-133 a和miR-133 b）抑制FSCN 1表达。来自荧光素酶报告基因测定的信号在2个miR-145靶位点和1个miR-133 a/B位点显著降低，表明两种miRNA直接调节FSCN 1。FSCN 1功能丧失试验发现了显著的细胞生长和侵袭抑制，这意味着FSCN 1与ESCC致癌相关。肿瘤抑制miRNAs的鉴定，miR-145，miR-133 a和miR-133 b，直接控制致癌FSCN 1基因。这些信号通路的研究为食管鳞癌的发生机制提供了新的思路。
MicroRNAs (miRNAs), noncoding RNAs 21-25 nucleotides in length, regulate gene expression primarily at the posttranscriptional level. Growing evidence suggests that miRNAs are aberrantly expressed in many human cancers, and that they play significant roles in carcinogenesis and cancer progression. A search for miRNAs with a tumor-suppressive function in esophageal squamous cell carcinoma (ESCC) was performed using the miRNA expression signatures obtained from ESCC clinical specimens. A subset of 15 miRNAs was significantly downregulated in ESCC. A comparison of miRNA signatures from ESCC and our previous report identified 4 miRNAs that are downregulated in common (miR-145, miR-30a-3p, miR-133a and miR-133b), suggesting that these miRNAs are candidate tumor suppressors. Gain-of-function analysis revealed that 3 transfectants (miR-145, miR-133a and miR-133b) inhibit cell proliferation and cell invasion in ESCC cells. These miRNAs (miR-145, miR-133a and miR-133b), which have conserved sequences in the 3'UTR of FSCN1 (actin-binding protein, Fascin homolog 1), inhibited FSCN1 expression. The signal from a luciferase reporter assay was significantly decreased at 2 miR-145 target sites and 1 miR-133a/b site, suggesting both miRNAs directly regulate FSCN1. An FSCN1 loss-of-function assay found significant cell growth and invasion inhibition, implying an FSCN1 is associated with ESCC carcinogenesis. The identification of tumor-suppressive miRNAs, miR-145, miR-133a and miR-133b, directly control oncogenic FSCN1 gene. These signal pathways of ESCC could provide new insights into potential mechanisms of ESCC carcinogenesis.