miRNA-558 promotes gastric cancer progression through attenuating Smad4-mediated repression of heparanase expression
miRNA-558 promotes gastric cancer progression through attenuating Smad4-mediated repression of heparanase expression
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miRNA-558通过减弱Smad4介导的乙酰肝素酶表达抑制促进胃癌进展
DOI：
10.1038/cddis.2016.293
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发表时间：
2016-09-01
影响因子：
9
通讯作者：
Tong, Qiangsong
中科院分区：
文献类型：
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作者：
Zheng, Liduan;Jiao, Wanju;Tong, Qiangsong
以往的研究表明，乙酰肝素酶（HPSE）作为唯一的哺乳动物内切β-D-葡萄糖醛酸酶，在胃癌中表达上调并与预后不良相关，但其机制尚不明确。在此，通过对公开数据集的综合分析，我们发现microRNA-558（miR-558）和SMAD家族成员4（Smad 4）是胃癌中HPSE表达的关键转录调控因子，其相邻靶位点位于HPSE启动子内。我们发现，内源性miR-558激活HPSE在胃癌细胞系中的转录和表达。Smad 4则通过直接与HPSE启动子结合抑制HPSE的转录和表达。在机制上，miR-558识别HPSE启动子内的互补位点，以Argonaute 1依赖性方式降低Smad 4的结合。异位表达或敲低实验表明，miR-558通过减弱Smad 4介导的HPSE表达抑制，促进胃癌细胞系的体外和体内肿瘤发生和侵袭性。在临床胃癌标本中，miR-558的上调和Smad 4的下调与HPSE的表达呈正相关。Kaplan-Meier生存分析显示miR-558和Smad 4分别与胃癌患者的不利和有利结局相关。因此，这些发现表明miR-558通过直接靶向HPSE启动子以减弱Smad 4介导的HPSE表达抑制而促进胃癌的进展。
Previous studies have indicated that as the only mammalian endo-beta-D-glucuronidase, heparanase (HPSE) is up-regulated and associated with poor prognosis in gastric cancer, while the underlying mechanisms still remain to be determined. Herein, through integrative analysis of public datasets, we found microRNA-558 (miR-558) and SMAD family member 4 (Smad4) as the crucial transcription regulators of HPSE expression in gastric cancer, with their adjacent target sites within the promoter of HPSE. We identified that endogenous miR-558 activated the transcription and expression of HPSE in gastric cancer cell lines. In contrast, Smad4 suppressed the nascent transcription and expression of HPSE via directly binding to its promoter. Mechanistically, miR-558 recognized its complementary site within HPSE promoter to decrease the binding of Smad4 in an Argonaute 1-dependent manner. Ectopic expression or knockdown experiments indicated that miR-558 promoted the in vitro and in vivo tumorigenesis and aggressiveness of gastric cancer cell lines via attenuating Smad4-mediated repression of HPSE expression. In clinical gastric cancer specimens, up-regulation of miR-558 and down-regulation of Smad4 were positively correlated with HPSE expression. Kaplan-Meier survival analysis revealed that miR-558 and Smad4 were associated with unfavourable and favourable outcome of gastric cancer patients, respectively. Therefore, these findings demonstrate that miR-558 facilitates the progression of gastric cancer through directly targeting the HPSE promoter to attenuate Smad4-mediated repression of HPSE expression.