ATF3 inhibits the tumorigenesis and progression of hepatocellular carcinoma cells via upregulation of CYR61 expression.
ATF3 inhibits the tumorigenesis and progression of hepatocellular carcinoma cells via upregulation of CYR61 expression.
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ATF3通过上调CYR61表达抑制肝癌细胞的肿瘤发生和进展
DOI：
10.1186/s13046-018-0919-8
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发表时间：
2018-10-30
期刊：
影响因子：
--
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Chen C;Ge C;Liu Z;Li L;Zhao F;Tian H;Chen T;Li H;Yao M;Li J
肝细胞癌（Hepatocellular carcinoma，HCC）是东亚地区最常见的恶性肿瘤之一，发病率和死亡率都很高。因此，寻找肝癌的生物标志物和阐明肝癌的调控机制具有重要意义。本研究旨在探讨转录因子激活因子3（ATF/cAMP反应元件结合蛋白家族成员之一）在肝癌中的作用及其机制。在体外和体内试验进行调查的功能作用的ATF 3在肝细胞癌。采用RNA-Seq技术筛选ATF 3下游差异表达基因。通过双荧光素酶报告基因检测、染色质免疫沉淀（Ch-IP）分析和功能拯救实验来确认ATF 3调控的靶基因。获得236例原发性肝癌组织的组织芯片（TMAs），并进行免疫组化染色，分析ATF 3的临床意义。结果ATF 3在体内外均能显著抑制肝癌细胞的增殖和迁移。富含半胱氨酸的血管生成诱导物61（CYR 61）是ATF 3转录调控的关键靶点。ATF 3和CYR 61在人肝癌组织中的表达均呈下调趋势，且二者的表达水平均显著正相关，提示ATF 3通过靶向和调节CYR 61在肝癌中发挥抑癌作用。
BackgroundHepatocellular carcinoma (HCC) is one of the most common malignant cancers with a high incidence and high mortality in East Asia. Identifying biomarkers and clarifying the regulatory mechanisms of HCC are of great importance. Herein, we report the role and mechanism of activating transcription factor 3 (ATF3), a member of the ATF/cAMP-responsive element-binding protein family of transcription factors in HCC.MethodsATF3 overexpression vector and shRNAs were transfected into HCC cancer cells to upregulate or downregulate ATF3 expression. In vitro and in vivo assays were performed to investigate the functional role of ATF3 in hepatocellular carcinoma. RNA-Seq was performed to screen the differentially expressed genes downstream of ATF3. The dual-luciferase reporter assay, chromatin immunoprecipitation (Ch-IP) analysis and functional rescue experiments were used to confirm the target gene regulated by ATF3. Tissue microarrays (TMAs) comprising 236 human primary HCC tissues were obtained and immunohistochemical staining were carried out to analyze the clinical significance of ATF3.ResultsThe results indicate that ATF3 significantly inhibited the proliferation and mobility of HCC cells both in vitro and in vivo. Cysteine-rich angiogenic inducer 61 (CYR61) is a key target for transcriptional regulation by ATF3. Both ATF3 and CYR61 were consistently downregulated in human HCC tissues, and their expression levels were significantly and positively correlated with each other.ConclusionsOur findings indicate that ATF3 functions as a tumor suppressor in HCC through targeting and regulating CYR61.
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