Long non-coding RNA CASC2 suppresses epithelial-mesenchymal transition of hepatocellular carcinoma cells through CASC2/miR-367/FBXW7 axis.
Long non-coding RNA CASC2 suppresses epithelial-mesenchymal transition of hepatocellular carcinoma cells through CASC2/miR-367/FBXW7 axis.
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长链非编码RNA CASC2通过CASC2/miR-367/FBXW7轴抑制肝细胞癌细胞的上皮-间质转化。
DOI：
10.1186/s12943-017-0702-z
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发表时间：
2017-07-17
期刊：
影响因子：
37.3
通讯作者：
Tu K
中科院分区：
文献类型：
--
作者：
Wang Y;Liu Z;Yao B;Li Q;Wang L;Wang C;Dou C;Xu M;Liu Q;Tu K
最近有报道称，长非编码RNA(Long Non-Coding RNA，LncRNA)的肿瘤易感候选基因2(CASC2)是一种新的肿瘤抑制因子，它通过海绵化microRNAs(MiRNAs)参与调控肿瘤的发生和抑制肿瘤的进展。然而，CASC2在肝细胞癌中的表达和功能尚不清楚。实时荧光定量聚合酶链式反应检测CASC2和miR-367在肝细胞癌标本和细胞系中的表达。采用Western blotting和免疫组织化学方法检测肝细胞癌组织中上皮间充质转化(EMT)标志物的表达。用Transwell法检测肝癌细胞的迁移和侵袭能力。建立小鼠肺转移模型，评价体内肝细胞癌转移情况。通过双荧光素酶报告基因分析、RIP实验和生物素下拉实验揭示了CASC2、miR-367和F-box与WD重复结构域7(FBXW7)之间的相关性。在这里，CASC2在肝细胞癌组织中的表达显著下调，特别是在侵袭性和复发性病例中。与此相一致的是，与LO2相比，CASC2在肝癌细胞系中低表达。体外和体内实验表明，CASC2抑制了肝癌细胞的迁移和侵袭。此外，CASC2还抑制了肝癌细胞的EMT过程。进一步的研究表明，CASC2可以作为竞争内源性RNA(CERNA)在肝癌细胞中通过海绵结合miR-367发挥作用。在功能上，获得和失去功能的研究表明miR-367促进了肝癌细胞的迁移、侵袭和EMT进展。进一步的研究发现，FBXW7是miR-367的下游靶点，而CASC2通过CASC2/miR-367/FBXW7轴抑制肝癌细胞的EMT进展，从而发挥其抗转移作用。临床上，CASC2低表达和miR-367高表达与肿瘤转移相关的临床病理特征密切相关。值得注意的是，CASC2低表达和miR-367高表达的肝细胞癌患者的临床结果最差。总之，我们得出结论，CASC2/miR-367/FBXW7轴可能是一个值得考虑的、有前景的肝癌治疗靶点。本文的在线版本(doi：10.1186/s12943-0170702-z)包含补充材料，授权用户可以使用。
Recently, it has been reported that long non-coding RNA (lncRNA) cancer susceptibility candidate 2 (CASC2), a novel tumor suppressor, participates in regulating the carcinogenesis and suppresses tumor progression by sponging microRNAs (miRNAs). However, the expression and function of CASC2 in hepatocellular carcinoma (HCC) remain unclear. The expression of CASC2 and miR-367 in HCC specimens and cell lines were detected by real-time PCR. Western blotting and immunohistochemistry were carried out for detection of epithelial-to-mesenchymal transition (EMT) markers in HCC. Transwell assays were used to determine migration and invasion of HCC cells. A mouse model for lung metastasis was established to evaluated HCC metastasis in vivo. The correlation among CASC2, miR-367 and F-box and WD repeat domain containing 7 (FBXW7) were disclosed by a dual-luciferase reporter assay, RIP assay and biotin pull-down assay. Here, CASC2 expression was significantly downregulated in HCC tissues, especially in aggressive and recurrent cases. In accordance, CASC2 underexpression was observed in HCC cell lines compared to LO2. In vitro and in vivo experiments revealed that CASC2 inhibited migration and invasion of HCC cells. Additionally, CASC2 repressed EMT process of HCC cells. Further studies demonstrated that CASC2 could function as a competing endogenous RNA (ceRNA) by sponging miR-367 in HCC cells. Functionally, gain- and loss-of-function studies showed that miR-367 promoted migration, invasion and EMT progression of HCC cells. Moreover, further investigations disclosed that FBXW7 was a downstream target of miR-367 and CASC2 prohibited EMT progression and subsequently exerted its anti-metastatic effects via CASC2/miR-367/FBXW7 axis in HCC cells. Clinically, CASC2 underexpression and miR-367 overexpression were closely correlated with the metastasis-associated clinicopathologic features. Notably, CASC2 low-expressing and miR-367 high-expressing HCC patients showed the poorest clinical outcome. Overall, we conclude that the CASC2/miR-367/FBXW7 axis may be a ponderable and promising therapeutic target for HCC. The online version of this article (doi:10.1186/s12943-017-0702-z) contains supplementary material, which is available to authorized users.
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