LINC00680 enhances hepatocellular carcinoma stemness behavior and chemoresistance by sponging miR-568 to upregulate AKT3.
LINC00680 enhances hepatocellular carcinoma stemness behavior and chemoresistance by sponging miR-568 to upregulate AKT3.
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LINC00680 通过海绵 miR-568 上调 AKT3 增强肝细胞癌干性行为和化疗耐药性
DOI：
10.1186/s13046-021-01854-5
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发表时间：
2021-01-26
期刊：
影响因子：
--
通讯作者：
Tang B
中科院分区：
文献类型：
--
作者：
Shu G;Su H;Wang Z;Lai S;Wang Y;Liu X;Dai L;Bi Y;Chen W;Huang W;Zhou Z;He S;Dai H;Tang B
背景由于化疗耐药性的发展，加上固有的干性特性增加，肝细胞癌（HCC）的预后极差。长链非编码 RNA (LncRNA) 是肿瘤细胞干性和化疗敏感性的关键调节因子。目前，LINC00680 与肿瘤进展之间的相关性仍然很大程度上未知，只有一项研究表明其在胶质母细胞瘤中的重要性。本研究旨在明确LINC00680在调节HCC干细胞性和化疗敏感性中的作用。方法采用QRT-PCR检测组织标本和细胞系中LINC00680、miR-568和AKT3的表达。应用功能获得或丧失分析来了解 LINC00680 在 HCC 细胞中的功能，包括细胞增殖和干性特性。 HCC 干性和化疗敏感性通过球体形成、细胞活力和集落形成来确定。进行荧光素酶报告基因、RNA 免疫沉淀 (RIP) 和 RNA Pull-down 测定来检查 LINC00680 和 miR-568 之间以及 miR-568 和 AKT3 之间的相互作用。建立裸鼠异种移植模型进行体内研究。结果我们发现LINC00680在HCC组织中显着上调。 LINC00680水平高的患者预后较差。 LINC00680 过表达显着增强 HCC 细胞干性，并降低体外和体内对 5-氟尿嘧啶 (5-Fu) 的化疗敏感性，而 LINC00680 敲低则导致相反的结果。机制研究表明，LINC00680通过海绵miR-568调节HCC干性和化疗敏感性，从而加速AKT3的表达，进一步激活其下游信号分子，包括mTOR、elF4EBP1和p70S6K。结论LINC00680通过海绵miR-568促进HCC干性特性并降低化疗敏感性。 激活 AKT3，表明 LINC00680 可能是潜在重要的 HCC 诊断标志物和治疗靶点。
BackgroundHepatocellular carcinoma (HCC) has an extremely poor prognosis due to the development of chemoresistance, coupled with inherently increased stemness properties. Long non-coding RNAs (LncRNAs) are key regulators for tumor cell stemness and chemosensitivity. Currently the relevance between LINC00680 and tumor progression was still largely unknown, with only one study showing its significance in glioblastoma. The study herein was aimed at identifying the role of LINC00680 in the regulation HCC stemness and chemosensitivity.MethodsQRT-PCR was used to detect the expression of LINC00680, miR-568 and AKT3 in tissue specimen and cell lines. Gain- or loss-of function assays were applied to access the function of LINC00680 in HCC cells, including cell proliferation and stemness properties. HCC stemness and chemosensitivity were determined by sphere formation, cell viability and colony formation. Luciferase reporter, RNA immunoprecipitation (RIP), and RNA pull-down assays were performed to examine the interaction between LINC00680 and miR-568 as well as that between miR-568 and AKT3. A nude mouse xenograft model was established for the in vivo study.ResultsWe found that LINC00680 was remarkably upregulated in HCC tissues. Patients with high level of LINC00680 had poorer prognosis. LINC00680 overexpression significantly enhanced HCC cell stemness and decreased in vitro and in vivo chemosensitivity to 5-fluorouracil (5-Fu), whereas LINC00680 knockdown led to opposite results. Mechanism study revealed that LINC00680 regulated HCC stemness and chemosensitivity through sponging miR-568, thereby expediting the expression of AKT3, which further activated its downstream signaling molecules, including mTOR, elF4EBP1, and p70S6K.ConclusionLINC00680 promotes HCC stemness properties and decreases chemosensitivity through sponging miR-568 to activate AKT3, suggesting that LINC00680 might be a potentially important HCC diagnosis marker and therapeutic target.
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