Long Noncoding RNA LINC01134 Promotes Hepatocellular Carcinoma Metastasis via Activating AKT1S1 and NF-κB Signaling
Long Noncoding RNA LINC01134 Promotes Hepatocellular Carcinoma Metastasis via Activating AKT1S1 and NF-κB Signaling
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DOI：
10.3389/fcell.2020.00429
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发表时间：
2020-06-12
影响因子：
5.5
通讯作者：
Zhang, Lei
中科院分区：
文献类型：
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作者：
Wang, Chao;Chen, Yan;Zhang, Lei
肝细胞癌（HCC）是最常见的恶性肿瘤之一，预后差。肝癌相关死亡的主要原因是复发和转移。长链非编码RNA（longnoncodingRNAs，lncRNA）是近年来发现的一种重要的肿瘤调控因子。然而，参与HCC复发和转移的lncRNA知之甚少。在这项研究中，通过分析The Cancer Genome Atlas Liver Hepatocellular Carcinoma数据集，我们发现了一种新的lncRNA LINC01134，它在HCC组织中高度表达，并与HCC患者的微血管浸润，大血管浸润，复发和总生存率低相关。功能实验表明，LINC01134的异位表达促进了肝癌细胞的体外迁移和侵袭，促进了肝癌细胞的体内肝转移和肺转移。LINC01134的敲低抑制了体外HCC细胞的迁移和侵袭以及体内HCC的肝转移和肺转移。从机制上讲，我们发现LINC01134直接结合AKT1S1的启动子并激活AKT1S1的表达。通过激活AKT1S1，LINC01134进一步激活NF-κ B信号传导。肝癌组织中LINC01134和AKT1S1的表达呈显著正相关。与LINC01134一致，AKT1S1也在HCC组织中高度表达，并与HCC患者的不良生存相关。功能拯救实验表明，抑制AKT1S1或NF-κ B信号传导消除了LINC01134在HCC中的作用。综上所述，这些发现将LINC01134确认为一种新的致癌lncRNA，其表明HCC患者的血管浸润、复发和较差的总体存活率。LINC01134通过激活AKT1S1表达并随后激活NF-κ B信号传导促进HCC转移。这项研究表明LINC01134是HCC潜在的预后生物标志物和治疗靶点。
Hepatocellular carcinoma (HCC) is one of the most common malignancies with poor outcomes. The main causes of HCC-related deaths are recurrence and metastasis. Long noncoding RNAs (lncRNAs) are recently identified as critical regulators in cancers. However, the lncRNAs involved in HCC recurrence and metastasis are poorly understood. In this study, via analyzing The Cancer Genome Atlas Liver Hepatocellular Carcinoma dataset, we identified a novel lncRNA LINC01134, which is highly expressed in HCC tissues and correlated with microvascular invasion, macrovascular invasion, recurrence, and poor overall survival of HCC patients. Functional experiments revealed that ectopic expression of LINC01134 promotes HCC cell migration and invasionin vitroand HCC liver metastasis and lung metastasisin vivo. Knockdown of LINC01134 represses HCC cell migration and invasionin vitroand HCC liver metastasis and lung metastasisin vivo. Mechanistically, we found that LINC01134 directly binds the promoter ofAKT1S1and activatesAKT1S1expression. Via activating AKT1S1, LINC01134 further activates NF-kappa B signaling. The expression of LINC01134 is significantly positively correlated with that of AKT1S1 in HCC tissues. In line with LINC01134, AKT1S1 is also highly expressed in HCC tissues and correlated with poor survival of HCC patients. Functional rescue experiments showed that repressing AKT1S1 or NF-kappa B signaling abrogates the roles of LINC01134 in HCC. Taken together, these findings recognized LINC01134 as a novel oncogenic lncRNA, which indicates vascular invasion, recurrence, and poor overall survival of HCC patients. LINC01134 promotes HCC metastasis via activating AKT1S1 expression and subsequently activating NF-kappa B signaling. This study suggested LINC01134 as a potential prognostic biomarker and therapeutic target for HCC.