Purpose

Emerging evidence indicates that dysfunction of long non-coding RNAs (lncRNAs) plays an essential role in the initiation and progression of hepatocellular carcinoma (HCC). In this study we investigated the potential roles and molecular mechanisms involving LINC01419 in HCC.

Methods

The expression of LINC01419 in 40 pairs of HCC/normal tissues and 6 HCC cell lines was detected by qRT-PCR. MTS, EdU, colony formation, scratch wound-healing and transwell assays were performed to assess the role of LINC01419 in HCC cell (SMMC7721 and SK-Hep1) proliferation, migration and invasion in vitro. Artificial modulation of LINC01419 (up- and downregulation) was performed to explore the role of LINC01419 in tumor growth and metastasis in vivo. Interaction of LINC01419 with NDRG1 was assessed using qRT-PCR, RNA sequencing, Western blotting and immunohistochemistry. Physical interaction of LINC01419 with the NDRG1 promoter was assessed using a dual-luciferase reporter assay.

Results

We observed LINC01419 overexpression in primary HCC tissues and HCC cell lines and that this overexpression positively correlated with large tumor size, increased vascular invasion and advanced TNM stage in 40 HCC patients. Exogenous LINC01419 expression significantly promoted HCC cell proliferation, migration and invasion in vitro, as well as tumorigenesis and metastasis in vivo. Conversely, we found that LINC01419 expression knockdown elicited opposite effects. Mechanistic investigations revealed that LINC01419 exerted its biological effects by regulating NDRG1. A dual-luciferase reporter assay revealed that LINC01419 interacts with a specific region within the NDRG1 promoter, resulting in its activation.

Conclusions

From our data we conclude that LINC01419 acts clinically, functionally and mechanistically oncogenic in HCC. LINC01419 may, therefore, serve as a promising prognostic indicator and therapeutic target for HCC.

中文翻译：

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LINC01419通过增强NDRG1启动子活性来促进肝细胞癌的细胞增殖和转移。

目的

越来越多的证据表明，较长的非编码RNA（lncRNA）的功能异常在肝细胞癌（HCC）的发生和发展中起着至关重要的作用。在这项研究中，我们调查了涉及LINC01419在肝癌中的潜在作用和分子机制。

方法

通过qRT-PCR检测LINC01419在40对HCC /正常组织和6个HCC细胞系中的表达。进行了MTS，EdU，集落形成，划痕伤口愈合和Transwell分析，以评估LINC01419在体外HCC细胞（SMMC7721和SK-Hep1）增殖，迁移和侵袭中的作用。进行了LINC01419的人工调节（上调和下调），以探索LINC01419在体内肿瘤生长和转移中的作用。使用qRT-PCR，RNA测序，蛋白质印迹和免疫组化评估了LINC01419与NDRG1的相互作用。LINC01419与NDRG1启动子之间的物理相互作用使用双荧光素酶报告基因分析进行了评估。

结果

我们观察到LINC01419在原发性HCC组织和HCC细胞系中的过度表达，并且这种过度表达与40例HCC患者中的大肿瘤大小，血管浸润增加和TNM分期晚期呈正相关。外源LINC01419表达在体外显着促进HCC细胞增殖，迁移和侵袭，以及体内肿瘤发生和转移。相反，我们发现LINC01419表达敲低引起相反的作用。机理研究表明，LINC01419通过调节NDRG1发挥其生物学作用。双重荧光素酶报告基因测定表明，LINC01419与NDRG1启动子内的特定区域相互作用，从而导致其激活。

结论

根据我们的数据，我们得出结论，LINC01419在HCC中具有临床，功能和机制上的致癌作用。因此，LINC01419可以作为HCC的有希望的预后指标和治疗靶标。