Long non-coding RNA DLGAP1-AS1 facilitates tumorigenesis and epithelial-mesenchymal transition in hepatocellular carcinoma via the feedback loop of miR-26a/b-5p/IL-6/JAK2/STAT3 and Wnt/β-catenin pathway
Long non-coding RNA DLGAP1-AS1 facilitates tumorigenesis and epithelial-mesenchymal transition in hepatocellular carcinoma via the feedback loop of miR-26a/b-5p/IL-6/JAK2/STAT3 and Wnt/β-catenin pathway
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长链非编码RNA DLGAP 1-AS 1通过miR-26 a/B-5 p/IL-6/JAK 2/STAT 3和Wnt/β-catenin通路促进肝癌发生和上皮-间质转化
DOI：
10.1038/s41419-019-2188-7
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发表时间：
2020-01-16
影响因子：
9
通讯作者：
Huang, Jianfeng
中科院分区：
文献类型：
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作者：
Lin, Ye;Jian, Zhixiang;Huang, Jianfeng
肝细胞癌（HCC）是世界范围内最常见、最致命的恶性肿瘤之一，上皮间质转化（epithelial-mesenchymal transition， EMT）是影响HCC进展和转移的关键因素。长链非编码rna （lncRNAs）已被证实在多种肿瘤的生物过程中起关键调节作用。在此，我们试图阐明lncRNA DLGAP1-AS1在调节HCC的肿瘤发生和EMT中的未被描述的功能和机制。在我们的研究中，我们发现DLGAP1-AS1在HCC细胞系中表达上调，能够促进HCC的进展和EMT。此外，DLGAP1-AS1被证明是一个分子海绵，可以隔离hcc抑制mirna miR-26a-5p和miR-26b-5p，从而提高致癌细胞因子IL-6的水平，IL-6可以激活JAK2/STAT3信号通路，并相互提高DLGAP1-AS1的转录活性，从而形成一个正反馈回路。此外，我们阐述了DLGAP1-AS1在HCC细胞中的致癌作用可以通过正向调节miR-26a/b-5p下游基因CDK8和LRP6激活Wnt/ β -catenin通路来实现。总之，我们的研究结果揭示了DLGAP1-AS1在体外和体内促进HCC进展和EMT的详细分子机制，并提示DLGAP1-AS1作为HCC治疗靶点的潜力。
Hepatocellular carcinoma (HCC) is one of the most common and lethal malignancies worldwide, and epithelial-mesenchymal transition (EMT) is a crucial factor affecting HCC progression and metastasis. Long noncoding RNAs (lncRNAs) have been validated to act as critical regulators of biological processes in various tumors. Herein, we attempted to elucidate the uncharacterized function and mechanism of lncRNA DLGAP1-AS1 in regulating tumorigenesis and EMT of HCC. In our study, DLGAP1-AS1 was shown to be upregulated in HCC cell lines and capable to promote HCC progression and EMT. Besides, DLGAP1-AS1 was proven to serve as a molecular sponge to sequester the HCC-inhibitory miRNAs, miR-26a-5p and miR-26b-5p, thus enhancing the level of an oncogenic cytokine IL-6, which could activate JAK2/STAT3 signaling pathway and reciprocally elevate the transcriptional activity of DLGAP1-AS1, thus forming a positive feedback loop. Moreover, we elaborated that the cancerogenic effects of DLGAP1-AS1 in HCC cells could be effectuated via activating Wnt/beta-catenin pathway by positively regulating CDK8 and LRP6, downstream genes of miR-26a/b-5p. In conclusion, our results demonstrated the detailed molecular mechanism of DLGAP1-AS1 in facilitating HCC progression and EMT in vitro and in vivo, and suggested the potentiality of DLGAP1-AS1 as a therapeutic target for HCC.