HIF-1α-activated long non-coding RNA KDM4A-AS1 promotes hepatocellular carcinoma progression via the miR-411-5p/KPNA2/AKT pathway.
HIF-1α-activated long non-coding RNA KDM4A-AS1 promotes hepatocellular carcinoma progression via the miR-411-5p/KPNA2/AKT pathway.
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DOI：
10.1038/s41419-021-04449-2
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发表时间：
2021-12-13
影响因子：
9
通讯作者：
Liu Q
中科院分区：
文献类型：
--
作者：
Chen T;Liu R;Niu Y;Mo H;Wang H;Lu Y;Wang L;Sun L;Wang Y;Tu K;Liu Q
肝细胞癌（HCC）是最常见的肝癌类型，临床结局较差。长链非编码RNA（lncRNA）广泛参与肝癌的发生和发展。然而，新的lncRNA及其对HCC的影响还有待进一步研究。在此，我们鉴定了一种新的lncRNA KDM 4A-AS 1，其在HCC组织中异常过表达，与不利的临床特征和患者的不良预后相关。KDM 4A-AS 1在体外促进HCC细胞增殖、迁移和侵袭，在体内促进HCC生长和肺转移。从机制上讲，KDM 4A-AS 1在转录后水平受到miR-411- 5 p的反向调节，并通过竞争性结合miR-411- 5 p促进Karyopherin α2（KPNA 2）表达，从而激活AKT通路。KPNA 2沉默、miR-411- 5 p过表达和AKT抑制剂（MK 2206）一致逆转了KDM 4A-AS 1增强的HCC细胞增殖、迁移率和EMT。KDM 4A-AS 1是一个新的低氧应答基因，在肝癌细胞中可被低氧诱导因子1α（HIF-1α）反式激活。反过来，KDM 4A-AS 1通过KPNA 2/AKT信号通路调节HIF-1α的表达。因此，本研究揭示了一种新的低氧应答lncRNA，KDM 4A-AS 1，其通过KDM 4A-AS 1/KPNA 2/HIF-1α信号通路促进HCC的生长和转移。我们的发现为HCC的预后和治疗提供了一个有希望的靶点。
Hepatocellular carcinoma (HCC) is the most common type of liver cancer with poor clinical outcomes. Long non-coding RNAs (lncRNAs) are extensively involved in the tumorigenesis and progression of HCC. However, more investigations should be carried out on novel lncRNAs and their effects on HCC. Here we identified a novel lncRNA KDM4A-AS1, which was aberrantly overexpressed in HCC tissues, associated with unfavorable clinical features and poor prognosis of patients. KDM4A-AS1 promoted HCC cell proliferation, migration, and invasion in vitro and contributed to HCC growth and lung metastasis in vivo. Mechanistically, KDM4A-AS1 was inversely modulated by miR-411-5p at the post-transcriptional level and facilitated Karyopherin α2 (KPNA2) expression by competitively binding miR-411-5p, thereby activating the AKT pathway. KPNA2 silencing, miR-411-5p overexpression, and AKT inhibitor (MK2206) consistently reversed KDM4A-AS1-enhanced proliferation, mobility, and EMT of HCC cells. KDM4A-AS1 was identified as a novel hypoxia-responsive gene and transactivated by hypoxia-inducible factor 1α (HIF-1α) in HCC cells. In turn, KDM4A-AS1 regulated HIF-1α expression through the KPNA2/AKT signaling pathway. Hence, this study revealed a novel hypoxia-responsive lncRNA, KDM4A-AS1, which contributed to HCC growth and metastasis via the KDM4A-AS1/KPNA2/HIF-1α signaling loop. Our findings provide a promising prognostic and therapeutic target for HCC.
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