Long non-coding RNA MAPKAPK5-AS1/PLAGL2/HIF-1α signaling loop promotes hepatocellular carcinoma progression.
Long non-coding RNA MAPKAPK5-AS1/PLAGL2/HIF-1α signaling loop promotes hepatocellular carcinoma progression.
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长非编码RNA MAPKAPK5-AS1/PLAGL2/HIF-1α信号环促进肝细胞癌进展
DOI：
10.1186/s13046-021-01868-z
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发表时间：
2021-02-17
期刊：
影响因子：
--
通讯作者：
Liu Q
中科院分区：
文献类型：
--
作者：
Wang L;Sun L;Liu R;Mo H;Niu Y;Chen T;Wang Y;Han S;Tu K;Liu Q
长链非编码RNA（longnoncodingRNA，lncRNA）通过调控肿瘤细胞的各种恶性行为，广泛参与人类肿瘤的发生发展。MAPKAPK 5-AS 1已被认为是结直肠癌中的癌基因。然而，MAPKAPK 5-AS 1在肝细胞癌（HCC）中的生物学作用尚未被探索。采用实时荧光定量PCR检测肝癌组织和细胞系中MAPKAPK 5-AS 1的表达水平。通过体外实验，包括MTT、集落形成、EdU、流式细胞术、transwell测定和裸鼠模型，评估MAPKAPK 5-AS 1对肿瘤生长和转移的影响。采用免疫印迹法检测上皮-间充质转化（EMT）标志物和AKT信号通路。通过荧光素酶报告基因分析和RNA免疫沉淀研究MAPKAPK 5-AS 1、miR-154- 5 p和PLAGL 2之间的相互作用。染色质免疫沉淀法检测HIF-1α对MAPKAPK 5-AS 1的调节作用。MAPKAPK 5-AS 1在HCC中表达显著升高，其过表达与恶性临床特征和生存率降低相关。在功能上，MAPKAPK 5-AS 1敲低抑制肝癌细胞的增殖、运动性和EMT并诱导细胞凋亡。MAPKAPK 5-AS 1的异位表达促进了肝癌细胞的体外增殖和侵袭。此外，MAPKAPK 5-AS 1沉默抑制，而MAPKAPK 5-AS 1过表达增强体内HCC生长和肺转移。在机制上，MAPKAPK 5-AS 1通过作为内源性竞争RNA（ceRNA）海绵miR-154- 5 p上调PLAG 1样锌指2（PLAGL 2）表达，从而激活EGFR/AKT信号传导。重要的是，拯救实验证明miR-154- 5 p/PLAGL 2轴介导HCC细胞中MAPKAPK 5-AS 1的功能。有趣的是，我们发现缺氧诱导因子1α（HIF-1α），一种转录因子，可以直接结合到启动子上激活MAPKAPK 5-AS 1的转录。MAPKAPK 5-AS 1通过PLAGL 2调控HIF-1α的表达，形成缺氧介导的MAPKAPK 5-AS 1/PLAGL 2/HIF-1α信号环。我们的研究结果揭示了MAPKAPK 5-AS 1/PLAGL 2/HIF-1α信号通路在HCC进展中的作用，提示MAPKAPK 5-AS 1可能成为HCC治疗的新靶点。在线版本包含补充材料，可通过10.1186/s13046-021-01868-z获得。
Long non-coding RNAs (lncRNAs) are widely involved in human cancers’ progression by regulating tumor cells’ various malignant behaviors. MAPKAPK5-AS1 has been recognized as an oncogene in colorectal cancer. However, the biological role of MAPKAPK5-AS1 in hepatocellular carcinoma (HCC) has not been explored. Quantitative real-time PCR was performed to detect the level of MAPKAPK5-AS1 in HCC tissues and cell lines. The effects of MAPKAPK5-AS1 on tumor growth and metastasis were assessed via in vitro experiments, including MTT, colony formation, EdU, flow cytometry, transwell assays, and nude mice models. The western blotting analysis was carried out to determine epithelial-mesenchymal transition (EMT) markers and AKT signaling. The interaction between MAPKAPK5-AS1, miR-154-5p, and PLAGL2 were explored by luciferase reporter assay and RNA immunoprecipitation. The regulatory effect of HIF-1α on MAPKAPK5-AS1 was evaluated by chromatin immunoprecipitation. MAPKAPK5-AS1 expression was significantly elevated in HCC, and its overexpression associated with malignant clinical features and reduced survival. Functionally, MAPKAPK5-AS1 knockdown repressed the proliferation, mobility, and EMT of HCC cells and induced apoptosis. Ectopic expression of MAPKAPK5-AS1 contributed to HCC cell proliferation and invasion in vitro. Furthermore, MAPKAPK5-AS1 silencing suppressed, while MAPKAPK5-AS1 overexpression enhanced HCC growth and lung metastasis in vivo. Mechanistically, MAPKAPK5-AS1 upregulated PLAG1 like zinc finger 2 (PLAGL2) expression by acting as an endogenous competing RNA (ceRNA) to sponge miR-154-5p, thereby activating EGFR/AKT signaling. Importantly, rescue experiments demonstrated that the miR-154-5p/PLAGL2 axis mediated the function of MAPKAPK5-AS1 in HCC cells. Interestingly, we found that hypoxia-inducible factor 1α (HIF-1α), a transcript factor, could directly bind to the promoter to activate MAPKAPK5-AS1 transcription. MAPKAPK5-AS1 regulated HIF-1α expression through PLAGL2 to form a hypoxia-mediated MAPKAPK5-AS1/PLAGL2/HIF-1α signaling loop in HCC. Our results reveal a MAPKAPK5-AS1/PLAGL2/HIF-1α signaling loop in HCC progression and suggest that MAPKAPK5-AS1 could be a potential novel therapeutic target of HCC. The online version contains supplementary material available at 10.1186/s13046-021-01868-z.
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