LncRNA Lnc-APUE is Repressed by HNF4α and Promotes G1/S Phase Transition and Tumor Growth by Regulating MiR-20b/E2F1 Axis.
LncRNA Lnc-APUE is Repressed by HNF4α and Promotes G1/S Phase Transition and Tumor Growth by Regulating MiR-20b/E2F1 Axis.
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LncRNA lnc-APUE 被 HNF4α 抑制并通过调节 miR-20b/E2F1 轴促进 G1/S 相变和肿瘤生长
DOI：
10.1002/advs.202003094
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Zhuang SM
中科院分区：
文献类型：
--
作者：
Li SY;Zhu Y;Li RN;Huang JH;You K;Yuan YF;Zhuang SM
许多长链非编码RNA（lncRNA）已被注释，但它们的功能仍然未知。作者发现了一种新的lnc-APUE（lncRNA通过上调E2 F1加速增殖），在不同的癌症类型中上调，包括肝细胞癌（HCC），高lnc-APUE水平与HCC患者的短期无复发生存期（RFS）相关。功能获得和丧失分析表明，lnc-APUE在体外加速了G1/S转换和肿瘤细胞生长，并使肝癌异种移植物在体内生长得更快。从机制上讲，lnc-APUE与miR-20 b结合并解除其对E2 F1表达的抑制，导致E2 F1水平增加，并加速G1/S期转变和细胞增殖。因此，lnc-APUE水平与HCC组织中E2 F1及其下游靶基因的表达呈正相关。进一步的研究发现，肝细胞核因子4 α（HNF 4 α）与lnc-APUE启动子结合，抑制lnc-APUE转录，然后减少E2 F1表达和细胞增殖。HCC组织中HNF 4 α表达降低，低HNF 4 α水平与lnc-APUE高表达相关。总的来说，鉴定了HNF 4 α/lnc-APUE/miR-20 b/E2 F1轴，其中HNF 4 α抑制lnc-APUE表达并使E2 F1保持在低水平。在肿瘤细胞中，HNF 4 α下调导致lnc-APUE上调，这阻止了miR-20 b对E2 F1表达的抑制，从而促进细胞周期进展和肿瘤生长。存在HNF 4 α/lnc-APUE/miR-20 b/E2 F1调节轴，其中HNF 4 α抑制lnc-APUE表达并使E2 F1保持在低水平。在肿瘤细胞中，HNF 4 α下调导致lnc-APUE上调，这可能作为miR-20 b海绵阻止miR-20 b介导的对E2 F1表达的抑制，导致E2 F1水平增加，进而加速G1/S转换和肿瘤生长。
Many long noncoding RNAs (lncRNAs) have been annotated, but their functions remain unknown. The authors found a novel lnc‐APUE (lncRNA accelerating proliferation by upregulating E2F1) that is upregulated in different cancer types, including hepatocellular carcinoma (HCC), and high lnc‐APUE level is associated with short recurrence‐free survival (RFS) of HCC patients. Gain‐ and loss‐of‐function analyses showed that lnc‐APUE accelerated G1/S transition and tumor cell growth in vitro and allows hepatoma xenografts to grow faster in vivo. Mechanistically, lnc‐APUE binds to miR‐20b and relieves its repression on E2F1 expression, resulting in increased E2F1 level and accelerated G1/S phase transition and cell proliferation. Consistently, lnc‐APUE level is positively associated with the expression of E2F1 and its downstream target genes in HCC tissues. Further investigations disclose that hepatocyte nuclear factor 4 alpha (HNF4α) binds to the lnc‐APUE promoter, represses lnc‐APUE transcription, then diminishes E2F1 expression and cell proliferation. HNF4α expression is reduced in HCC tissues and low HNF4α level is correlated with high lnc‐APUE expression. Collectively, a HNF4α/lnc‐APUE/miR‐20b/E2F1 axis in which HNF4α represses lnc‐APUE expression and keeps E2F1 at a low level is identified. In tumor cells, HNF4α downregulation leads to lnc‐APUE upregulation, which prevents the inhibition of miR‐20b on E2F1 expression and thereby promotes cell cycle progression and tumor growth. There exists a HNF4α/lnc‐APUE/miR‐20b/E2F1 regulatory axis, in which HNF4α represses lnc‐APUE expression and keeps E2F1 at a low level. In tumor cells, HNF4α downregulation leads to lnc‐APUE upregulation, which may work as a miR‐20b sponge to prevent the miR‐20b‐mediated repression on E2F1 expression, resulting in increase of E2F1 level and in turn acceleration of G1/S transition and tumor growth.
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