Long noncoding RNA NNT-AS1 promotes hepatocellular carcinoma progression and metastasis through miR-363/CDK6 axis.
Long noncoding RNA NNT-AS1 promotes hepatocellular carcinoma progression and metastasis through miR-363/CDK6 axis.
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DOI：
10.18632/oncotarget.21321
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发表时间：
2017-10-24
期刊：
影响因子：
--
通讯作者：
Zhang Q
中科院分区：
文献类型：
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作者：
Lu YB;Jiang Q;Yang MY;Zhou JX;Zhang Q
长链非编码RNA（lncRNA）已被证实在肝癌的发生和发展中起着重要的调节作用。烟酰胺核苷酸转氢酶反义RNA 1（NNT-AS 1）参与肿瘤的发生。然而，NNT-AS 1在肝细胞癌（HCC）中的确切分子机制仍不清楚。在目前的研究中，我们的团队确定了NNT-AS 1在HCC组织和细胞系中的表达与邻近的非癌组织和正常细胞相比上调。此外，高NNT-AS 1水平的HCC患者的预后比低NNT-AS 1水平的患者差（p=0.0089）。体外功能获得和功能丧失实验表明，NNT-AS 1表达增强可促进细胞增殖，缓解细胞周期阻滞和凋亡，而NNT-AS 1敲低则可抑制细胞增殖，诱导G 0/G1期阻滞和凋亡。在体内，NNT-AS 1敲低抑制HCC肿瘤体积和重量。生物信息学分析和荧光素酶报告基因分析证实miR-363靶向NNT-AS 1和CDK 6的3 '-UTR。miR-363在HCC组织和细胞中表达下调。NNT-AS 1与CDK 6竞争miR-363结合，并可增加CDK 6表达。总之，我们的研究结果表明NNT-AS 1通过miR-363/CDK 6轴在HCC肿瘤发生中的致癌作用，为人类HCC提供了新的治疗靶点。
Long non-coding RNAs (lncRNAs) have been tested to act as important regulator in liver cancer genesis and progression. LncRNA Nicotinamide Nucleotide Transhydrogenase-antisense RNA1 (NNT-AS1) has been reported to participate in the tumorigenesis. However, the exact molecular mechanism of NNT-AS1 in hepatocellular carcinoma (HCC) is still unknown. In present study, our team identified the up-regulated expression of NNT-AS1 in HCC tissue and cell lines compared with adjacent noncancerous tissue and normal cells. Moreover, HCC patients with high NNT-AS1 levels had poor prognosis than that with low NNT-AS1 level (p=0.0089). In vitro, gain- and loss-of-function experiments revealed that enhanced NNT-AS1 expression promoted the proliferation ability and alleviated the cycle arrest and apoptosis, while NNT-AS1 knockdown suppressed the proliferation and induced G0/G1 phase arrest and apoptosis. In vivo, NNT-AS1 knockdown inhibited the HCC neoplastic tumor volume and weight. Bioinformatics analysis and luciferase reporter assay validated that miR-363 targeted NNT-AS1 and CDK6 3’-UTR. MiR-363 was down-regulated in HCC tissue and cells. NNT-AS1 competed with CDK6 for miR-363 binding and could increase CDK6 expression. In summary, our results suggest the oncogenic role of NNT-AS1 in HCC tumorigenesis through miR-363/CDK6 axis, providing a novel therapeutic target for human HCC.