MicroRNA-1468 promotes tumor progression by activating PPAR-γ-mediated AKT signaling in human hepatocellular carcinoma.
MicroRNA-1468 promotes tumor progression by activating PPAR-γ-mediated AKT signaling in human hepatocellular carcinoma.
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MicroRNA-1468 通过激活人肝细胞癌中 PPAR-γ 介导的 AKT 信号传导促进肿瘤进展
DOI：
10.1186/s13046-018-0717-3
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发表时间：
2018-03-06
期刊：
影响因子：
--
通讯作者：
Tu K
中科院分区：
文献类型：
--
作者：
Liu Z;Wang Y;Dou C;Sun L;Li Q;Wang L;Xu Q;Yang W;Liu Q;Tu K
越来越多的证据证实microRNAs（miRNAs）的异常表达与肝细胞癌（HCC）的发生、发展有关。既往研究报道miR-1468在TCGA数据库中表达上调，可能成为HCC患者预后的生物标志物。然而，miR-1468的作用及其在HCC生长和转移中的潜在机制仍然缺乏研究。采用CCK-8、EdU、集落形成和流式细胞术检测肝癌细胞的增殖、细胞周期进程和凋亡。建立裸鼠皮下移植瘤模型，检测肝癌在体内的生长情况。通过荧光素酶报告基因分析证实miR-1468与Cbp/p300相互作用的反式激活因子CITED 2和Up-frameshift protein 1（UPF 1）的3 'UTR直接结合。在这里，我们证明了miR-1468在HCC组织和细胞系中的表达上调。临床分析显示，miR-1468水平升高与恶性预后特征和较短生存期显著相关。功能获得和功能丧失实验表明，miR-1468在体外和体内促进肝癌细胞增殖、集落形成、细胞周期进展并诱导凋亡。此外，CITED 2和UPF 1被鉴定为miR-1468在HCC细胞中的直接下游靶点，并介导miR-1468在HCC中的功能效应，导致过氧化物酶体增殖物激活受体-γ（PPAR-γ）/AKT信号转导激活。在HCC的临床样本中，miR-1468与CITED 2和UPF 1的水平呈负相关，这两种蛋白在HCC中被证实下调。CITED 2或UPF 1表达的恢复至少部分消除了miR-1468对HCC细胞的生物学效应。此外，PPAR-γ或AKT磷酸化的改变可以逆转miR-1468在HCC中的功能。综上所述，这项研究支持了miR-1468通过靶向CITED 2和UPF 1激活PPAR-γ/AKT通路在HCC中发挥致癌作用的第一个证据，并代表了HCC患者有希望的治疗策略。本文的在线版本（10.1186/s13046-018-0717-3）包含补充材料，可供授权用户使用。
Accumulating evidence confirm that aberrant microRNAs (miRNAs) expression contributes to hepatocellular carcinoma (HCC) development and progression. Previous study reported that miR-1468 showed an up-regulated tendency and might be a potential prognostic biomarker in HCC samples derived from TCGA database. However, the role of miR-1468 and its underlying mechanisms involved in the growth and metastasis of HCC remain poorly investigated. CCK-8, EdU, colony formation and flow cytometry were used to determine proliferation, cell cycle progression and apoptosis of HCC cells in vitro. The subcutaneous tumor model in nude mice was established to detect tumor growth of HCC in vivo. The direct binding of miR-1468 to 3’UTR of Cbp/p300 interacting transactivator with Glu/Asp rich carboxy-terminal domain 2 (CITED2) and Up-frameshift protein 1 (UPF1) was confirmed by luciferase reporter assay. Here, we demonstrated that miR-1468 expression was up-regulated in HCC tissues and cell lines. Clinical analysis revealed that increased miR-1468 level was significantly correlated with malignant prognostic features and shorter survival. Gain- and loss-of-function experiments indicated that miR-1468 promoted cell proliferation, colony formation, cell cycle progression and induced apoptosis of HCC cells in vitro and in vivo. Moreover, CITED2 and UPF1 were identified as direct downstream targets of miR-1468 in HCC cells, and mediated the functional effects of miR-1468 in HCC, resulting in peroxisome proliferator-activated receptor-γ (PPAR-γ)/AKT signaling activation. In clinical samples of HCC, miR-1468 inversely correlated with the levels of CITED2 and UPF1, which were confirmed to be down-regulated in HCC. Restoration of CITED2 or UPF1 expression at least partially abolished the biological effects of miR-1468 on HCC cells. Moreover, alteration of PPAR-γ or AKT phosphorylation could reverse the function of miR-1468 in HCC. Taken together, this research supports the first evidence that miR-1468 plays an oncogenic role in HCC via activating PPAR-γ/AKT pathway by targeting CITED2 and UPF1, and represents a promising therapeutic strategy for HCC patients. The online version of this article (10.1186/s13046-018-0717-3) contains supplementary material, which is available to authorized users.
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影响因子：
5.7
作者：
Minemura H;Takagi K;Sato A;Takahashi H;Miki Y;Shibahara Y;Watanabe M;Ishida T;Sasano H;Suzuki T
通讯作者：
Suzuki T
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影响因子：
--
作者：
Liu Z;Dou C;Yao B;Xu M;Ding L;Wang Y;Jia Y;Li Q;Zhang H;Tu K;Song T;Liu Q
通讯作者：
Liu Q
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影响因子：
--
作者：
Liu Z;Dou C;Yao B;Xu M;Ding L;Wang Y;Jia Y;Li Q;Zhang H;Tu K;Song T;Liu Q
通讯作者：
Liu Q
影响因子：
1.6
作者：
Ge YZ;Xu LW;Xu Z;Wu R;Xin H;Zhu M;Lu TZ;Geng LG;Liu H;Zhou CC;Yu P;Zhao YC;Hu ZK;Zhao Y;Zhou LH;Wu JP;Li WC;Zhu JG;Jia RP
通讯作者：
Jia RP
影响因子：
3.4
作者：
Liu, Zhikui;Dou, Changwei;Song, Tao
通讯作者：
Song, Tao