MicroRNA-93 activates c-Met/PI3K/Akt pathway activity in hepatocellular carcinoma by directly inhibiting PTEN and CDKN1A.
MicroRNA-93 activates c-Met/PI3K/Akt pathway activity in hepatocellular carcinoma by directly inhibiting PTEN and CDKN1A.
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DOI：
10.18632/oncotarget.3085
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发表时间：
2015-02-20
期刊：
影响因子：
--
通讯作者：
Hoon DS
中科院分区：
文献类型：
--
作者：
Ohta K;Hoshino H;Wang J;Ono S;Iida Y;Hata K;Huang SK;Colquhoun S;Hoon DS
为了评估microRNA（miR）在肝细胞癌（HCC）中的作用，我们使用HCC细胞系进行了全面的microRNA表达谱分析，并将miR-93鉴定为与HCC相关的新靶点。我们通过直接PCR检测进一步验证了晚期HCC肿瘤（n=47）中miR-93的表达水平，发现miR-93表达水平升高与预后不良显著相关。升高的miR-93表达显著刺激体外细胞增殖、迁移和侵袭，并且另外抑制凋亡。我们证实miR-93分别与肿瘤抑制基因PTEN和CDKN 1A的3′非翻译区直接结合，并抑制其表达。作为这种抑制的结果，c-Met/PI 3 K/Akt途径活性增强。HCC肿瘤的IHC分析显示c-Met蛋白表达水平与miR-93表达水平之间存在显著相关性。无论肝细胞生长因子（HGF）处理与否，c-Met的敲低抑制了c-Met/PI 3 K/Akt通路的激活，并进一步降低了这些HCC细胞中miR-93的表达。miR-93还使细胞对索拉非尼和蒂万替尼治疗更敏感。我们的结论是，miR-93通过致癌的c-Met/PI 3 K/Akt途径刺激细胞增殖、迁移和侵袭，并通过直接抑制人HCC中的PTEN和CDKN 1A表达来抑制细胞凋亡。
To assess the role of microRNAs (miR) in hepatocellular carcinoma (HCC), we performed comprehensive microRNA expression profiling using HCC cell lines and identified miR-93 as a novel target associated with HCC. We further verified miR-93 expression levels in advanced HCC tumors (n=47) by a direct PCR assay and found that elevated miR-93 expression level is significantly correlated with poor prognosis. Elevated miR-93 expression significantly stimulated in vitro cell proliferation, migration and invasion, and additionally inhibited apoptosis. We confirmed that miR-93 directly bound with the 3′ untranslated regions of the tumor-suppressor genes PTEN and CDKN1A, respectively,and inhibited their expression. As a result of this inhibition, the c-Met/PI3K/Akt pathway activity was enhanced. IHC analysis of HCC tumors showed significant correlation between c-Met protein expression levels and miR-93 expression levels. Knockdown of c-Met inhibited the activation of the c-Met/PI3K/Akt pathway regardless of hepatocyte growth factor (HGF) treatment, and furthermore reduced the expression of miR-93 in these HCC cells. miR-93 also rendered cells to be more sensitive to sorafenib and tivantinib treatment. We concluded that miR-93 stimulated cell proliferation, migration, and invasion through the oncogenic c-Met/PI3K/Akt pathway and also inhibited apoptosis by directly inhibiting PTEN and CDKN1A expression in human HCC.
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在致癌 BRAF 诱导的黑色素瘤小鼠模型中体内鉴定肿瘤抑制性 PTEN ceRNA。
影响因子：
64.5
作者：
Karreth FA;Tay Y;Perna D;Ala U;Tan SM;Rust AG;DeNicola G;Webster KA;Weiss D;Perez-Mancera PA;Krauthammer M;Halaban R;Provero P;Adams DJ;Tuveson DA;Pandolfi PP
通讯作者：
Pandolfi PP
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
影响因子：
158.5
作者：
SATO, Y;NAKATA, K;NAGATAKI, S
通讯作者：
NAGATAKI, S
DOI：
10.1073/pnas.81.20.6378
发表时间：
1984-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
ISOM, HC;GEORGOFF, I
通讯作者：
GEORGOFF, I
索拉非尼对亚太地区晚期肝细胞癌患者的疗效和安全性：一项 III 期随机、双盲、安慰剂对照试验
影响因子：
51.1
作者：
Cheng, Ann-Lii;Kang, Yoon-Koo;Guan, Zhongzhen
通讯作者：
Guan, Zhongzhen