Upregulated TRIM29 promotes proliferation and metastasis of nasopharyngeal carcinoma via PTEN/AKT/mTOR signal pathway
Upregulated TRIM29 promotes proliferation and metastasis of nasopharyngeal carcinoma via PTEN/AKT/mTOR signal pathway
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TRIM29上调通过PTEN/AKT/mTOR信号通路促进鼻咽癌增殖和转移
DOI：
10.18632/oncotarget.7215
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发表时间：
2016-03-22
期刊：
影响因子：
--
通讯作者：
Mai, Shi-Juan
中科院分区：
文献类型：
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作者：
Zhou, Xiao-Min;Sun, Rui;Mai, Shi-Juan
据报道，含有三分基序的29（TRIM 29）在人类癌症中失调。在我们之前的研究中，通过全基因组转录组分析首次在NPC细胞系中观察到TRIM 29的上调。但其在鼻咽癌中的表达、生物学功能及临床意义尚不清楚。在这项研究中，TRIM 29的表达通过qRT-PCR和免疫组化验证在69个NPC样本。TRIM 29蛋白表达与肿瘤大小、临床分期及转移密切相关。TRIM 29被鉴定为miR-335- 5 p和miR-15 b-5 p的直接靶点，这两种miR-335- 5 p和miR-15 b-5 p在NPC细胞系和临床样品中均下调并与TRIM 29表达负相关。TRIM 29的异位表达促进鼻咽癌细胞的增殖、上皮间质转化（EMT）、迁移和侵袭，而TRIM 29的缺失则抑制细胞的侵袭和EMT表型。机制上，TRIM 29过表达降低了PTEN表达，并增加了AKT、p70 S6 K和4 E-BP 1的磷酸化蛋白水平。相应地，AKT抑制剂和雷帕霉素阻断TRIM 29对细胞侵袭的作用。总之，我们的结果表明，miR-335- 5 p和miR-15 b-5 p下调导致TRIM 29过表达，从而通过PTEN/AKT/mTOR信号通路诱导NPC的增殖、EMT和转移。
Tripartite motif-containing 29 (TRIM29) has been reported to be dysregulated in human cancers. Up-regulation of TRIM29 was first observed in NPC cell lines by a genome-wide transcriptome analysis in our previous study. However, its expression biological function and clinical significance in nasopharyngeal carcinoma (NPC) remain unclear. In this study, TRIM29 expression was validated by qRT-PCR and immunohistochemistry in 69 NPC samples. Notably, TRIM29 protein expression was significantly and positively correlated with the tumor size, clinical stage and metastasis. TRIM29 was identified as the direct target of miR-335-5p and miR-15b-5p, both of which were down-regulated and negatively associated with TRIM29 expression in NPC cell lines and clinical samples. Ectopic TRIM29 expression promoted proliferation, epithelial-mesenchymal transition (EMT), migration and invasion in NPC cells, while its depletion inhibited cell invasion and EMT phenotype. Mechanistically, TRIM29 overexpression reduced PTEN expression and increase phosphorylated protein level of AKT, p70S6K and 4E-BP1. Correspondingly, AKT inhibitor and Rapamycin blocked the effect of TRIM29 on cell invasion. In conclusion, our results suggest that miR-335-5p and miR-15b-5p down-regulation results in TRIM29 over-expression, which induces proliferation, EMT and metastasis of NPC through the PTEN/AKT/mTOR signaling pathway.