Overexpression of Mitochondria Mediator Gene TRIAP1 by miR-320b Loss Is Associated with Progression in Nasopharyngeal Carcinoma.
Overexpression of Mitochondria Mediator Gene TRIAP1 by miR-320b Loss Is Associated with Progression in Nasopharyngeal Carcinoma.
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miR-320b 缺失导致线粒体介导基因 TRIAP1 过度表达与鼻咽癌进展相关
DOI：
10.1371/journal.pgen.1006183
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发表时间：
2016-07
期刊：
影响因子：
4.5
通讯作者：
Ma J
中科院分区：
文献类型：
--
作者：
Li Y;Tang X;He Q;Yang X;Ren X;Wen X;Zhang J;Wang Y;Liu N;Ma J
晚期鼻咽癌（NPC）的治疗策略仍然具有挑战性。迫切需要发现鼻咽癌的新治疗靶点。因此，了解鼻咽癌肿瘤发生和进展的机制对于开发新的治疗策略至关重要。在这里，我们发现 TP53 调节的细胞凋亡抑制剂 (TRIAP1) 异常过度表达，并与鼻咽癌患者的不良生存相关。 TRIAP1过表达在体外和体内促进NPC细胞增殖并抑制细胞死亡，而TRIAP1敲低则通过诱导线粒体断裂、膜电位改变和细胞色素c从线粒体释放到细胞质中来抑制细胞肿瘤发生并增强细胞凋亡。与我们之前的 miRNA 数据和可用的生物信息学算法相结合，miR-320b 被鉴定并验证为 TRIAP1 的负调节因子。进一步的研究表明，在体外和体内，miR-320b的过表达抑制鼻咽癌细胞增殖并增强线粒体断裂和细胞凋亡，而miR-320b的沉默促进肿瘤生长并抑制细胞凋亡。此外，TRIAP1 恢复消除了 miR-320b 诱导的增殖抑制和细胞凋亡。此外，鼻咽癌患者中 miR-320b 表达的丧失与 TRIAP1 过度表达呈负相关。这种新发现的 miR-320b/TRIAP1 通路提供了对导致鼻咽癌肿瘤发生和不良临床结果的机制的深入了解，这可能代表鼻咽癌治疗的预后标志物和潜在治疗靶点。晚期鼻咽癌（NPC）的治疗策略仍然具有挑战性。鼻咽癌最迫切的需求是新的治疗靶点。因此，了解鼻咽癌肿瘤发生和进展的机制对于开发新的治疗策略至关重要。在这里，我们发现TRIAP1可以作为鼻咽癌的预后生物标志物，并通过抑制细胞色素c的释放在鼻咽癌肿瘤发生和线粒体凋亡中发挥癌基因的作用。此外，miR-320b转录后调节TRIAP1表达，并通过靶向TRIAP1表现出抑制增殖和促进凋亡的作用。因此，我们的研究为鼻咽癌肿瘤发生和进展的机制提供了新的见解，并确定了鼻咽癌治疗的新治疗靶点。
The therapeutic strategy for advanced nasopharyngeal carcinoma (NPC) is still challenging. It is an urgent need to uncover novel treatment targets for NPC. Therefore, understanding the mechanisms underlying NPC tumorigenesis and progression is essential for the development of new therapeutic strategies. Here, we showed that TP53-regulated inhibitor of apoptosis (TRIAP1) was aberrantly overexpressed and associated with poor survival in NPC patients. TRIAP1 overexpression promoted NPC cell proliferation and suppressed cell death in vitro and in vivo, whereas TRIAP1 knockdown inhibited cell tumorigenesis and enhanced apoptosis through the induction of mitochondrial fragmentation, membrane potential alteration and release of cytochrome c from mitochondria into the cytosol. Intersecting with our previous miRNA data and available bioinformatic algorithms, miR-320b was identified and validated as a negative regulator of TRIAP1. Further studies showed that overexpression of miR-320b suppressed NPC cell proliferation and enhanced mitochondrial fragmentation and apoptosis both in vitro and in vivo, while silencing of miR-320b promoted tumor growth and suppressed apoptosis. Additionally, TRIAP1 restoration abrogated the proliferation inhibition and apoptosis induced by miR-320b. Moreover, the loss of miR-320b expression was inversely correlated with TRIAP1 overexpression in NPC patients. This newly identified miR-320b/TRIAP1 pathway provides insights into the mechanisms leading to NPC tumorigenesis and unfavorable clinical outcomes, which may represent prognostic markers and potential therapeutic targets for NPC treatment. The therapeutic strategy for advanced nasopharyngeal carcinoma (NPC) is still challenging. The most urgent need for NPC is novel treatment targets. Therefore, understanding the mechanisms underlying NPC tumorigenesis and progression is essential for the development of new therapeutic strategies. Here, we identified TRIAP1 could serve as a prognostic biomarker in NPC, and function as an oncogene in NPC tumorigenesis and mitochondrial apoptosis through inhibiting the release of cytochrome c. Moreover, miR-320b post-transcriptionally regulated TRIAP1 expression, and exhibited inhibitory effects on proliferation and promoted apoptosis through targeting TRIAP1. Thus, our study provides new insights into the mechanisms of NPC tumorigenesis and progression and identifies novel therapeutic targets for NPC treatment.