A novel TP53 pathway influences the HGS-mediated exosome formation in colorectal cancer.
A novel TP53 pathway influences the HGS-mediated exosome formation in colorectal cancer.
复制标题
一种新的 TP53 通路影响结直肠癌中 HGS 介导的外泌体形成。
DOI：
10.1038/srep28083
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发表时间：
2016-06-17
影响因子：
4.6
通讯作者：
Zhao X
中科院分区：
文献类型：
--
作者：
Sun Y;Zheng W;Guo Z;Ju Q;Zhu L;Gao J;Zhou L;Liu F;Xu Y;Zhan Q;Zhou Z;Sun W;Zhao X
肿瘤来源的外泌体对于细胞-细胞通信是重要的。然而，TP 53在控制结直肠癌（CRC）中的外泌体产生中的作用是有争议和不清楚的。评估了从HCT 116 TP 53-野生型（WT）、TP 53-敲除（KO）和构建的TP 53（R273 H）-突变体（MT）细胞分泌的外泌体的特征。与WT细胞相比，来自MT和KO细胞的外泌体表现出显著减小的尺寸。使用用于相对和绝对定量的同量异位素标签（iTRAQ）-2D-LC-MS/MS策略对外来体蛋白进行全面的蛋白质组学分析。共鉴定了3437个蛋白质组，具有≥2个匹配肽。具体而言，肝细胞生长因子调节的酪氨酸激酶底物（HGS）在MT和KO细胞的外泌体中持续下调。功能研究表明，低HGS水平是外泌体大小减小的原因。TP 53调节HGS表达，从而调节HGS依赖性外泌体形成。HGS的表达随结直肠癌的发生而逐渐增加，是一个独立的不良预后因素。总之，在CRC中鉴定了外泌体形成中的新的HGS依赖性TP 53机制。HGS可作为一种新的预后生物标志物和治疗干预的候选靶点。
Tumor-derived exosomes are important for cell-cell communication. However, the role of TP53 in the control of exosome production in colorectal cancer (CRC) is controversial and unclear. The features of exosomes secreted from HCT116 TP53-wild type (WT), TP53-knockout (KO) and constructed TP53 (R273H)-mutant (MT) cells were assessed. The exosomes from the MT and KO cells exhibited significantly reduced sizes compared with the WT cells. A comprehensive proteomic analysis of exosomal proteins was performed using the isobaric tag for relative and absolute quantitation (iTRAQ)-2D-LC-MS/MS strategy. A total of 3437 protein groups with ≥2 matched peptides were identified. Specifically, hepatocyte growth factor-regulated tyrosine kinase substrate (HGS) was consistently down-regulated in the exosomes from the MT and KO cells. Functional studies demonstrated that low HGS levels were responsible for the decreased exosome size. TP53 regulated HGS expression and thus HGS-dependent exosome formation. Furthermore, the HGS expression was gradually increased concomitant with CRC carcinogenesis and was an independent poor prognostic factor. In conclusion, a novel HGS-dependent TP53 mechanism in exosome formation was identified in CRC. HGS may serve as a novel prognostic biomarker and a candidate target for therapeutic interventions.