PDF(Pubmed)
Abstract：
Oncogenic intercellular signaling is regulated by extracellular vesicles (EVs), but the underlying mechanisms remain mostly unclear. Since TCTP (translationally controlled tumor protein) is an EV component, we investigated whether it has a role in genotoxic stress signaling and malignant transformation. By generating a Tctp-inducible knockout mouse model (Tctp-/f-), we report that Tctp is required for genotoxic stress-induced apoptosis signaling via small EVs (sEVs). Human breast cancer cells knocked-down for TCTP show impaired spontaneous EV secretion, thereby reducing sEV-dependent malignant growth. Since Trp53-/- mice are prone to tumor formation, we derived tumor cells from Trp53-/-;Tctp-/f- double mutant mice and describe a drastic decrease in tumori-genicity with concomitant decrease in sEV secretion and content. Remarkably, Trp53-/-;Tctp-/f- mice show highly prolonged survival. Treatment of Trp53-/- mice with sertraline, which inhibits TCTP function, increases their survival. Mechanistically, TCTP binds DDX3, recruiting RNAs, including miRNAs, to sEVs. Our findings establish TCTP as an essential protagonist in the regulation of sEV-signaling in the context of apoptosis and tumorigenicity.
摘要：
致癌细胞间信号传导是由细胞外囊泡（EV），但潜在的机制仍不清楚。由于TCTP（翻译控制的肿瘤蛋白）是一种EV成分，我们调查了它是否在基因毒性应激信号和恶性转化中发挥作用.通过生成Tctp诱导的敲除小鼠模型（Tctp-/f-），我们报道Tctp是通过小型EV(sEV)的基因毒性应激诱导的细胞凋亡信号传导所必需的.TCTP敲低的人乳腺癌细胞显示自发EV分泌受损，从而减少sEV依赖性恶性生长。由于Trp53-/-小鼠容易形成肿瘤，我们从Trp53-/-;Tctp-/f-双突变小鼠中获得了肿瘤细胞，并描述了肿瘤发生性的急剧下降，同时sEV的分泌和含量也随之下降。值得注意的是,Trp53-/-;Tctp-/f-小鼠显示高度延长的存活。用舍曲林治疗Trp53-/-小鼠，抑制TCTP功能，增加他们的生存。机械上,TCTP结合DDX3，招募RNA，包括miRNAs,到sEV。我们的发现将TCTP确立为凋亡和致瘤性背景下sEV信号调节的重要主角。
