IFIT3 (interferon induced protein with tetratricopeptide repeats 3) modulates STAT1 expression in small extracellular vesicles.
IFIT3 (interferon induced protein with tetratricopeptide repeats 3) modulates STAT1 expression in small extracellular vesicles.
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DOI：
10.1042/bcj20210580
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发表时间：
2021-11-12
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我们先前已经表明αvβ6整合素在促进前列腺癌（PrCa）中起关键作用，并且它可以通过小细胞外囊泡（sEV）转移到受体细胞。此外，我们在蛋白质组学分析中报告了αvβ6整合素下调增加了PrCa细胞及其衍生的sEV中IFIT 3（具有三肽重复序列3的干扰素诱导蛋白）的表达。IFIT 3是一种众所周知的抗病毒效应蛋白，但最近它在癌症中的作用也得到了阐明。为了研究IFIT 3和STAT 1（信号转导和转录激活因子1）之间的关系，IFIT 3的上游调节因子，在PrCa细胞及其释放的sEV中，我们使用CRISPR/Cas9技术下调β6整合素亚基IFIT 3或STAT 1的表达。我们的研究结果表明，IFIT 3和STAT 1在缺乏β6整合素亚基的PrCa细胞中高度表达。然而，IFIT 3而不是STAT 1存在于来源于缺乏β6整联蛋白亚基的PrCa细胞的sEV中。我们证明，IFIT 3的缺失产生富含STAT 1的sEV，但降低了细胞中STAT 1的水平。正如预期的那样，在STAT 1阴性细胞或sEV中检测不到IFIT 3。因此，我们提出，所观察到的STAT 1富集sEV是IFIT 3损失的补偿机制。总的来说，这些结果为IFIT 3作为sEV中STAT 1表达的调节剂和PrCa中细胞间通讯的内在作用提供了新的见解。
We have previously shown that the αvβ6 integrin plays a key role in promoting prostate cancer (PrCa) and it can be transferred to recipient cells via small extracellular vesicles (sEVs). Furthermore, we have reported in a proteomic analysis that αvβ6 integrin down-regulation increases the expression of IFIT3 (interferon induced protein with tetratricopeptide repeats 3) in PrCa cells and their derived sEVs. IFIT3 is a protein well known for being an antiviral effector, but recently its role in cancer has also been elucidated. To study the relationship between IFIT3 and STAT1 (signal transducer and activator of transcription 1), an upstream regulator of IFIT3, in PrCa cells and their released sEVs, we used CRISPR/Cas9 techniques to down-regulate the expression of the β6 integrin subunit, IFIT3 or STAT1. Our results show that IFIT3 and STAT1 are highly expressed in PrCa cells devoid of the β6 integrin subunit. However, IFIT3 but not STAT1, is present in sEVs derived from PrCa cells lacking the β6 integrin subunit. We demonstrate that loss of IFIT3 generates sEVs enriched in STAT1 but reduces the levels of STAT1 in the cells. As expected, IFIT3 is not detectable in STAT1 negative cells or sEVs. We thus propose that the observed STAT1 enrichment in sEVs is a compensatory mechanism for the loss of IFIT3. Overall, these results provide new insights into the intrinsic role of IFIT3 as a regulator of STAT1 expression in sEVs and in intercellular communication in PrCa.