Serum exosomes contain ECRG4 mRNA that suppresses tumor growth via inhibition of genes involved in inflammation, cell proliferation, and angiogenesis
Serum exosomes contain ECRG4 mRNA that suppresses tumor growth via inhibition of genes involved in inflammation, cell proliferation, and angiogenesis
复制标题
血清外泌体含有 ECRG4 mRNA，可通过抑制炎症、细胞增殖和血管生成相关基因来抑制肿瘤生长
DOI：
10.1038/s41417-018-0032-3
复制
发表时间：
2018-10-01
影响因子：
6.4
通讯作者：
Dang, Xitong
中科院分区：
文献类型：
--
作者：
Mao, Liang;Li, Xue;Dang, Xitong
食管癌相关基因 4 (Ecrg4) 已被证明是许多器官的肿瘤抑制因子。外泌体是天然分泌的纳米颗粒，携带信号分子，包括微小RNA (miRNA)、长链非编码RNA (lncRNA) 和信使RNA (mRNA) 等。内化后，外泌体卸载其货物，进而调节受体细胞的生物学特性。越来越多的证据表明外泌体 miRNA 具有功能。然而，关于外泌体携带功能性 mRNA 的报道仍然很少。我们发现血清外泌体含有ECRG4开放阅读框。为了模拟血清外泌体 ECRG4，创建了表达 ECRG4 的稳定细胞系，从中分离和表征外泌体，并评估外泌体 ECRG4 的内化和由此产生的生物学效应。结果表明，健康个体的血清外泌体中 ECRG4 mRNA 的含量高于癌症个体。外泌体 ECRG4 可以被内化并将封装的 ECRG4 卸载到受体细胞中，随后抑制体外细胞增殖，并抑制异种移植小鼠模型中的肿瘤生长。从机制上讲，含有 ECRG4 的外泌体在内化时会抑制通常与炎症、细胞增殖和血管生成有关的基因的表达。鉴于外泌体是治疗递送的理想载体，并且 ECRG4 是肿瘤抑制基因，因此外泌体 ECRG4 可用作癌症基因治疗的制剂。
Esophageal cancer related gene-4 (Ecrg4) has been shown to be a tumor suppressor in many organs. Exosomes are naturally secreted nanosized particles that carry signal molecules including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and messenger RNAs (mRNAs) among others. Upon internalization, exosomes unload their cargos that in turn modulate the biology of the recipient cells. Mounting evidence has shown that exosomal miRNAs are functional. However, reports that exosomes carry functional mRNAs remain scarce. We found that serum exosomes contain ECRG4 open reading frame. To simulate serum exosomal ECRG4, stable cell line expressing ECRG4 was created, from which exosomes were isolated and characterized, and the internalization and the resulting biological effects of exosomal ECRG4 were evaluated. Results showed that serum exosomes contain higher levels of ECRG4 mRNA in healthy individuals than their cancer counterparts. Exosomal ECRG4 can be internalized and unload the encapsulated ECRG4 into recipient cells, which subsequently suppressed cell proliferation in vitro, and inhibited tumor growth in a xenograft mouse model. Mechanistically, ECRG4-containing exosomes, when internalized, suppressed the expression of genes commonly implicated in inflammation, cell proliferation, and angiogenesis. Given that exosome is an ideal vehicle for therapeutics delivery and that ECRG4 is a tumor suppressor gene, the exosomal ECRG4 can be exploited as a formulation for cancer gene therapy.