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Serum exosomes contain ECRG4 mRNA that suppresses tumor growth via inhibition of genes involved in inflammation, cell proliferation, and angiogenesis

Cancer Gene Therapy volume 25, pages 248–259 (2018)Cite this article

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Abstract

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.

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Acknowledgements

The research was supported by Luzhou-Sichuan Medical University joint scientific funding (2015LZCYD-S03(4/7)), funding from National Natural Science Foundation of China (#81770336 to XD), and Promotion/Application Project of the Committee of Health and Family Planning of Sichuan (16PJ535 to LM), and Key Project of Educational Department of Sichuan (17ZA0443 to LM). The funding agencies have no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript

Author contributions:

Conceived the research and wrote the manuscript: XD; performed the experiments, collected and analyzed data: LM, XL, SG, HY, YJ, WH, XS. All authors have read and approved the final version of the manuscript.

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  1. These authors contributed equally: Liang Mao, Xue Li.

Authors and Affiliations

  1. Institute of Cardiovascular Research, The Key Laboratory of Medical Electrophysiology, Ministry of Education, Southwest Medical University, Luzhou, Sichuan, 646000, China

    Liang Mao, Xue Li, Haiyang Yuan, Yu Jiang, Wenjun Huang & Xitong Dang

  2. Department of Pathophysiology, Southwest Medical University, Luzhou, Sichuan, 646000, China

    Shu Gong

  3. Department of Pathology, Southwest Medical University, Luzhou, Sichuan, 646000, China

    Xingwang Sun

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Correspondence to Xitong Dang.

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Mao, L., Li, X., Gong, S. et al. Serum exosomes contain ECRG4 mRNA that suppresses tumor growth via inhibition of genes involved in inflammation, cell proliferation, and angiogenesis. Cancer Gene Ther 25, 248–259 (2018). https://doi.org/10.1038/s41417-018-0032-3

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