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The critical role of STAT3 in biogenesis of tumor-derived exosomes with potency of inducing cancer cachexia in vitro and in vivo

Oncogene volume 41, pages 1050–1062 (2022)Cite this article

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Abstract

Tumor-derived exosomes are emerging mediators of cancer cachexia. Clarifying the regulation of exosome biogenesis and finding possible targets for cancer cachexia therapy are important and necessary. In the present study, systemic analysis of the roles of STAT3 in controlling exosome biogenesis of murine C26 colon tumor cells and its contribution to the development of cancer cachexia is conducted. The genetic manipulation of STAT3 expression, STAT3 knockout (KO) or overexpression (OE), significantly affected the exosome biogenesis and also the potency of C26 conditioned medium (CM) in inducing muscle atrophy and lipolysis in vitro. The genetic manipulation of STAT3 expression caused change in phosphorylation of PKM2 and glycolysis. PKM2/SNAP23 pathway was involved in regulation of exosome biogenesis by STAT3 genetic manipulation as well as by STAT3 inhibitors in C26 cells. Mice inoculated with STAT3 knockout or overexpression C26 cells exhibited ameliorated or aggravated cancer cachexia symptoms, with a positive correlation with the serum exosome and IL-6 levels. The STAT3/PKM2/SNAP23 pathway was affected in C26 tumor tissues with genetic manipulation of STAT3 expression. The capacity of exosome biogenesis of different human cancer cells also exhibited a positive correlation with the activation of STAT3/PKM2/SNAP23 pathway. The research presented here confirms that STAT3 plays a critical role in regulating biogenesis of tumor-derived exosomes which could contribute to cancer cachexia development.

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Fig. 1: Changes in STAT3 expression level and activation could influence the biogenesis of exosomes in C26 cells.
Fig. 2: Effects of CM of C26-STAT3-KO or C26-STAT3-OE cells in inducing atrophy of C2C12 myotubes and lipolysis of 3T3-L1 adipocytes.
Fig. 3: The STAT3/PKM2/SNAP23 pathway might be involved in the exosome biogenesis regulation.
Fig. 4: Effects of C26-STAT3-KO or C26-STAT3-OE cells in inducing cancer cachexia in mice.
Fig. 5: Effects of C26-STAT3-KO or C26-STAT3-OE cells in inducing muscle atrophy and fat loss in mice.
Fig. 6: The roles of STAT3 in the regulation of exosome biogenesis in human cancer cells.
Fig. 7: STAT3 activates PKM2 and SNAP23 phosphorylation to regulate the exosome secretion of C26 tumor cells which is involved in the induction of cancer cachexia.

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Acknowledgements

This work was supported by National Nature Science Foundation of China (No. 81872496 and 81873056), and the Science and Technology Commission of Shanghai Municipality (20S11902200 and 16DZ2280100).

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  1. Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China

    Meng Fan, Weikuan Sun, Xiaofan Gu, Shanshan Lu & Xiongwen Zhang

  2. Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    Qiang Shen & Xuan Liu

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  1. Meng Fan
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MF performed the experiments, analyzed the data, and drafted the manuscript. WS, XG, SL, and QS were involved in performing the experiments. XL and XZ supervised the project, designed the study, and revised the manuscript. All authors reviewed and approved the final manuscript.

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Fan, M., Sun, W., Gu, X. et al. The critical role of STAT3 in biogenesis of tumor-derived exosomes with potency of inducing cancer cachexia in vitro and in vivo. Oncogene 41, 1050–1062 (2022). https://doi.org/10.1038/s41388-021-02151-3

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