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Hypoxic gastric cancer-derived exosomes promote progression and metastasis via MiR-301a-3p/PHD3/HIF-1α positive feedback loop

Oncogene volume 39, pages 6231–6244 (2020)Cite this article

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A Correction to this article was published on 08 September 2021

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Abstract

Hypoxic tumor microenvironment(TME) is a universal feature in solid carcinoma and is associated with unfavorable prognosis. Tumor-derived exosomes are now significantly implicating in mediating cellular communication and interactions in TME. The aim of this study was to identify exosomal miR-301a-3p involved in gastric cancer(GC) progression and metastasis. Here, we found hypoxia promote GC exosomes release and miR-301a-3p expression in an HIF-1α-dependent manner. In hypoxic TME, enriched miR-301a-3p could be transmitted between GC cells via exosomes and then contributed to inhibit HIF-1α degradation through targeting PHD3, that were capable to hydroxylate HIF-1α subunits to ubiquitinate degradation. This synergistical positive feedback loop between HIF-1α and miR-301a-3p facilitated GC proliferation, invasion, migration, and epithelial–mesenchymal transition. In clinical samples, we further discovered circulating exosomal miR-301a-3p in serum was positively related with peritoneal metastasis. Collectively, these data indicate that GC cells could generate miR-301a-3p–rich exosomes in the hypoxic TME, which then help to HIF-1α accumulation and promote GC malignant behaviors and metastasis. Exosomal miR-301a-3p/HIF-1α signaling axis may serve as a promising predictor and potential therapeutic target of GC with metastasis.

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Fig. 1: HIF-1α-facilitated exosomes release both in GC cells and tissues under hypoxia.
Fig. 2: Hypoxia GC-derived exosomes promoted GC proliferation, invasion, migration, and colony formation both in vitro and in vivo.
Fig. 3: MiR-301a-3p was highly expressed in H-exo and can be direct transfer between GC cells.
Fig. 4: Hypoxia-induced GC-exosomal miR-301a-3p promoted GC progression and metastasis.
Fig. 5: HIF-1α-induced miR-301a-3p increased stability of HIF-1α by targeting PHD3.
Fig. 6: MiR-301a-3p positively correlated with HIF-1α in GC and is associated with GC peritoneal metastasis in serum exosomes.
Fig. 7: Schematic model of exo-miR-301a-3p in gastric cancer progression.

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Acknowledgements

We kindly thank the editor and reviewers for careful review and valuable comments, which have led to a significant improvement of the manuscript. XX wants to thank the care and support from his parents, Xiaokang Xia and Xiaoping Li, thank Huiying Lu for the heartbeat at first glimpse she gave.

Funding

The National Natural Science Foundation of China (grant numbers: 81802313 and 81972206). Shanghai Sailing Program (Grant No. 17YF1415700). The funding bodies had no role in the design of the study and collection, analysis, and interpretation of data and in the writing of the manuscript.

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  1. These authors contributed equally: Xiang Xia, Shuchang Wang, Bo Ni

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  1. Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Xiang Xia, Shuchang Wang, Bo Ni, Hui Cao, Zizhen Zhang, Fengrong Yu, Enhao Zhao & Gang Zhao

  2. Department of Critical Care, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Shunpeng Xing

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Xia, X., Wang, S., Ni, B. et al. Hypoxic gastric cancer-derived exosomes promote progression and metastasis via MiR-301a-3p/PHD3/HIF-1α positive feedback loop. Oncogene 39, 6231–6244 (2020). https://doi.org/10.1038/s41388-020-01425-6

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