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Exosomal miR-155 Derived from Hepatocellular Carcinoma Cells Under Hypoxia Promotes Angiogenesis in Endothelial Cells

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Abstract

Purpose

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In this study, we aim to clarify whether exosomes secreted from hepatocellular carcinoma (HCC) cells under hypoxia affect angiogenesis in endothelial cells.

Methods

Exosomes derived from human liver cancer cell lines were cultured under hypoxic or normoxic conditions for 24 h, isolated using ExoQuick-TC®, and co-cultured with HUVECs to evaluate angiogenic activity. We also evaluated the expression of miR-155 in the exosomes from 40 patients with HCC.

Results

Exosomes under hypoxia remarkably enhanced tube formation of HUVECs. Both cellular and exosomal miR-155 were significantly up-regulated under hypoxic conditions. Knockdown of miR-155 in HCC cells attenuated the promotion of tube formation by exosomes under hypoxia in HUVECs, and high expression of exosomal miR-155 in preoperative plasma was significantly correlated with early recurrence.

Conclusion

These results suggest that exosomes derived from HCC cells under hypoxia induce tube formation of HUVECs and that exosomal miR-155 may affect angiogenic activity in HCC.

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Acknowledgments

This work was supported by JSPS KAKENHI Grant No. JP 26462043.

Author information

Authors and Affiliations

  1. Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2, E-2, Yamadaoka, Suita, Osaka, 565-0871, Japan

    Yusuke Matsuura, Hiroshi Wada, Hidetoshi Eguchi, Kunihito Gotoh, Shogo Kobayashi, Mitsuru Kinoshita, Masahiko Kubo, Koji Hayashi, Yoshifumi Iwagami, Daisaku Yamada, Tadafumi Asaoka, Takehiro Noda, Koichi Kawamoto, Yutaka Takeda, Masahiro Tanemura, Yuichiro Doki & Masaki Mori

  2. Department of Surgery, Kansai Rosai Hospital, Inabasou 3-1-69, Amagasaki, Hyogo, 660-8511, Japan

    Yutaka Takeda

  3. Department of Surgery, Osaka Police Hospital, Tennoji-ku, Kitayamacho 10-31, Osaka, 543-0035, Japan

    Masahiro Tanemura

  4. Division of Health Sciences, Graduate School of Medicine, Osaka University, 2-2, E-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Koji Umeshita

Authors
  1. Yusuke Matsuura
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Corresponding author

Correspondence to Hidetoshi Eguchi.

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Supplementary Figure 1

a Exosomes secreted from HCC cells suppressed the growth of HCC, but there was no difference between effects of exosomes from normoxic and hypoxic conditions in PLC/PRF/5and HuH7. b Exosomes secreted from HCC cells suppressed the growth of HUVECs, but there was no difference between the effects of exosomes from normoxic and hypoxic conditions in PLC/PRF/5 and HuH7 (TIF 787 kb)

Supplementary Figure 2

The expression of exosomal miRNA of PLC/PRF/5 associated with angiogenesis. Only miR-155 in hypoxia was significantly higher than that in normoxia (**p < 0.01) (TIF 776 kb)

Supplementary Figure 3

The expression of cellular a and exosomal b miR-155 in hypoxia was significantly higher than that in normoxia, in both PLC and HuH7 (**p < 0.01). c The expression of cellular miR-155 exposed to CoCl2 was significantly higher than control (**p < 0.01) (TIF 763 kb)

Supplementary Figure 4

a Transfection of anti-miR-155 inhibitor significantly suppressed the expression of cellular miR-155. b Transfection of anti-miR-155 inhibitor significantly suppressed the expression of exosomal miR-155, which was upregulated by hypoxia (TIF 767 kb)

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Matsuura, Y., Wada, H., Eguchi, H. et al. Exosomal miR-155 Derived from Hepatocellular Carcinoma Cells Under Hypoxia Promotes Angiogenesis in Endothelial Cells. Dig Dis Sci 64, 792–802 (2019). https://doi.org/10.1007/s10620-018-5380-1

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  • DOI: https://doi.org/10.1007/s10620-018-5380-1

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