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Hypoxia-induced macropinocytosis represents a metabolic route for liver cancer

Author

Listed:
  • Misty Shuo Zhang

    (The University of Hong Kong
    The University of Hong Kong)

  • Jane Di Cui

    (The University of Hong Kong
    The University of Hong Kong)

  • Derek Lee

    (The University of Hong Kong
    The University of Hong Kong)

  • Vincent Wai-Hin Yuen

    (The University of Hong Kong
    The University of Hong Kong)

  • David Kung-Chun Chiu

    (The University of Hong Kong
    The University of Hong Kong)

  • Chi Ching Goh

    (The University of Hong Kong
    The University of Hong Kong)

  • Jacinth Wing-Sum Cheu

    (The University of Hong Kong
    The University of Hong Kong)

  • Aki Pui-Wah Tse

    (The University of Hong Kong
    The University of Hong Kong)

  • Macus Hao-Ran Bao

    (The University of Hong Kong
    The University of Hong Kong)

  • Bowie Po Yee Wong

    (The University of Hong Kong
    The University of Hong Kong)

  • Carrie Yiling Chen

    (The University of Hong Kong
    The University of Hong Kong)

  • Chun-Ming Wong

    (The University of Hong Kong
    The University of Hong Kong)

  • Irene Oi-Lin Ng

    (The University of Hong Kong
    The University of Hong Kong)

  • Carmen Chak-Lui Wong

    (The University of Hong Kong
    The University of Hong Kong)

Abstract

Hepatocellular carcinoma (HCC) invariably exhibits inadequate O2 (hypoxia) and nutrient supply. Hypoxia-inducible factor (HIF) mediates cascades of molecular events that enable cancer cells to adapt and propagate. Macropinocytosis is an endocytic process initiated by membrane ruffling, causing the engulfment of extracellular fluids (proteins), protein digestion and subsequent incorporation into the biomass. We show that macropinocytosis occurs universally in HCC under hypoxia. HIF-1 activates the transcription of a membrane ruffling protein, EH domain-containing protein 2 (EHD2), to initiate macropinocytosis. Knockout of HIF-1 or EHD2 represses hypoxia-induced macropinocytosis and prevents hypoxic HCC cells from scavenging protein that support cell growth. Germline or somatic deletion of Ehd2 suppresses macropinocytosis and HCC development in mice. Intriguingly, EHD2 is overexpressed in HCC. Consistently, HIF-1 or macropinocytosis inhibitor suppresses macropinocytosis and HCC development. Thus, we show that hypoxia induces macropinocytosis through the HIF/EHD2 pathway in HCC cells, harnessing extracellular protein as a nutrient to survive.

Suggested Citation

  • Misty Shuo Zhang & Jane Di Cui & Derek Lee & Vincent Wai-Hin Yuen & David Kung-Chun Chiu & Chi Ching Goh & Jacinth Wing-Sum Cheu & Aki Pui-Wah Tse & Macus Hao-Ran Bao & Bowie Po Yee Wong & Carrie Yili, 2022. "Hypoxia-induced macropinocytosis represents a metabolic route for liver cancer," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28618-9
    DOI: 10.1038/s41467-022-28618-9
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    References listed on IDEAS

    as
    1. Craig Ramirez & Andrew D. Hauser & Emily A. Vucic & Dafna Bar-Sagi, 2019. "Plasma membrane V-ATPase controls oncogenic RAS-induced macropinocytosis," Nature, Nature, vol. 576(7787), pages 477-481, December.
    2. Cosimo Commisso & Shawn M. Davidson & Rengin G. Soydaner-Azeloglu & Seth J. Parker & Jurre J. Kamphorst & Sean Hackett & Elda Grabocka & Michel Nofal & Jeffrey A. Drebin & Craig B. Thompson & Joshua D, 2013. "Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells," Nature, Nature, vol. 497(7451), pages 633-637, May.
    3. Vaishali Jayashankar & Aimee L. Edinger, 2020. "Macropinocytosis confers resistance to therapies targeting cancer anabolism," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    4. David Kung-Chun Chiu & Aki Pui-Wah Tse & Iris Ming-Jing Xu & Jane Cui & Robin Kit-Ho Lai & Lynna Lan Li & Hui-Yu Koh & Felice Ho-Ching Tsang & Larry Lai Wei & Chun-Ming Wong & Irene Oi-Lin Ng & Carmen, 2017. "Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma," Nature Communications, Nature, vol. 8(1), pages 1-12, December.
    5. Julianty Frost & Carles Galdeano & Pedro Soares & Morgan S. Gadd & Katarzyna M. Grzes & Lucy Ellis & Ola Epemolu & Satoko Shimamura & Marcus Bantscheff & Paola Grandi & Kevin D. Read & Doreen A. Cantr, 2016. "Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition," Nature Communications, Nature, vol. 7(1), pages 1-12, December.
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