Hypoxia-induced macropinocytosis represents a metabolic route for liver cancer

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 Yiling Chen, Chun-Ming Wong, Irene Oi-Lin Ng and Carmen Chak-Lui Wong ()
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Misty Shuo Zhang: The University of Hong Kong
Jane Di Cui: The University of Hong Kong
Derek Lee: The University of Hong Kong
Vincent Wai-Hin Yuen: The University of Hong Kong
David Kung-Chun Chiu: The University of Hong Kong
Chi Ching Goh: The University of Hong Kong
Jacinth Wing-Sum Cheu: The University of Hong Kong
Aki Pui-Wah Tse: The University of Hong Kong
Macus Hao-Ran Bao: The University of Hong Kong
Bowie Po Yee Wong: The University of Hong Kong
Carrie Yiling Chen: The University of Hong Kong
Chun-Ming Wong: The University of Hong Kong
Irene Oi-Lin Ng: The University of Hong Kong
Carmen Chak-Lui Wong: The University of Hong Kong

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28618-9

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