Hypoxia-induced macropinocytosis represents a metabolic route for liver cancer

Hepatocellular carcinoma (HCC) invariably exhibits inadequate O 2 (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...

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Published inNature communications Vol. 13; no. 1; pp. 954 - 19
Main Authors Zhang, Misty Shuo, Cui, Jane Di, Lee, Derek, Yuen, Vincent Wai-Hin, Chiu, David Kung-Chun, Goh, Chi Ching, Cheu, Jacinth Wing-Sum, Tse, Aki Pui-Wah, Bao, Macus Hao-Ran, Wong, Bowie Po Yee, Chen, Carrie Yiling, Wong, Chun-Ming, Ng, Irene Oi-Lin, Wong, Carmen Chak-Lui
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 17.02.2022
Nature Publishing Group
Nature Portfolio
Subjects
13
13/106
14/19
14/28
38/15
59/5
631/67/2327
64/60
692/4020/1503/1504/1610/4029
82/58
Animals
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - immunology
Carcinoma, Hepatocellular - pathology
Carrier Proteins - genetics
Carrier Proteins - metabolism
Cell Line, Tumor
Gene Expression Regulation, Neoplastic - immunology
Gene Knockdown Techniques
Hepatocellular carcinoma
Humanities and Social Sciences
Humans
Hypoxia
Hypoxia-inducible factor 1
Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors
Hypoxia-Inducible Factor 1, alpha Subunit - genetics
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Liver cancer
Liver Neoplasms - genetics
Liver Neoplasms - immunology
Liver Neoplasms - pathology
Membrane proteins
Membrane ruffling
Membranes
Mice
Mice, Knockout
multidisciplinary
Nutrients
Pinocytosis - drug effects
Pinocytosis - genetics
Pinocytosis - immunology
Proof of Concept Study
Proteins
Scavenging
Science
Science (multidisciplinary)
Transcription
Tumor Hypoxia - genetics
Tumor Hypoxia - immunology
Xenograft Model Antitumor Assays
Online AccessGet full text

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Abstract Hepatocellular carcinoma (HCC) invariably exhibits inadequate O 2 (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. Cancer cells rely on macropinocytosis to scavenge extracellular proteins for growth. Here the authors show that macropinocytosis supports the survival of hypoxic hepatocellular carcinoma cells and this is dependent on HIF-1, which in turns activates the transcription of a membrane ruffling protein, EH domain-containing protein 2.
AbstractList Hepatocellular carcinoma (HCC) invariably exhibits inadequate O 2 (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. Cancer cells rely on macropinocytosis to scavenge extracellular proteins for growth. Here the authors show that macropinocytosis supports the survival of hypoxic hepatocellular carcinoma cells and this is dependent on HIF-1, which in turns activates the transcription of a membrane ruffling protein, EH domain-containing protein 2.
Hepatocellular carcinoma (HCC) invariably exhibits inadequate O (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.
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.Cancer cells rely on macropinocytosis to scavenge extracellular proteins for growth. Here the authors show that macropinocytosis supports the survival of hypoxic hepatocellular carcinoma cells and this is dependent on HIF-1, which in turns activates the transcription of a membrane ruffling protein, EH domain-containing protein 2.
Hepatocellular carcinoma (HCC) invariably exhibits inadequate O 2 (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.
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.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.
Cancer cells rely on macropinocytosis to scavenge extracellular proteins for growth. Here the authors show that macropinocytosis supports the survival of hypoxic hepatocellular carcinoma cells and this is dependent on HIF-1, which in turns activates the transcription of a membrane ruffling protein, EH domain-containing protein 2.
ArticleNumber 954
Author Tse, Aki Pui-Wah
Goh, Chi Ching
Chen, Carrie Yiling
Wong, Carmen Chak-Lui
Lee, Derek
Chiu, David Kung-Chun
Bao, Macus Hao-Ran
Yuen, Vincent Wai-Hin
Wong, Chun-Ming
Cheu, Jacinth Wing-Sum
Zhang, Misty Shuo
Cui, Jane Di
Ng, Irene Oi-Lin
Wong, Bowie Po Yee
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  email: carmencl@pathology.hku.hk
  organization: Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, State Key Laboratory of Liver Research, The University of Hong Kong
BackLink https://www.ncbi.nlm.nih.gov/pubmed/35177645$$D View this record in MEDLINE/PubMed
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SSID ssj0000391844
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Snippet Hepatocellular carcinoma (HCC) invariably exhibits inadequate O 2 (hypoxia) and nutrient supply. Hypoxia-inducible factor (HIF) mediates cascades of molecular...
Hepatocellular carcinoma (HCC) invariably exhibits inadequate O (hypoxia) and nutrient supply. Hypoxia-inducible factor (HIF) mediates cascades of molecular...
Hepatocellular carcinoma (HCC) invariably exhibits inadequate O2 (hypoxia) and nutrient supply. Hypoxia-inducible factor (HIF) mediates cascades of molecular...
Cancer cells rely on macropinocytosis to scavenge extracellular proteins for growth. Here the authors show that macropinocytosis supports the survival of...
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pubmedcentral
proquest
pubmed
crossref
springer
SourceType Open Website
Open Access Repository
Aggregation Database
Index Database
Enrichment Source
Publisher
StartPage 954
SubjectTerms 13
13/106
14/19
14/28
38/15
59/5
631/67/2327
64/60
692/4020/1503/1504/1610/4029
82/58
Animals
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - immunology
Carcinoma, Hepatocellular - pathology
Carrier Proteins - genetics
Carrier Proteins - metabolism
Cell Line, Tumor
Gene Expression Regulation, Neoplastic - immunology
Gene Knockdown Techniques
Hepatocellular carcinoma
Humanities and Social Sciences
Humans
Hypoxia
Hypoxia-inducible factor 1
Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors
Hypoxia-Inducible Factor 1, alpha Subunit - genetics
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Liver cancer
Liver Neoplasms - genetics
Liver Neoplasms - immunology
Liver Neoplasms - pathology
Membrane proteins
Membrane ruffling
Membranes
Mice
Mice, Knockout
multidisciplinary
Nutrients
Pinocytosis - drug effects
Pinocytosis - genetics
Pinocytosis - immunology
Proof of Concept Study
Proteins
Scavenging
Science
Science (multidisciplinary)
Transcription
Tumor Hypoxia - genetics
Tumor Hypoxia - immunology
Xenograft Model Antitumor Assays
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Title Hypoxia-induced macropinocytosis represents a metabolic route for liver cancer
URI https://link.springer.com/article/10.1038/s41467-022-28618-9
https://www.ncbi.nlm.nih.gov/pubmed/35177645
https://www.proquest.com/docview/2629521775
https://www.proquest.com/docview/2630920909
https://pubmed.ncbi.nlm.nih.gov/PMC8854584
https://doaj.org/article/8f5cd23985f9487db506e2ab8cfaa555
Volume 13
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