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Hypoxia-inducible Factor Orchestrates Adenosine Metabolism to Promote Liver Cancer Development by Jacinth Wing-Sum Cheu; David Kung-Chun Chiu; Kenneth Kin-Leung Kwan; Chunxue Yang; Vincent Wai-Hin Yuen; Chi Ching Goh; Noreen Nog-Qin Chui; Wei Shen; Cheuk-Ting Law; Qidong Li; Misty Shuo Zhang; Macus Hao-Ran Bao; Bowie Po-Yee Wong; Cerise Yuen-Ki Chan; Cindy Xinqi Liu; Grace Fu-Wan Sit; Zher Yee Ooi; Haijing Deng; Aki Pui-Wah Tse; Irene Oi-Lin Ng; Carmen Chak-Lui Wong is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

What is Hypoxia-inducible Factor Orchestrates Adenosine Metabolism to Promote Liver Cancer Development about?

Hypoxia-induced adenosine creates an immunosuppressive tumor microenvironment (TME) and dampens the efficacy of immune checkpoint inhibitors (ICIs). We found that hypoxia-inducible factor 1 (HIF-1) orchestrates adenosine efflux through two steps in hepatocellular carcinoma (HCC). First, HIF-1 activates transcriptional repressor MXI1, which inhibits adenosine kinase (ADK), resulting in the failure of adenosine phosphorylation to adenosine monophosphate. This leads to adenosine accumulation in hypoxic cancer cells. Second, HIF-1 transcriptionally activates equilibrative nucleoside transporter 4, pumping adenosine into the interstitial space of HCC, elevating extracellular adenosine levels. Multiple in vitro assays demonstrated the immunosuppressive role of adenosine on T cells and myeloid cells. Knockout of ADK in vivo skewed intratumoral immune cells to protumorigenic and promoted tumor progression. Therapeutically, combination treatment of adenosine receptor antagonists and anti–PD-1 prolonged survival of HCC-bearing mice. We illustrated the dual role of hypoxia in establishing an adenosine-mediated immunosuppressive TME and offered a potential therapeutic approach that synergizes

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Author

Jacinth Wing-Sum Cheu; David Kung-Chun Chiu; Kenneth Kin-Leung Kwan; Chunxue Yang; Vincent Wai-Hin Yuen; Chi Ching Goh; Noreen Nog-Qin Chui; Wei Shen; Cheuk-Ting Law; Qidong Li; Misty Shuo Zhang; Macus Hao-Ran Bao; Bowie Po-Yee Wong; Cerise Yuen-Ki Chan; Cindy Xinqi Liu; Grace Fu-Wan Sit; Zher Yee Ooi; Haijing Deng; Aki Pui-Wah Tse; Irene Oi-Lin Ng; Carmen Chak-Lui Wong

Publisher

American Association for the Advancement of Science (AAAS)

Published

2023

Language

EN

Field

Biochemistry, Genetics and Molecular Biology (Physical Sciences)