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Hypoxia signaling in hepatocellular carcinoma: Challenges and therapeutic opportunities

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Abstract

Hepatocellular carcinoma (HCC) is one of the most common cancers with a relatively high cancer-related mortality. The uncontrolled proliferation of HCC consumes a significant amount of oxygen, causing the development of a hypoxic tumor microenvironment (TME). Hypoxia-inducible factors (HIFs), crucial regulators in the TME, activate several cancer hallmarks leading to the hepatocarcinogenesis of HCC and resistance to current therapeutics. As such, HIFs and their signaling pathways have been explored as potential therapeutic targets for the future management of HCC. This review discusses the current understanding of the structure and function of HIFs and their complex relationship with the various cancer hallmarks. To address tumor hypoxia, this review provides an insight into the various potential novel therapeutic agents for managing HCC, such as hypoxia-activated prodrugs, HIF inhibitors, nanomaterials, antisense oligonucleotides, and natural compounds, that target HIFs/hypoxic signaling pathways in HCC. Because of HCC’s relatively high incidence and mortality rates in the past decades, greater efforts should be put in place to explore novel therapeutic approaches to improve the outcome for HCC patients.

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Acknowledgements

We would like to express our sincere thanks to Dr. Jennie Wong, Head of Medical & Scientific Communication, Research Support Unit & Assistant Director, Office of the Dean, Yong Loo Lin School of Medicine, National University of Singapore, for her valuable advice and kind help for the revision of this article. K.S.R. thanks the Council of Scientific and Industrial Research and the Indian Science Congress Association (ISCA) for providing an Emeritus Scientist Fellowship and the Asutosh Mookerjee Fellowship, respectively. K.S.R. and C.D.M. thank the DST Promotion of University Research and Scientific Excellence (PURSE), Institution of Excellence, University of Mysore, for providing the laboratory facilities.

Funding

This research is supported by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative and Joint NCIS and NUS Cancer Program Seed Funding Grants (R713-009–272-733) (Wang L.). This work was also supported by the Ministry of Education Tier 1 grant to GS.

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  1. Sin Qinxiang Shant, Chakrabhavi Dhananjaya Mohan and Robby Miguel Wen-Jing Goh contributed equally to this work and are equal first authors.

Authors and Affiliations

  1. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore

    Shant Qinxiang Sin, Robby Miguel Wen-Jing Goh & Lingzhi Wang

  2. Department of Studies in Molecular Biology, University of Mysore, Manasagangotri, Mysore, 570006, India

    Chakrabhavi Dhananjaya Mohan

  3. Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou Cancer Institute, Hangzhou, 31002, China

    Mingliang You

  4. Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou, 31002, China

    Mingliang You

  5. Department of Studies in Biotechnology, University of Mysore, Manasagangotri, Mysore, 570006, India

    Siddaiah Chandra Nayak

  6. College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China

    Lu Chen

  7. Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China

    Lu Chen

  8. NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Gautam Sethi & Lingzhi Wang

  9. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Gautam Sethi & Lingzhi Wang

  10. Institution of Excellence, Vijnana Bhavan, University of Mysore, Manasagangotri, Mysore, 570006, India

    Kanchugarakoppal Subbegowda Rangappa

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Sin, S.Q., Mohan, C.D., Goh, R.M.WJ. et al. Hypoxia signaling in hepatocellular carcinoma: Challenges and therapeutic opportunities. Cancer Metastasis Rev 42, 741–764 (2023). https://doi.org/10.1007/s10555-022-10071-1

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