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Oxidative stress in obesity-associated hepatocellular carcinoma: sources, signaling and therapeutic challenges

Oncogene volume 40, pages 5155–5167 (2021)Cite this article

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Abstract

Obesity affects more than 650 million individuals worldwide and is a well-established risk factor for the development of hepatocellular carcinoma (HCC). Oxidative stress can be considered as a bona fide tumor promoter, contributing to the initiation and progression of liver cancer. Indeed, one of the key events involved in HCC progression is excessive levels of reactive oxygen species (ROS) resulting from the fatty acid influx and chronic inflammation. This review provides insights into the different intracellular sources of obesity-induced ROS and molecular mechanisms responsible for hepatic tumorigenesis. In addition, we highlight recent findings pointing to the role of the dysregulated activity of BCL-2 proteins and protein tyrosine phosphatases (PTPs) in the generation of hepatic oxidative stress and ROS-mediated dysfunctional signaling, respectively. Finally, we discuss the potential and challenges of novel nanotechnology strategies to prevent ROS formation in obesity-associated HCC.

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Fig. 1: Progression from nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH), fibrosis, and HCC.
Fig. 2: ROS production in different cell compartments and their contributions to HCC development.
Fig. 3: Redox-regulated transcription factors.
Fig. 4: BCL-2 family proteins are components of programmed cell death that can also regulate cellular metabolism.
Fig. 5: Protein tyrosine phosphatases (PTPs) are important modulators of the insulin receptor (IR) and PTP oxidation plays a role in insulin resistance.
Fig. 6: Obesity contributes to the development of NASH and HCC by independent mechanisms.
Fig. 7: Schematic illustration of nanotheronostic agents targeting oxidative stress-dependent pathways in obesity-associated HCC.

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Acknowledgements

We thank Pu Chun Ke for critical reading of the manuscript. This work was supported by Fonds National de la Recherche Scientifique (FNRS)-MIS grant (33650793), FNRS-WELBIO grant (35112672), FNRS-CDR grant (35275350), European Research Council (ERC) Consolidator grant METAPTPs (GA817940), a JDRF Career Development Award (CDA-2019-758-A-N), National Science Foundation grant (CBET-1943302) and National Institutes of Health grant (R35GM133795). E.T. and E.N.G. are Research Associates of the FNRS, Belgium.

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  1. These authors contributed equally: Manoja K. Brahma, Eduardo H. Gilglioni.

Authors and Affiliations

  1. Signal Transduction and Metabolism Laboratory, Laboratoire de Gastroentérologie Expérimental et Endotools, Université libre de Bruxelles, Brussels, Belgium

    Manoja K. Brahma, Eduardo H. Gilglioni & Esteban N. Gurzov

  2. Materials Research and Education Center, Auburn University, Auburn, AL, 36849, United States

    Lang Zhou & Pengyu Chen

  3. Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, C.U.B. Hôpital Erasme, Université libre de Bruxelles, Brussels, Belgium

    Eric Trépo

  4. Laboratory of Experimental Gastroenterology, Université libre de Bruxelles, Brussels, Belgium

    Eric Trépo

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  1. Manoja K. Brahma
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Correspondence to Esteban N. Gurzov.

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Brahma, M.K., Gilglioni, E.H., Zhou, L. et al. Oxidative stress in obesity-associated hepatocellular carcinoma: sources, signaling and therapeutic challenges. Oncogene 40, 5155–5167 (2021). https://doi.org/10.1038/s41388-021-01950-y

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