The NADPH oxidase NOX4 regulates redox and metabolic homeostasis preventing HCC progression

Peñuelas‐Haro, Irene; Espinosa‐Sotelo, Rut; Crosas‐Molist, Eva; Herranz‐Itúrbide, Macarena; Caballero‐Díaz, Daniel; Alay, Ania; Solé, Xavier; Ramos, Emilio; Serrano, Teresa; Martínez‐Chantar, María Luz; Knaus, Ulla G.; Cuezva, José M.; Zorzano, António; Bertrán, Esther; Fabregat, Isabel

doi:10.1002/hep.32702

Cited by 22 publications

(5 citation statements)

References 40 publications

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“…On the other hand, NOX4 has been reported to act as a tumour suppressor or oncogene depending on the tumour type. In HCC, NOX4 has been described to prevent cancer progression (Crosas-Molist et al , 2014, Penuelas-Haro et al , 2022). For these reasons we analyzed Nox4 expression, and observed reduced Nox4 mRNA levels in all three cell lines upon glutamine deprivation (Fig.…”

Section: Resultsmentioning

confidence: 99%

Glutamine deprivation alters TGF-β signaling in hepatocellular carcinoma

Gélabert,

Campisano,

Golán

et al. 2024

Preprint

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Metabolic reprogramming is one of the hallmarks of cancer. Glutamine is one of the most important nutrients that fuels the TCA cycle and therefore takes part in the production of energy. Glutamine is used as starting metabolite for the synthesis of nucleotides, fatty acids and non-essential amino acids. Since nutrients are uptaken from the blood stream, and considering the 3-dimensional state of solid tumors, access of nutrients is highly dependent on the location of individual cells within a tumor, which results in affecting their metabolic activity. This gives rise to two disctincts cell population: the ones that have access to nutrient and the ones that are nutrient-deprived. We studied the effect of the lack of glutamine by creating glutamine-resistent hepatocellular carcinoma cell lines chosen based on their epithelial (Hep3B) or mesenchymal phenotype (SNU-499 and HLF). We found that glutamine deprivation decreased the proliferation rate, clonogenicity and stemness frequency of the three cell lines but in a greater extent of the mesenchymal cells. Transcriptomic analysis performed in HLF cells showed that glutamine deprivation decreased the activation of signaling pathways involved in cell-cell junction, cell-extracellular matrix interactions and decreased the expression of the hallmarks of epithelial-to-mesenchymal transition. We therefore investigated the role of TGFβ, a master regulator of these three processes, by transcriptomic and functional analyses in epithelial (Hep3B) and mesenchymal cells (HLF). We found that the lack of glutamine strongly impaired the activation of TGFβ signaling which correlated with an altered regulation of TGFβ target genes: the expression of mesenchymal genes was no longer induced by TGFβ while the epithelial genes were more strongly induced. Functional analyses showed that glutamine deprivation abolished the invasive capacities of HCCs and decreased cell adhesion. Altogether, our results show that glutamine metabolism is necessary to maintain a mesenchymal phenotype and to maintain an efficient TGFβ signaling in hepatocellularcarcinoma.

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Section: Resultsmentioning

confidence: 99%

Glutamine deprivation alters TGF-β signaling in hepatocellular carcinoma

Gélabert,

Campisano,

Golán

et al. 2024

Preprint

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“…A research group from Shanghai detected preoperative and postoperative circulating tumor cells (CTCs) of 193 patients and found the predictive value of CTCs for tumor recurrence in patients with HCC following LT 51 . Also, multiomics technologies such as mass cytometry, proteomics, transcriptomics, radiomics, and metabolomics, can be powerful tools to explore the mechanisms of tumor development and identify key molecule or cell cluster in cancer recurrence 52 – 55 .…”

Section: Discussionmentioning

confidence: 99%

Insights into the history and tendency of liver transplantation for liver cancer: A bibliometric-based visual analysis

He,

Xu,

Tang

et al. 2023

International Journal of Surgery

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Research on liver transplantation (LT) for liver cancer has gained increasing attention. This paper has comprehensively described the current status, hotspots and trends in this field. A total of 2991 relevant articles from January 1, 1963 to February 28, 2023 were obtained from the Web of Science Core Collection. VOSviewer and CiteSpace software were utilized as bibliometric tools to analyze and visualize knowledge mapping. Between 1963 and 2023, the number of papers in the area of LT for liver cancer increased continuously. A total of 70 countries/regions, 2303 institutions and 14840 researchers have published research articles, with the United States and China being the two most productive countries. Our bibliometric-based visual analysis revealed the expansion of LT indications for liver cancer and prevention/treatment of cancer recurrence as ongoing research hotspots over the past decades. Meanwhile, emerging studies also focus on downstaging/bridging treatments before LT and long-term survival of LT recipient, in particular the precise application of immunosuppressants.

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“…The maintenance of redox homeostasis is closely linked to the development of HCC. Notably, studies have demonstrated that the deletion of NADPH oxidase NOX4 triggers the activation of the MYC pathway, resulting in a perturbation of redox homeostasis, perturbed oxidative metabolism, and ultimately facilitating the progression of HCC [92].…”

Section: Redox Metabolismmentioning

confidence: 99%

Macrophage metabolism, phenotype, function, and therapy in hepatocellular carcinoma (HCC)

Huang,

Wu,

Geller

et al. 2023

J Transl Med

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The pivotal role of the tumor microenvironment (TME) in the initiation and advancement of hepatocellular carcinoma (HCC) is widely acknowledged, as it fosters the proliferation and metastasis of HCC cells. Within the intricate TME of HCC, tumor-associated macrophages (TAMs) represent a significant constituent of non-malignant cells. TAMs engage in direct communication with cancer cells in HCC, while also exerting influence on other immune cells to adopt a tumor-supportive phenotype that facilitates tumor progression. Among the multifaceted mechanisms at play, the metabolic reprogramming of both tumor cells and macrophages leads to phenotypic alterations and functional modifications in macrophages. This comprehensive review elucidates the intricate interplay between cellular metabolism and macrophage phenotype/polarization, while also providing an overview of the associated signaling molecules and potential therapeutic strategies for HCC.

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The NADPH oxidase NOX4 regulates redox and metabolic homeostasis preventing HCC progression

Cited by 22 publications

References 40 publications

Glutamine deprivation alters TGF-β signaling in hepatocellular carcinoma

Glutamine deprivation alters TGF-β signaling in hepatocellular carcinoma

Insights into the history and tendency of liver transplantation for liver cancer: A bibliometric-based visual analysis

Macrophage metabolism, phenotype, function, and therapy in hepatocellular carcinoma (HCC)

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