Mitochondrial Metabolic Signatures in Hepatocellular Carcinoma

Nga, Ha Thi; Tian, Jingwen; Yi, Hyon‐Seung

doi:10.3390/cells10081901

Cited by 58 publications

(42 citation statements)

References 114 publications

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“…Due to the link between mitochondrial dysfunction and liver injury, GDF15 is currently considered a biomarker of diverse chronic liver diseases [259]. First of all, this factor has been demonstrated, as expected, to be a possible prognostic HCC marker because its upregulation as a consequence of mitochondrial oxidative phosphorylation defects and ROS production is associated with liver cancer development, progression, and metastasis [260]. Taking into consideration the same physiopathological considerations, it is not surprising that the factor has also a potential prognostic role in hepatitis B and C chronic viral hepatitis, with an increasing degree of diagnostic accuracy in compensated and decompensated liver cirrhosis [261][262][263].…”

Section: Biomarkers Of Oxidative Stress In Nafld/nashmentioning

confidence: 87%

Oxidative Stress in Non-Alcoholic Fatty Liver Disease

Smirne

Croce

Benedetto

et al. 2022

Livers

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Non-alcoholic fatty liver disease (NAFLD) is a challenging disease caused by multiple factors, which may partly explain why it still remains an orphan of adequate therapies. This review highlights the interaction between oxidative stress (OS) and disturbed lipid metabolism. Several reactive oxygen species generators, including those produced in the gastrointestinal tract, contribute to the lipotoxic hepatic (and extrahepatic) damage by fatty acids and a great variety of their biologically active metabolites in a “multiple parallel-hit model”. This leads to inflammation and fibrogenesis and contributes to NAFLD progression. The alterations of the oxidant/antioxidant balance affect also metabolism-related organelles, leading to lipid peroxidation, mitochondrial dysfunction, and endoplasmic reticulum stress. This OS-induced damage is at least partially counteracted by the physiological antioxidant response. Therefore, modulation of this defense system emerges as an interesting target to prevent NAFLD development and progression. For instance, probiotics, prebiotics, diet, and fecal microbiota transplantation represent new therapeutic approaches targeting the gut microbiota dysbiosis. The OS and its counter-regulation are under the influence of individual genetic and epigenetic factors as well. In the near future, precision medicine taking into consideration genetic or environmental epigenetic risk factors, coupled with new OS biomarkers, will likely assist in noninvasive diagnosis and monitoring of NAFLD progression and in further personalizing treatments.

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Section: Biomarkers Of Oxidative Stress In Nafld/nashmentioning

confidence: 87%

Oxidative Stress in Non-Alcoholic Fatty Liver Disease

Smirne

Croce

Benedetto

et al. 2022

Livers

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“…Emerging evidence from human, rodent, and cell models of HCC suggests that mitochondrial reprogramming plays an important role in HCC metabolism and disease progression ( 4 , 5 ). HCC tumors commonly present with marked upregulation of glycolytic enzymes and metabolites ( 6 – 8 ), decreased mitochondrial DNA (mtDNA) copy number ( 9 , 10 ), and increased mtDNA mutational burden ( 11 – 14 ).…”

Section: Introductionmentioning

confidence: 99%

Bioenergetic Phenotyping of DEN-Induced Hepatocellular Carcinoma Reveals a Link Between Adenylate Kinase Isoform Expression and Reduced Complex I-Supported Respiration

et al. 2022

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Hepatocellular carcinoma (HCC) is the most common form of liver cancer worldwide. Increasing evidence suggests that mitochondria play a central role in malignant metabolic reprogramming in HCC, which may promote disease progression. To comprehensively evaluate the mitochondrial phenotype present in HCC, we applied a recently developed diagnostic workflow that combines high-resolution respirometry, fluorometry, and mitochondrial-targeted nLC-MS/MS proteomics to cell culture (AML12 and Hepa 1-6 cells) and diethylnitrosamine (DEN)-induced mouse models of HCC. Across both model systems, CI-linked respiration was significantly decreased in HCC compared to nontumor, though this did not alter ATP production rates. Interestingly, CI-linked respiration was found to be restored in DEN-induced tumor mitochondria through acute in vitro treatment with P1, P5-di(adenosine-5′) pentaphosphate (Ap5A), a broad inhibitor of adenylate kinases. Mass spectrometry-based proteomics revealed that DEN-induced tumor mitochondria had increased expression of adenylate kinase isoform 4 (AK4), which may account for this response to Ap5A. Tumor mitochondria also displayed a reduced ability to retain calcium and generate membrane potential across a physiological span of ATP demand states compared to DEN-treated nontumor or saline-treated liver mitochondria. We validated these findings in flash-frozen human primary HCC samples, which similarly displayed a decrease in mitochondrial respiratory capacity that disproportionately affected CI. Our findings support the utility of mitochondrial phenotyping in identifying novel regulatory mechanisms governing cancer bioenergetics.

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“…However, mitochondrial functionality seemed to be significantly enriched due to the down-regulation of the MT-TF and MT-CO3 transcripts. Deregulation of mitochondria and impaired respiration have been linked with HCC, in particular, the loss of mtDNA [ 54 , 55 ]. Therefore, the down-regulation of mitochondrial components might constitute a pro-survival mechanism.…”

Section: Discussionmentioning

confidence: 99%

miR-200c-3p, miR-222-5p, and miR-512-3p Constitute a Biomarker Signature of Sorafenib Effectiveness in Advanced Hepatocellular Carcinoma

Cruz‐Ojeda

Schmid

Boix

et al. 2022

Cells

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Background: Sorafenib constitutes a suitable treatment alternative for patients with advanced hepatocellular carcinoma (HCC) in whom atezolizumab + bevacizumab therapy is contraindicated. The aim of the study was the identification of a miRNA signature in liquid biopsy related to sorafenib response. Methods: miRNAs were profiled in hepatoblastoma HepG2 cells and tested in animal models, extracellular vesicles (EVs), and plasma from HCC patients. Results: Sorafenib altered the expression of 11 miRNAs in HepG2 cells. miR-200c-3p and miR-27a-3p exerted an anti-tumoral activity by decreasing cell migration and invasion, whereas miR-122-5p, miR-148b-3p, miR-194-5p, miR-222-5p, and miR-512-3p exerted pro-tumoral properties by increasing cell proliferation, migration, or invasion, or decreasing apoptosis. Sorafenib induced a change in EVs population with an increased number of larger EVs, and promoted an accumulation of miR-27a-3p, miR-122-5p, miR-148b-3p, miR-193b-3p, miR-194-5p, miR-200c-3p, and miR-375 into exosomes. In HCC patients, circulating miR-200c-3p baseline levels were associated with increased survival, whereas high levels of miR-222-5p and miR-512-3p after 1 month of sorafenib treatment were related to poor prognosis. The RNA sequencing revealed that miR-200c-3p was related to the regulation of cell growth and death, whereas miR-222-5p and miR-512-3p were related to metabolic control. Conclusions: The study showed that Sorafenib regulates a specific miRNA signature in which miR-200c-3p, miR-222-5p, and miR-512-3p bear prognostic value and contribute to treatment response.

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Mitochondrial Metabolic Signatures in Hepatocellular Carcinoma

Cited by 58 publications

References 114 publications

Oxidative Stress in Non-Alcoholic Fatty Liver Disease

Oxidative Stress in Non-Alcoholic Fatty Liver Disease

Bioenergetic Phenotyping of DEN-Induced Hepatocellular Carcinoma Reveals a Link Between Adenylate Kinase Isoform Expression and Reduced Complex I-Supported Respiration

miR-200c-3p, miR-222-5p, and miR-512-3p Constitute a Biomarker Signature of Sorafenib Effectiveness in Advanced Hepatocellular Carcinoma

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