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Aging is characterized by increased reactive species, leading to redox imbalance, oxidative damage, and senescence. The adverse effects of alcohol consumption potentiate aging-associated alterations, promoting several diseases, including liver diseases. Nucleoredoxin (NXN) is a redox-sensitive enzyme that targets reactive oxygen species and regulates key cellular processes through redox protein-protein interactions. Here, we determine the effect of chronic alcohol consumption on NXN-dependent redox interactions in the liver of aged mice. We found that chronic alcohol consumption preferentially promotes the localization of NXN either into or alongside senescent cells, declines its interacting capability, and worsens the altered interaction ratio of NXN with FLII, MYD88, CAMK2A, and PFK1 proteins induced by aging. In addition, carbonylated protein and cell proliferation increased, and the ratios of collagen I and collagen III were inverted. Thus, we demonstrate an emerging phenomenon associated with altered redox homeostasis during aging, as shown by the declining capability of NXN to interact with partner proteins, which is enhanced by chronic alcohol consumption in the mouse liver. This evidence opens an attractive window to elucidate the consequences of both aging and chronic alcohol consumption on the downstream signaling pathways regulated by NXN-dependent redox-sensitive interactions.
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Hepatocellular carcinoma (HCC) is one of the most lethal malignant tumours worldwide. The mortality-to-incidence ratio is up to 91.6% in many countries, representing the third leading cause of cancer-related deaths. Systemic drugs, including the multikinase inhibitors sorafenib and lenvatinib, are first-line drugs used in HCC treatment. Unfortunately, these therapies are ineffective in most cases due to late diagnosis and the development of tumour resistance. Thus, novel pharmacological alternatives are urgently needed. For instance, immune checkpoint inhibitors have provided new approaches targeting cells of the immune system. Furthermore, monoclonal antibodies against programmed cell death-1 have shown benefits in HCC patients. In addition, drug combinations, including first-line treatment and immunotherapy, as well as drug repurposing, are promising novel therapeutic alternatives. Here, we review the current and novel pharmacological approaches to fight HCC. Preclinical studies, as well as approved and ongoing clinical trials for liver cancer treatment, are discussed. The pharmacological opportunities analysed here should lead to significant improvement in HCC therapy.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Sorafenibe/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Terapia de Alvo Molecular , ImunoterapiaRESUMO
Hepatocellular carcinoma (HCC) is a highly lethal liver cancer with late diagnosis; therefore, the identification of new early biomarkers could help reduce mortality. We determine the tissue and plasma status of five annexins during hepatocarcinogenesis by diethylnitrosamine-induced cirrhosis-HCC. We found that Anxa5 was the earliest upregulated gene at week 12 after HCC initiation, while Anxa1 and Anxa2 were upregulated in advanced HCC stages (weeks 18 and 22). Furthermore, the protein level of Annexin A1, A2, A5 and A10 was increased from the early stages. Immunofluorescence and subcellular fractionation revealed Annexin A1, A2, and A5 in the cytoplasm and nuclei of tumor cells. Notably, increased plasma levels of Annexin A5 significantly (r2 = 0.8203) correlated with Annexin A5 levels in liver tissue from week 12 and gradually increased until week 22. Using the TCGA database, we found that the expression of ANXA2 (HR = 1.7, p = 0.0046) and ANXA5 (HR = 1.8, p = 0.00077) was associated with poor survival in HCC patients. In conclusion, we have identified Annexin A1 and A5 as potentially useful early biomarkers for poor prognosis in HCC patients.
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Anexina A1 , Anexina A2 , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Anexina A1/genética , Anexina A1/metabolismo , Anexina A5/metabolismo , Anexina A2/genética , Anexina A2/metabolismo , Anexinas/genética , Anexinas/metabolismo , Biomarcadores Tumorais/metabolismoRESUMO
Following an Assessment by the Autonomous University of Hidalgo State and the National Institute of Genomic Medicine, this erratum corrects the authorship of this article by adding Dulce María MORENO-GARCÍA as the first author.
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Hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide, often preceded by cirrhosis and usually diagnosed at advanced stages; therefore, identifying molecular changes at early stages is an attractive strategy for detection and timely treatment. Here, we investigated the progressive transcriptomic changes during experimental hepatocarcinogenesis to identify novel early tumor markers in an HCC model induced by chronic administration of sublethal doses of diethylnitrosamine. An analysis of differentially expressed genes showed that four processes associated with oxidation-reduction and detoxification were significantly over-represented during hepatocarcinogenesis progression, of which the Nuclear Factor, Erythroid 2 Like 2 pathway showed several dysregulated genes. Interestingly, we also identified 91 genes dysregulated at early HCC stages, but the expression of the indolethylamine N-methyltransferase gene (INMT), as well as the level of its encoding protein, were strongly downregulated. INMT was increased in perivenular hepatocytes of normal livers but decreased in livers of experimental HCC. Furthermore, a gene expression and survival analysis performed using data from the liver hepatocellular carcinoma project of The Cancer Genome Atlas Program revealed that INMT is also significantly downregulated in human HCC and is associated with poor overall survival. In conclusion, by performing a transcriptome analysis of the HCC progression, we identified that INMT is early downregulated in the rat hepatocarcinogenesis and is associated with poor prognosis in human HCC, suggesting that INMT downregulation may be a promising prognostic marker for HCC in high-risk populations.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Carcinogênese/genética , Carcinoma Hepatocelular/patologia , Regulação para Baixo , Humanos , Neoplasias Hepáticas/patologia , Metiltransferases/genética , RatosRESUMO
Nucleoredoxin (NXN), an oxidoreductase enzyme, contributes to cellular redox homeostasis by regulating different signaling pathways in a redox-dependent manner. By interacting with seven proteins so far, namely disheveled (DVL), protein phosphatase 2A (PP2A), phosphofructokinase-1 (PFK1), translocation protein SEC63 homolog (SEC63), myeloid differentiation primary response gene-88 (MYD88), flightless-I (FLII), and calcium/calmodulin-dependent protein kinase II type alpha (CAMK2A), NXN is involved in the regulation of several key cellular processes, including proliferation, organogenesis, cell cycle progression, glycolysis, innate immunity and inflammation, motility, contraction, protein transport into the endoplasmic reticulum, neuronal plasticity, among others; as a result, NXN has been implicated in different pathologies, such as cancer, alcoholic and polycystic liver disease, liver fibrogenesis, obesity, Robinow syndrome, diabetes mellitus, Alzheimer's disease, and retinitis pigmentosa. Together, this evidence places NXN as a strong candidate to be a master redox regulator of cell physiology and as the hub of different redox-sensitive signaling pathways and associated pathologies. This review summarizes and discusses the current insights on NXN-dependent redox regulation and its implication in different pathologies.
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The activation of Nuclear Factor, Erythroid 2 Like 2 - Kelch Like ECH Associated Protein 1 (NRF2-KEAP1) signaling pathway plays a critical dual role by either protecting or promoting the carcinogenesis process. However, its activation or nuclear translocation during hepatocellular carcinoma (HCC) progression has not been addressed yet. This study characterizes the subcellular localization of both NRF2 and KEAP1 during diethylnitrosamine-induced hepatocarcinogenesis in the rat. NRF2-KEAP1 pathway was continuously activated along with the increased expression of its target genes, namely Nqo1, Hmox1, Gclc, and Ptgr1. Similarly, the nuclear translocation of NRF2, MAF, and KEAP1 increased in HCC cells from weeks 12 to 22 during HCC progression. Likewise, colocalization of NRF2 with KEAP1 was higher in the cell nuclei of HCC neoplastic nodules than in surrounding cells. Moreover, immunofluorescence analyses revealed that the interaction of KEAP1 with filamentous Actin was disrupted in HCC cells. This disruption may be contributing to the release and nuclear translocation of NRF2 since the cortical actin cytoskeleton serves as anchoring of KEAP1. In conclusion, this evidence indicates that NRF2 is progressively activated and promotes the progression of experimental HCC.
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Carcinoma Hepatocelular/patologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Neoplasias Hepáticas/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Citoesqueleto de Actina/metabolismo , Animais , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/veterinária , Núcleo Celular/metabolismo , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 1/metabolismo , Dietilnitrosamina/toxicidade , Progressão da Doença , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/veterinária , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/genética , Proteínas Proto-Oncogênicas c-maf/genética , Proteínas Proto-Oncogênicas c-maf/metabolismo , Ratos , Ratos Endogâmicos F344RESUMO
Hepatocellular carcinoma expressing hepatobiliary progenitor markers, is considered of poor prognosis. By using a hepatocarcinogenesis model, laser capture microdissection, and RNA-Sequencing analysis, we identified an expression profile in GGT/KRT19-positive experimental tumors; 438 differentially expressed genes were found in early and late nodules along with increased collagen deposition. Dysregulated genes were involved in Fatty Acid Metabolism, RXR function, and Hepatic Stellate Cells Activation. Downregulation of Slc27a5, Acsl1, and Cyp2e1, demonstrated that Retinoid X Receptor α (RXRα) function is compromised in GGT/KRT19-positive nodules. Since RXRα controls NRF2 pathway activation, we determined the expression of NRF2 targeted genes; Akr1b8, Akr7a3, Gstp1, Abcc3, Ptgr1, and Txnrd1 were upregulated, indicating NRF2 pathway activation. A comparative analysis in human HCC showed that SLC27A5, ACSL1, CYP2E1, and RXRα gene expression is mutually exclusive with KRT19 gene expression. Our results indicate that the downregulation of Slc27a5, Acsl1, Rxrα, and Cyp2e1 genes is an early event within GGT/KRT19-positive HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/metabolismo , Ácidos Graxos , Humanos , Neoplasias Hepáticas/metabolismo , Receptor X Retinoide alfa/genética , Receptor X Retinoide alfa/metabolismo , TranscriptomaRESUMO
Hepatocellular carcinoma (HCC), which is the most frequent primary liver malignancy, is ranked as the sixth most common cancer and the third leading cause of cancer-related deaths worldwide, with its incidence expected to continue rising. One of the reasons is that most patients are diagnosed at an advanced stage when therapeutic options are ineffective. The development of HCC is attributed to a chronic exposition to either one or a combination of low amounts of different hepatotoxins, such as in hepatitis virus infection, alcohol consumption, aflatoxin from contaminated foods, metabolic factors, and exposure to chemical carcinogens from tobacco smoke (Forner et al., 2018). Integrative studies combining exome sequencing, transcriptome analysis, and the genomic characterization of HCC have shown that these etiological factors may raise the frequency of particular genetic alterations, resulting in intra-tumor heterogeneity that presents a huge challenge for treatment. For example, mutations in the catenin ß-1 (CTNNB1) gene (a proto-oncogene in the WNT signaling pathway that encodes the ß|-catenin transcription factor) are strongly associated with alcohol-related HCC, whereas mutations in the telomerase reverse transcriptase (TERT) promoter and tumor protein p53 (TP53) genes are the most commonly observed in hepatitis B virus (HBV)|-associated HCC (Calderaro et al., 2017; Cancer Genome Atlas Research Network, 2017). The above findings emphasize the molecular diversity of HCC and the associations of different etiologies with distinct mechanisms in HCC progression. Consequently, prevention strategies are still attractive for HCC management.
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Neoplasias Hepáticas Experimentais/prevenção & controle , Tenebrio , Animais , Dietilnitrosamina , Antígeno Ki-67/análise , Larva , Neoplasias Hepáticas Experimentais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pupa , beta Catenina/análise , beta Catenina/genéticaRESUMO
Chronic liver injury promotes the molecular alterations that precede the establishment of cancer. Usually, several decades of chronic insults are needed to develop the most common primary liver tumor known as hepatocellular carcinoma. As other cancer types, liver cancer cells are governed by a common set of rules collectively called the hallmarks of cancer. Although those rules have provided a conceptual framework for understanding the complex pathophysiology of established tumors, therapeutic options are still ineffective in advanced stages. Thus, the molecular alterations that precede the establishment of cancer remain an attractive target for therapeutic interventions. Here, we first summarize the chemopreventive interventions targeting the early liver carcinogenesis stages. After an integrative analysis on the plethora of molecular alterations regulated by anticancer agents, we then underline and discuss that two critical processes namely oxidative stress and genetic alterations, play the role of 'dirty work laborer' in the initial cell damage and drive the transformation of preneoplastic into neoplastic cells, respectively; besides, the activation of cellular senescence works as a key mechanism in attempting to prevent the onset and establishment of liver cancer. Whereas the detrimental effects of the binomial made up of oxidative stress and genetic alterations are either eliminated or reduced, senescence activation is promoted by anticancer agents. We argue that collectively, oxidative stress, genetic alterations, and senescence are key events that influence the fate of initiated cells and the establishment of the hallmarks of cancer.