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1.
J Pathol ; 257(1): 82-95, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35064579

RESUMO

Oncostatin M (OSM) is a pleiotropic cytokine of the interleukin (IL)-6 family that contributes to the progression of chronic liver disease. Here we investigated the role of OSM in the development and progression of hepatocellular carcinoma (HCC) in non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). The role of OSM was investigated in (1) selected cohorts of NAFLD/NASH HCC patients, (2) liver cancer cells exposed to human recombinant OSM or stably transfected to overexpress human OSM, (3) murine HCC xenografts, and (4) a murine NASH-related model of hepatic carcinogenesis. OSM was found to be selectively overexpressed in HCC cells of NAFLD/NASH patients, depending on tumor grade. OSM serum levels, barely detectable in patients with simple steatosis or NASH, were increased in patients with cirrhosis and more evident in those carrying HCC. In this latter group, OSM serum levels were significantly higher in the subjects with intermediate/advanced HCCs and correlated with poor survival. Cell culture experiments indicated that OSM upregulation in hepatic cancer cells contributes to HCC progression by inducing epithelial-to-mesenchymal transition and increased invasiveness of cancer cells as well as by inducing angiogenesis, which is of critical relevance. In murine xenografts, OSM overexpression was associated with slower tumor growth but an increased rate of lung metastases. Overexpression of OSM and its positive correlation with the angiogenic switch were also confirmed in a murine model of NAFLD/NASH-related hepatocarcinogenesis. Consistent with this, analysis of liver specimens from human NASH-related HCCs with vascular invasion showed that OSM was expressed by liver cancer cells invading hepatic vessels. In conclusion, OSM upregulation appears to be a specific feature of HCC arising on a NAFLD/NASH background, and it correlates with clinical parameters and disease outcome. Our data highlight a novel pro-carcinogenic contribution for OSM in NAFLD/NASH, suggesting a role of this factor as a prognostic marker and a putative potential target for therapy. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Oncostatina M , Animais , Carcinogênese , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia
3.
Int J Mol Sci ; 24(13)2023 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-37445809

RESUMO

Chronic liver disease (CLD) is a major global health threat and has emerged as a leading cause of human death [...].


Assuntos
Hepatopatias , Humanos , Doença Crônica , Hepatopatias/diagnóstico , Hepatopatias/etiologia , Hepatopatias/terapia
4.
Int J Mol Sci ; 24(8)2023 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-37108625

RESUMO

Hepatocellular carcinoma is the most common primary liver cancer, ranking third among the leading causes of cancer-related mortality worldwide and whose incidence varies according to geographical area and ethnicity. Metabolic rewiring was recently introduced as an emerging hallmark able to affect tumor progression by modulating cancer cell behavior and immune responses. This review focuses on the recent studies examining HCC's metabolic traits, with particular reference to the alterations of glucose, fatty acid and amino acid metabolism, the three major metabolic changes that have gained attention in the field of HCC. After delivering a panoramic picture of the peculiar immune landscape of HCC, this review will also discuss how the metabolic reprogramming of liver cancer cells can affect, directly or indirectly, the microenvironment and the function of the different immune cell populations, eventually favoring the tumor escape from immunosurveillance.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Glicólise , Microambiente Tumoral , Imunidade
5.
Molecules ; 27(3)2022 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-35164326

RESUMO

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and is characterized by poor clinical outcomes, with the majority of patients not being eligible for curative therapy and treatments only being applicable for early-stage tumors. CD44 is a receptor for hyaluronic acid (HA) and is involved in HCC progression. The aim of this work is to propose HA- and PEGylated-liposomes as promising approaches for the treatment of HCC. It has been found, in this work, that CD44 transcripts are up-regulated in HCC patients, as well as in a murine model of NAFLD/NASH-related hepatocarcinogenesis. Cell culture experiments indicate that HA-liposomes are more rapidly and significantly internalized by Huh7 cells that over-express CD44, compared with HepG2 cells that express low levels of the receptor, in which the uptake seems due to endocytic events. By contrast, human and murine macrophage cell lines (THP-1, RAW264.7) show improved and rapid uptake of PEG-modified liposomes without the involvement of the CD44. Moreover, the internalization of PEG-modified liposomes seems to induce polarization of THP1 towards the M1 phenotype. In conclusion, data reported in this study indicate that this strategy can be proposed as an alternative for drug delivery and one that dually and specifically targets liver cancer cells and infiltrating tumor macrophages in order to counteract two crucial aspect of HCC progression.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Ácido Hialurônico/farmacologia , Lipossomos/administração & dosagem , Macrófagos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Polietilenoglicóis/química , Animais , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Humanos , Ácido Hialurônico/química , Lipossomos/química , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/patologia
6.
Int J Mol Sci ; 22(19)2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34639123

RESUMO

GPR21 is a constitutively active, orphan, G-protein-coupled receptor, with in vivo studies suggesting its involvement in the modulation of insulin sensitivity. However, its precise contribution is not fully understood. As the liver is both a major target of insulin signalling and critically involved in glucose metabolism, the aim of this study was to examine the role of GPR21 in the regulation of glucose uptake and production in human hepatocytes. In particular, HepG2 cells, which express GPR21, were adopted as cellular models. Compared with untreated cells, a significant increase in glucose uptake was measured in cells treated with siRNA to downregulate GPR21 expression or with the GPR21-inverse agonist, GRA2. Consistently, a significantly higher membrane translocation of GLUT-2 was measured under these conditions. These effects were accompanied by an increased ratio of phAKT(Ser473)/tot-AKT and phGSK-3ß(Ser9)/tot-GSK-3ß, thus indicating a marked activation of the insulin signalling pathway. Moreover, a significant reduction in ERK activation was observed with GPR21 inhibition. Collectively, these results indicate that GPR21 mediates the negative effects on glucose uptake by the liver cells. In addition, they suggest that the pharmacological inhibition of GPR21 could be a novel strategy to improve glucose homeostasis and counteract hepatic insulin resistance.


Assuntos
Glucose/metabolismo , Hepatócitos/metabolismo , Resistência à Insulina , Insulina/metabolismo , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Células Hep G2 , Humanos , Transdução de Sinais
7.
Arch Biochem Biophys ; 689: 108445, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32524998

RESUMO

Liver fibrogenesis is defined as a dynamic and highly integrated process occurring during chronic injury to liver parenchyma that can result in excess deposition of extracellular matrix (ECM) components (i.e., liver fibrosis). Liver fibrogenesis, together with chronic inflammatory response, is then primarily involved in the progression of chronic liver diseases (CLD) irrespective of the specific etiology. In the present review we will first offer a synthetic and updated overview of major basic concepts in relation to the role of myofibroblasts (MFs), macrophages and other hepatic cell populations involved in CLD to then offer an overview of established and emerging issues and mechanisms that have been proposed to favor and/or promote CLD progression. A special focus will be dedicated to selected issues that include emerging features in the field of cholangiopathies, the emerging role of genetic and epigenetic factors as well as of hypoxia, hypoxia-inducible factors (HIFs) and related mediators.


Assuntos
Cirrose Hepática/patologia , Fígado/patologia , Animais , Doença Crônica , Progressão da Doença , Epigênese Genética , Humanos , Inflamação/genética , Inflamação/patologia , Fígado/metabolismo , Cirrose Hepática/genética , Macrófagos/metabolismo , Macrófagos/patologia , Miofibroblastos/metabolismo , Miofibroblastos/patologia
8.
Hepatology ; 67(6): 2196-2214, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29266399

RESUMO

Mechanisms underlying progression of nonalcoholic fatty liver disease (NAFLD) are still incompletely characterized. Hypoxia and hypoxia-inducible factors (HIFs) have been implicated in the pathogenesis of chronic liver diseases, but the actual role of HIF-2α in the evolution of NAFLD has never been investigated in detail. In this study, we show that HIF-2α is selectively overexpressed in the cytosol and the nuclei of hepatocytes in a very high percentage (>90%) of liver biopsies from a cohort of NAFLD patients at different stages of the disease evolution. Similar features were also observed in mice with steatohepatitis induced by feeding a methionine/choline-deficient diet. Experiments performed in mice carrying hepatocyte-specific deletion of HIF-2α and related control littermates fed either a choline-deficient L-amino acid-defined or a methionine/choline-deficient diet showed that HIF-2α deletion ameliorated the evolution of NAFLD by decreasing parenchymal injury, fatty liver, lobular inflammation, and the development of liver fibrosis. The improvement in NAFLD progression in HIF-2α-deficient mice was related to a selective down-regulation in the hepatocyte production of histidine-rich glycoprotein (HRGP), recently proposed to sustain macrophage M1 polarization. In vitro experiments confirmed that the up-regulation of hepatocyte HRGP expression was hypoxia-dependent and HIF-2α-dependent. Finally, analyses performed on specimens from NAFLD patients indicated that HRGP was overexpressed in all patients showing hepatocyte nuclear staining for HIF-2α and revealed a significant positive correlation between HIF-2α and HRGP liver transcript levels in these patients. CONCLUSIONS: These results indicate that hepatocyte HIF-2α activation is a key feature in both human and experimental NAFLD and significantly contributes to the disease progression through the up-regulation of HRGP production. (Hepatology 2018;67:2196-2214).


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Hepatócitos/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Proteínas/metabolismo , Animais , Células Cultivadas , Progressão da Doença , Humanos , Masculino , Camundongos
9.
Int J Mol Sci ; 20(11)2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31159366

RESUMO

Fibrogenic progression of chronic liver disease, whatever the etiology, is characterized by persistent chronic parenchymal injury, chronic activation of inflammatory response, and sustained activation of liver fibrogenesis, and of pathological wound healing response. A critical role in liver fibrogenesis is played by hepatic myofibroblasts (MFs), a heterogeneous population of α smooth-muscle actin-positive cells that originate from various precursor cells through a process of activation and transdifferentiation. In this review, we focus the attention on the role of extracellular signal-regulated kinase (ERK) signaling pathway as a critical one in modulating selected profibrogenic phenotypic responses operated by liver MFs. We will also analyze major therapeutic antifibrotic strategies developed in the last two decades in preclinical studies, some translated to clinical conditions, designed to interfere directly or indirectly with the Ras/Raf/MEK/ERK signaling pathway in activated hepatic MFs, but that also significantly increased our knowledge on the biology and pathobiology of these fascinating profibrogenic cells.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células Estreladas do Fígado/metabolismo , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Sistema de Sinalização das MAP Quinases , Miofibroblastos/metabolismo , Animais , Biomarcadores , Comunicação Celular , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Terapia Combinada , Humanos , Imunomodulação , Cirrose Hepática/patologia , Cirrose Hepática/terapia , Terapia de Alvo Molecular , Fenótipo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
10.
Int J Mol Sci ; 19(12)2018 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-30518128

RESUMO

The cholangipathies are a class of liver diseases that specifically affects the biliary tree. These pathologies may have different etiologies (genetic, autoimmune, viral, or toxic) but all of them are characterized by a stark inflammatory infiltrate, increasing overtime, accompanied by an excess of periportal fibrosis. The cellular types that mount the regenerative/reparative hepatic response to the damage belong to different lineages, including cholagiocytes, mesenchymal and inflammatory cells, which dynamically interact with each other, exchanging different signals acting in autocrine and paracrine fashion. Those messengers may be proinflammatory cytokines and profibrotic chemokines (IL-1, and 6; CXCL1, 10 and 12, or MCP-1), morphogens (Notch, Hedgehog, and WNT/ß-catenin signal pathways) and finally growth factors (VEGF, PDGF, and TGFß, among others). In this review we will focus on the main molecular mechanisms mediating the establishment of a fibroinflammatory liver response that, if perpetuated, can lead not only to organ dysfunction but also to neoplastic transformation. Primary Sclerosing Cholangitis and Congenital Hepatic Fibrosis/Caroli's disease, two chronic cholangiopathies, known to be prodrome of cholangiocarcinoma, for which several murine models are also available, were also used to further dissect the mechanisms of fibroinflammation leading to tumor development.


Assuntos
Doenças dos Ductos Biliares/patologia , Cirrose Hepática/patologia , Fígado/lesões , Lesões Pré-Cancerosas/patologia , Animais , Epitélio/patologia , Humanos , Fígado/patologia , Mesoderma/patologia
11.
Gut ; 64(9): 1454-65, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25183205

RESUMO

OBJECTIVE: The extracellular signal-regulated kinase 5 (ERK5 or BMK1) is involved in tumour development. The ERK5 gene may be amplified in hepatocellular carcinoma (HCC), but its biological role has not been clarified. In this study, we explored the role of ERK5 expression and activity in HCC in vitro and in vivo. DESIGN: ERK5 expression was evaluated in human liver tissue. Cultured HepG2 and Huh-7 were studied after ERK5 knockdown by siRNA or in the presence of the specific pharmacological inhibitor, XMD8-92. The role of ERK5 in vivo was assessed using mouse Huh-7 xenografts. RESULTS: In tissue specimens from patients with HCC, a higher percentage of cells with nuclear ERK5 expression was found both in HCC and in the surrounding cirrhotic tissue compared with normal liver tissue. Inhibition of ERK5 decreased HCC cell proliferation and increased the proportion of cells in G0/G1 phase. These effects were associated with increased expression of p27 and p15 and decreased CCND1. Treatment with XMD8-92 or ERK5 silencing prevented cell migration induced by epidermal growth factor or hypoxia and caused cytoskeletal remodelling. In mouse xenografts, the rate of tumour appearance and the size of tumours were significantly lower when Huh-7 was silenced for ERK5. Moreover, systemic treatment with XMD8-92 of mice with established HCC xenografts markedly reduced tumour growth and decreased the expression of the proto-oncogene c-Rel. CONCLUSIONS: ERK5 regulates the biology of HCC cells and modulates tumour development and growth in vivo. This pathway should be investigated as a possible therapeutic target in HCC.


Assuntos
Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Proteína Quinase 7 Ativada por Mitógeno/genética , Animais , Biópsia por Agulha , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/fisiopatologia , Proliferação de Células/genética , Modelos Animais de Doenças , Progressão da Doença , Xenoenxertos , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/fisiopatologia , Camundongos , Transplante de Neoplasias , Proto-Oncogene Mas , RNA Interferente Pequeno/análise , Sensibilidade e Especificidade , Células Tumorais Cultivadas
12.
Arch Biochem Biophys ; 548: 20-37, 2014 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-24631571

RESUMO

Liver fibrogenesis is a dynamic and highly integrated molecular, tissue and cellular process, potentially reversible, that drives the progression of chronic liver diseases (CLD) towards liver cirrhosis and hepatic failure. Hepatic myofibroblasts (MFs), the pro-fibrogenic effector cells, originate mainly from activation of hepatic stellate cells and portal fibroblasts being characterized by a proliferative and survival attitude. MFs also contract in response to vasoactive agents, sustain angiogenesis and recruit and modulate activity of cells of innate or adaptive immunity. Chronic activation of wound healing and oxidative stress as well as derangement of epithelial-mesenchymal interactions are "major" pro-fibrogenic mechanisms, whatever the etiology. However, literature has outlined a complex network of pro-fibrogenic factors and mediators proposed to modulate CLD progression, with some of them being at present highly debated in the field, including the role of epithelial to mesenchymal transition and Hedgehog signaling pathways. Hypoxia and angiogenesis as well as inflammasomes are recently emerged as ubiquitous pro-inflammatory and pro-fibrogenic determinants whereas adipokines are mostly involved in CLD related to metabolic disturbances (metabolic syndrome and/or obesity and type 2 diabetes). Finally, autophagy as well as natural killer and natural killer-T cells have been recently proposed to significantly affect fibrogenic CLD progression.


Assuntos
Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Fígado/citologia , Fígado/patologia , Animais , Doença Crônica , Progressão da Doença , Matriz Extracelular/imunologia , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Fígado/imunologia , Fígado/metabolismo , Cirrose Hepática/metabolismo , Miofibroblastos/imunologia , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Estresse Oxidativo
13.
Aliment Pharmacol Ther ; 59(3): 380-392, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37990490

RESUMO

BACKGROUND: SerpinB3 is a cysteine protease inhibitor involved in liver disease progression due to its proinflammatory and profibrogenic properties. The polymorphic variant SerpinB3-PD (SB3-PD), presents a substitution in its reactive centre loop, determining the gain of function. AIMS: To disclose the clinical characteristics of a cohort of patients with cirrhosis in relation to the presence of SB3-PD and to assess the effect of this genetic variant on fibrogenic and inflammatory cytokines in vitro. METHODS: We assessed SB3 polymorphism in 90 patients with cirrhosis, prospectively followed up in our referral centre. We used HepG2 and HuH-7 cells transfected to overexpress either wild-type SB3 (SB3-WT) or SB3-PD to assess their endogenous effect, while LX2 and THP-1 cells were treated with exogenous SB3-WT or SB3-PD proteins. RESULTS: Patients carrying SB3-PD had more severe portal hypertension and higher MELD scores, than patients carrying SB3-WT. In multivariate analysis, SB3-PD was an independent predictor of cirrhosis complications. Patients with SB3-PD polymorphism presented with more severe liver fibrosis and inflammatory features. Hepatoma cells overexpressing SB3-PD showed higher TGF-ß1 expression than controls. The addition of recombinant SB3-PD induced an up-regulation of TGF-ß1 in LX2 cells and a more prominent inflammatory profile in THP-1 cells, compared to the effect of SB3-WT protein. CONCLUSIONS: The polymorphic variant SB3-PD is highly effective in determining activation of TGF-ß1 and inflammation in vitro. Patients with cirrhosis who carry SB3-PD polymorphism may be more prone to develop severe liver disease progression. However, further validation studies are warranted to support the in vivo relevance of this polymorphism.


Assuntos
Hepatopatias , Fator de Crescimento Transformador beta1 , Humanos , Progressão da Doença , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
14.
Mol Metab ; 81: 101889, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38307387

RESUMO

OBJECTIVE: The serine protease inhibitor SerpinB3 has been described as critical mediator of liver fibrosis and it has been recently proposed as an additional hepatokine involved in NASH development and insulin resistance. Protease Activated Receptor 2 has been identified as a novel regulator of hepatic metabolism. A targeted therapeutic strategy for NASH has been investigated, using 1-Piperidine Propionic Acid (1-PPA), since this compound has been recently proposed as both Protease Activated Receptor 2 and SerpinB3 inhibitor. METHODS: The effect of SerpinB3 on inflammation and fibrosis genes was assessed in human macrophage and stellate cell lines. Transgenic mice, either overexpressing SerpinB3 or carrying Serpinb3 deletion and their relative wild type strains, were used in experimental NASH models. Subgroups of SerpinB3 transgenic mice and their controls were also injected with 1-PPA to assess the efficacy of this compound in NASH inhibition. RESULTS: 1-PPA did not present significant cell and organ toxicity and was able to inhibit SerpinB3 and PAR2 in a dose-dependent manner. This effect was associated to a parallel reduction of the synthesis of the molecules induced by endogenous SerpinB3 or by its paracrine effects both in vitro and in vivo, leading to inhibition of lipid accumulation, inflammation and fibrosis in experimental NASH. At mechanistic level, the antiprotease activity of SerpinB3 was found essential for PAR2 activation, determining upregulation of the CCAAT Enhancer Binding Protein beta (C/EBP-ß), another pivotal regulator of metabolism, inflammation and fibrosis, which in turn determined SerpinB3 synthesis. CONCLUSIONS: 1-PPA treatment was able to inhibit the PAR2 - C/EBP-ß - SerpinB3 axis and to protect from NASH development and progression, supporting the potential use of a similar approach for a targeted therapy of NASH.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Humanos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptor PAR-2 , Proteína beta Intensificadora de Ligação a CCAAT , Cirrose Hepática/tratamento farmacológico , Camundongos Transgênicos , Inflamação
15.
Front Immunol ; 15: 1342404, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38469298

RESUMO

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously non-alcoholic fatty liver disease (NAFLD), is a leading cause of chronic liver disease worldwide. In 20%-30% of MASLD patients, the disease progresses to metabolic dysfunction-associated steatohepatitis (MASH, previously NASH) which can lead to fibrosis/cirrhosis, liver failure as well as hepatocellular carcinoma (HCC). Here we investigated the role of histidine-rich glycoprotein (HRG), a plasma protein produced by hepatocytes, in MASLD/MASH progression and HCC development. Methods: The role of HRG was investigated by morphological, cellular, and molecular biology approaches in (a) HRG knock-out mice (HRG-/- mice) fed on a CDAA dietary protocol or a MASH related diethyl-nitrosamine/CDAA protocol of hepatocarcinogenesis, (b) THP1 monocytic cells treated with purified HRG, and (c) well-characterized cohorts of MASLD patients with or without HCC. Results: In non-neoplastic settings, murine and clinical data indicate that HRG increases significantly in parallel with disease progression. In particular, in MASLD/MASH patients, higher levels of HRG plasma levels were detected in subjects with extensive fibrosis/cirrhosis. When submitted to the pro-carcinogenic protocol, HRG-/- mice showed a significant decrease in the volume and number of HCC nodules in relation to decreased infiltration of macrophages producing pro-inflammatory mediators, including IL-1ß, IL-6, IL-12, IL-10, and VEGF as well as impaired angiogenesis. The histopathological analysis (H-score) of MASH-related HCC indicate that the higher HRG positivity in peritumoral tissue significantly correlates with a lower overall patient survival and an increased recurrence. Moreover, a significant increase in HRG plasma levels was detected in cirrhotic (F4) patients and in patients carrying HCC vs. F0/F1 patients. Conclusion: Murine and clinical data indicate that HRG plays a significant role in MASLD/MASH progression to HCC by supporting a specific population of tumor-associated macrophages with pro-inflammatory response and pro-angiogenetic capabilities which critically support cancer cell survival. Furthermore, our data suggest HRG as a possible prognostic predictor in HCC patients with MASLD/MASH-related HCCs.


Assuntos
Acetamidas , Carcinoma Hepatocelular , Neoplasias Hepáticas , Doenças Metabólicas , Hepatopatia Gordurosa não Alcoólica , Proteínas , Humanos , Animais , Camundongos , Carcinoma Hepatocelular/etiologia , Neoplasias Hepáticas/etiologia , Carcinogênese , Cirrose Hepática/etiologia , Progressão da Doença
16.
J Pathol ; 226(4): 588-97, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21959987

RESUMO

Liver fibrogenesis is sustained by pro-fibrogenic myofibroblast-like cells (MFs), mainly originating from activated hepatic stellate cells (HSC/MFs) or portal (myo)fibroblasts, and is favoured by hypoxia-dependent angiogenesis. Human HSC/MFs were reported to express vascular-endothelial growth factor (VEGF) and VEGF-receptor type 2 and to migrate under hypoxic conditions. This study was designed to investigate early and delayed signalling mechanisms involved in hypoxia-induced migration of human HSC/MFs. Signal transduction pathways and intracellular generation of reactive oxygen species (ROS) were evaluated by integrating morphological, cell, and molecular biology techniques. Non-oriented and oriented migration were evaluated by using wound healing assay and the modified Boyden's chamber assay, respectively. The data indicate that hypoxia-induced migration of HSC/MFs is a biphasic process characterized by the following sequence of events: (a) an early (15 min) and mitochondria-related increased generation of intracellular ROS which (b) was sufficient to switch on activation of ERK1/2 and JNK1/2 that were responsible for the early phase of oriented migration; (c) a delayed and HIF-1α-dependent increase in VEGF expression (facilitated by ROS) and its progressive, time-dependent release in the extracellular medium that (d) was mainly responsible for sustained migration of HSC/MFs. Finally, immunohistochemistry performed on HCV-related fibrotic/cirrhotic livers revealed HIF-2α and haem-oxygenase-1 positivity in hepatocytes and α-SMA-positive MFs, indicating that MFs were likely to be exposed in vivo to both hypoxia and oxidative stress. In conclusion, hypoxia-induced migration of HSC/MFs involves an early, mitochondrial-dependent ROS-mediated activation of ERK and JNK, followed by a delayed- and HIF-1α-dependent up-regulation and release of VEGF.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Movimento Celular/fisiologia , Células Estreladas do Fígado/fisiologia , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 8 Ativada por Mitógeno/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Hipóxia Celular , Células Cultivadas , Cultura em Câmaras de Difusão , Inativação Gênica , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Células Estreladas do Fígado/citologia , Hepatite C/metabolismo , Hepatite C/patologia , Hepatite C/virologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Hepatócitos/virologia , Humanos , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Mitocôndrias/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Cicatrização/fisiologia
17.
Biosci Rep ; 43(1)2023 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-36691794

RESUMO

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide. In the recent years nonalcoholic fatty liver disease (NAFLD) is becoming a growing cause of HCCs and the incidence of NAFLD-related HCCs is expected to further dramatically increase by the next decade. Chronic inflammation is regarded as the driving force of NAFLD progression and a key factor in hepatic carcinogenesis. Hepatic inflammation in NAFLD results from the persistent stimulation of innate immunity in response to hepatocellular injury and gut dysbiosis as well as by the activation of adaptive immunity. However, the relative roles of innate and adaptive immunity in the processes leading to HCC are still incompletely characterized. This is due to the complex interplay between different liver cell populations, which is also strongly influenced by gut-derived bacterial products, metabolic/nutritional signals. Furthermore, carcinogenic mechanisms in NAFLD/NASH appear to involve the activation of signals mediated by hypoxia inducible factors. This review discusses recent data regarding the contribution of different inflammatory cells to NAFLD-related HCC and their possible impact on patient response to current treatments.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Humanos , Carcinoma Hepatocelular/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Neoplasias Hepáticas/patologia , Inflamação
18.
Biology (Basel) ; 12(6)2023 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-37372056

RESUMO

Abnormal activation of the Wnt-ß-catenin signaling cascade is involved in tumor growth and dissemination. SerpinB3 has been shown to induce ß-catenin, and both molecules are overexpressed in tumors, particularly in those with poor prognoses. The aim of this study was to evaluate the ability of SerpinB3 to modulate the Wnt pathway in liver cancer and in monocytic cells, the main type of inflammatory cells in the tumor microenvironment. The Wnt cascade, Wnt co-receptors, and low-density lipoprotein receptor-related protein (LRP) members were analyzed in different cell lines and human monocytes in the presence or absence of SerpinB3. The Wnt-ß-catenin axis was also evaluated in liver tumors induced in mice with different extents of SeprinB3 expression. In monocytic cells, SerpinB3 induced a significant upregulation of Wnt-1/7, nuclear ß-catenin, and c-Myc, which are associated with increased cell lifespan and proliferation. In liver tumors in mice, the expression of ß-catenin was significantly correlated with the presence of SerpinB3. In hepatoma cells, Wnt co-receptors LRP-5/6 and LRP-1, implicated in cell survival and invasiveness, were upregulated by SerpinB3. The LRP pan-inhibitor RAP not only induced a decrease in LRP expression, but also a dose-dependent reduction in SerpinB3-induced invasiveness. In conclusion, SerpinB3 determines the activation of the Wnt canonical pathway and cell invasiveness through the upregulation of LRP family members.

19.
Mol Carcinog ; 51(10): 783-95, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21882253

RESUMO

Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, has been reported to exert chemopreventive and antitumor effects on colon cancer, one of the most common solid epithelial malignancy worldwide. The aim of this study was to elucidate whether celecoxib may be able to affect epithelial-mesenchymal transition (EMT), a critical process involved in cancer cell invasiveness and metastasis and then proposed to be relevant for cancer progression. Human HT-29 colon cancer cells were exposed to carefully controlled hypoxic conditions and/or epidermal growth factor (EGF) and then investigated for EMT changes and signal transduction pathways involved by using morphological, molecular, and cell biology techniques. Celecoxib inhibited basal and EGF-stimulated proliferation, hypoxia-related HIF-1α recruitment/stabilization as well as hypoxia- and EGF-dependent activation of ERK and PI3K. Interestingly, celecoxib prevented EMT-related changes, as shown by modifications of ß-catenin intracellular localization or vimentin and E-cadherin levels, as well as HT-29 invasiveness induced by hypoxia, EGF, or hypoxia plus EGF. Finally, experiments performed on SW-480 colon cancer cells (i.e., cells lacking COX-2) exposed to hypoxia, used here as a stimulus able to induce EMT and invasiveness, revealed that in these cells celecoxib was ineffective. Results of the present study indicate that celecoxib has the potential to negatively affect induction of EMT and increased invasiveness of colon cancer cells as elicited by different signals originating from tumor microenvironment (i.e., hypoxia and EGF). Moreover, these effects are likely be related to the pharmacological inhibitory effect exerted on COX-2 activity.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Fator de Crescimento Epidérmico/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Caderinas/metabolismo , Celecoxib , Hipóxia Celular , Proliferação de Células , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Fator de Crescimento Epidérmico/farmacologia , Receptores ErbB/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células HT29 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vimentina/metabolismo , beta Catenina/metabolismo
20.
Stem Cells ; 29(6): 952-63, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21563276

RESUMO

Hypoxic conditions have been reported to facilitate preservation of undifferentiated mesenchymal stem cell (MSC) phenotype and positively affect their colony-forming potential, proliferation, and migration/mobilization. In this study, designed to dissect mechanisms underlying hypoxia-dependent migration of bone marrow-derived human MSC (hMSC), signal transduction, and molecular mechanisms were evaluated by integrating morphological, molecular, and cell biology techniques, including the wound healing assay (WHA) and modified Boyden's chamber assay (BCA) to monitor migration. Exposure of hMSCs to moderate hypoxia resulted in a significant increase of migration of hMSCs in both WHA (from 6 to 20 hours) and BCA (within 6 hours). Mechanistic experiments outlined the following sequence of hypoxia-dependent events: (a) very early (15 minutes) increased generation of intracellular reactive oxygen species (ROS), which (b) was sufficient to switch on activation of extracellular regulated kinase 1/2 and c-Jun N-terminal protein kinase 1/2, found to be relevant for the early phase of hMSC migration; (c) hypoxia inducible factor-1 (HIF-1)-dependent increased expression of vascular endothelial growth factor (VEGF) (facilitated by ROS) and its progressive release that was responsible for (d) a delayed and sustained migration of hMSCs. These results suggest that hypoxia-dependent migration relies on a previously unrecognized biphasic scenario involving an early phase, requiring generation of ROS, and a delayed phase sustained by HIF-1-dependent expression and release of VEGF.


Assuntos
Células da Medula Óssea/fisiologia , Movimento Celular , Células-Tronco Mesenquimais/fisiologia , Antígenos CD/metabolismo , Células da Medula Óssea/citologia , Hipóxia Celular , Células Cultivadas , Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Células-Tronco Mesenquimais/metabolismo , Mitocôndrias/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estabilidade Proteica , Espécies Reativas de Oxigênio/metabolismo , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
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