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Heavy alcohol intake induces a wide spectrum of liver diseases ranging from steatosis, steatohepatitis, cirrhosis, and HCC. Although alcohol consumption is a well-known risk factor for the development, morbidity, and mortality of HCC globally, alcohol-associated hepatocellular carcinoma (A-HCC) is poorly characterized compared to viral hepatitis-associated HCC. Most A-HCCs develop after alcohol-associated cirrhosis (AC), but the direct carcinogenesis from ethanol and its metabolites to A-HCC remains obscure. The differences between A-HCC and HCCs caused by other etiologies have not been well investigated in terms of clinical prognosis, genetic or epigenetic landscape, molecular mechanisms, and heterogeneity. Moreover, there is a huge gap between basic research and clinical practice due to the lack of preclinical models of A-HCC. In the current review, we discuss the pathogenesis, heterogeneity, preclinical approaches, epigenetic, and genetic profiles of A-HCC, and discuss the current insights into and the prospects for future research on A-HCC. The potential effect of alcohol on cholangiocarcinoma and liver metastasis is also discussed.
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OBJECTIVE: The current treatment for hepatocellular carcinoma (HCC) to block angiogenesis and immunosuppression provides some benefits only for a subset of patients with HCC, thus optimised therapeutic regimens are unmet needs, which require a thorough understanding of the underlying mechanisms by which tumour cells orchestrate an inflamed tumour microenvironment with significant myeloid cell infiltration. MicroRNA-223 (miR-223) is highly expressed in myeloid cells but its role in regulating tumour microenvironment remains unknown. DESIGN: Wild-type and miR-223 knockout mice were subjected to two mouse models of inflammation-associated HCC induced by injection of diethylnitrosamine (DEN) or orthotopic HCC cell implantation in chronic carbon tetrachloride (CCl4)-treated mice. RESULTS: Genetic deletion of miR-223 markedly exacerbated tumourigenesis in inflammation-associated HCC. Compared with wild-type mice, miR-223 knockout mice had more infiltrated programmed cell death 1 (PD-1+) T cells and programmed cell death ligand 1 (PD-L1+) macrophages after DEN+CCl4 administration. Bioinformatic analyses of RNA sequencing data revealed a strong correlation between miR-223 levels and tumour hypoxia, a condition that is well-documented to regulate PD-1/PD-L1. In vivo and in vitro mechanistic studies demonstrated that miR-223 did not directly target PD-1 and PD-L1 in immune cells rather than indirectly downregulated them by modulating tumour microenvironment via the suppression of hypoxia-inducible factor 1α-driven CD39/CD73-adenosine pathway in HCC. Moreover, gene delivery of miR-223 via adenovirus inhibited angiogenesis and hypoxia-mediated PD-1/PD-L1 activation in both HCC models, thereby hindering HCC progression. CONCLUSION: The miR-223 plays a critical role in modulating hypoxia-induced tumour immunosuppression and angiogenesis, which may serve as a novel therapeutic target for HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Camundongos , Animais , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Antígeno B7-H1 , Receptor de Morte Celular Programada 1 , Terapia de Imunossupressão , Carcinogênese , Camundongos Knockout , MicroRNAs/genética , Inflamação , Hipóxia , Microambiente TumoralRESUMO
Epithelial-mesenchymal transition (EMT) is a crucial process for cancer cells to acquire metastatic potential, which primarily causes death in gastric cancer (GC) patients. Bone morphogenetic protein 4 (BMP4) is a member of the TGF-ß family that plays an indispensable role in human cancers. However, little is known about its roles in GC metastasis. In this study, BMP4 was found to be frequently overexpressed in GC tissues and was correlated with poor patient's prognosis. BMP4 was upregulated in GC cell lines and promoted EMT and metastasis of GC cells both in vitro and in vivo, whereas knockdown of BMP4 significantly inhibited EMT and metastasis of GC cells. Furthermore, the inhibitor of DNA binding 1 (also known as DNA-binding protein inhibitor ID1) was identified as a downstream target of BMP4 using PCR arrays and was upregulated via SMAD1/5/8 phosphorylation. ID1 knockdown attenuated BMP4-induced EMT and invasion in GC cells. Moreover, ID1 overexpression in BMP4 knockdown cells restored the promotion of EMT and cell invasion. In summary, BMP4 induced EMT and promoted GC metastasis by upregulating ID1 expression. Antagonizing BMP4 could be a potential therapeutic strategy for GC metastasis.
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Transição Epitelial-Mesenquimal , Neoplasias Gástricas , Proteína Morfogenética Óssea 4/genética , Linhagem Celular Tumoral , Movimento Celular , Humanos , Proteína 1 Inibidora de Diferenciação/genética , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias Gástricas/genéticaRESUMO
BACKGROUND & AIMS: Interleukin (IL)-20 and IL-22 belong to the IL-10 family. IL-10 is a well-documented anti-inflammatory cytokine while IL-22 is well known for epithelial protection and its antibacterial function, showing great therapeutic potential for organ damage; however, the function of IL-20 remains largely unknown. METHODS: Il20 knockout (Il20-/-) mice and wild-type littermates were generated and injected with Concanavalin A (ConA) and Klebsiella pneumoniae (K.P.) to induce acute hepatitis and bacterial infection, respectively. RESULTS: Il20-/- mice were resistant to acute hepatitis and exhibited selectively elevated levels of the hepatoprotective cytokine IL-6. Such selective inhibition of IL-6 by IL-20 was due to IL-20 targeting hepatocytes that produce high levels of IL-6 but a limited number of other cytokines. Mechanistically, IL-20 upregulated NAD(P)H: quinone oxidoreductase 1 (NQO1) expression and subsequently promoted the protein degradation of transcription factor IκBζ, resulting in selective downregulation of the IκBζ-dependent gene Il6 as well several other IκBζ-dependent genes including lipocalin-2 (Lcn2). Given the important role of IL-6 and LCN2 in limiting bacterial infection, we examined the effect of IL-20 on bacterial infection and found Il20-/- mice were resistant to K.P. infection and exhibited elevated levels of hepatic IκBζ-dependent antibacterial genes. Moreover, IL-20 upregulated hepatic NQO1 by binding to IL-22R1/IL-20R2 and activating ERK/p38MAPK/NRF2 signaling pathways. Finally, the levels of hepatic IL1B, IL20, and IκBζ target genes were elevated, and correlated with each other, in patients with severe alcoholic hepatitis. CONCLUSIONS: IL-20 selectively inhibits hepatic IL-6 production rather than exerting IL-10-like broad anti-inflammatory properties. Unlike IL-22, IL-20 aggravates acute hepatitis and bacterial infection. Thus, anti-IL-20 therapy could be a promising option to control acute hepatitis and bacterial infection. LAY SUMMARY: Several interleukin (IL)-20 family cytokines have been shown to play important roles in controllimg inflammatory responses, infection and tissue damage, but the role of IL-20 remains unclear. Herein, we elucidated the role of IL-20 in liver disease and bacterial infection. We show that IL-20 can aggravate hepatitis and bacterial infection; thus, targeting IL-20 holds promise for the treatment of patients with liver disease.
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Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Infecções Bacterianas , Hepatite Alcoólica , Hepatite , Interleucina-1beta/metabolismo , Interleucinas/metabolismo , Animais , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/imunologia , Infecções Bacterianas/metabolismo , Descoberta de Drogas , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatite/tratamento farmacológico , Hepatite/imunologia , Hepatite/metabolismo , Hepatite Alcoólica/imunologia , Hepatite Alcoólica/metabolismo , Humanos , Fígado/metabolismo , Camundongos , Camundongos Knockout , NAD(P)H Desidrogenase (Quinona)/metabolismo , Proteólise , Regulação para CimaRESUMO
Activation of autophagy significantly affects cancer cell behaviors, such as proliferation, differentiation, and invasiveness. Epithelial-to-mesenchymal transition (EMT) as an initial step of malignant transformation of cancer cells was linked to the activation of autophagy, but the detailed molecular mechanisms are still unknown. The present study investigates the effects of Beclin-1, a key molecule involved in activation of autophagy, on EMT of colon cancer cells. The normal colon epithelia cell line of CCD-18Co and six colon cancer cell lines with different expression levels of Beclin-1 were used in this study. The activation of autophagy and EMT markers of cancer cells were monitored by Western blotting and quantitative real-time PCR assay in the presence or absence of rapamycin (autophagy activator) and 3-MA (autophagy inhibitor). The expression of Beclin-1 in selected cell lines was modulated using small interfering RNA, and consequentially EMT markers, and cancer cell behaviors including migration and invasion, were also explored. Activation or inhibition of autophagy in colon cancer cells had positive or negative impacts on the expression of EMT markers and malignant behaviors such as cell migration and invasion. Knockdown of beclin-1 by siRNA apparently inhibited the activation of autophagy induced by rapamycin, consequentially resulted in suppression of EMT and attenuation of invasiveness of colon cancer cells. The results in this study demonstrated an association between activation of autophagy and EMT in colon cancer cells. The results showed suppression of Beclin-1 expression significantly reduced EMT and invasive behaviors in colon cancer cells.
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Proteína Beclina-1/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/metabolismo , Transição Epitelial-Mesenquimal , Proteínas de Neoplasias/metabolismo , Proteína Beclina-1/genética , Biomarcadores Tumorais/genética , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Técnicas de Silenciamento de Genes , Células HCT116 , Humanos , Invasividade Neoplásica , Proteínas de Neoplasias/genéticaRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant diseases worldwide. It is refractory to conventional treatments, and consequently has a documented 5-year survival rate as low as 7%. Increasing evidence indicates that activated pancreatic stellate cells (PSCs), one of the stromal components in tumor microenvironment (TME), play a crucial part in the desmoplasia, carcinogenesis, aggressiveness, metastasis associated with PDAC. Despite the current understanding of PSCs as a "partner in crime" to PDAC, detailed regulatory roles of PSCs and related microenvironment remain obscure. In addition to multiple paracrine signaling pathways, recent research has confirmed that PSCs-mediated tumor microenvironment may influence behaviors of PDAC via diverse mechanisms, such as rewiring metabolic networks, suppressing immune responses. These new activities are closely linked with treatment and prognosis of PDAC. In this review, we discuss the recent advances regarding new functions of activated PSCs, including PSCs-cancer cells interaction, mechanisms involved in immunosuppressive regulation, and metabolic reprogramming. It's clear that these updated experimental or clinical studies of PSCs may provide a promising approach for PDAC treatment in the near future.
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Carcinoma Ductal Pancreático/etiologia , Carcinoma Ductal Pancreático/metabolismo , Metabolismo Energético , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/metabolismo , Células Estreladas do Pâncreas/metabolismo , Comunicação Parácrina , Evasão Tumoral/imunologia , Animais , Biomarcadores , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/terapia , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Regulação da Expressão Gênica , Humanos , Terapia de Alvo Molecular , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Células Estreladas do Pâncreas/patologia , Transdução de Sinais , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Neoplasias PancreáticasRESUMO
Alcohol-associated liver disease (ALD) is a major cause of chronic liver disease worldwide, and comprises a spectrum of several different disorders, including simple steatosis, steatohepatitis, cirrhosis, and superimposed hepatocellular carcinoma. Although tremendous progress has been made in the field of ALD over the last 20 years, the pathogenesis of ALD remains obscure, and there are currently no FDA-approved drugs for the treatment of ALD. In this Review, we discuss new insights into the pathogenesis and therapeutic targets of ALD, utilizing the study of multiomics and other cutting-edge approaches. The potential translation of these studies into clinical practice and therapy is deliberated. We also discuss preclinical models of ALD, interplay of ALD and metabolic dysfunction, alcohol-associated liver cancer, the heterogeneity of ALD, and some potential translational research prospects for ALD.
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Carcinoma Hepatocelular , Fígado Gorduroso , Hepatopatias Alcoólicas , Neoplasias Hepáticas , Humanos , Hepatopatias Alcoólicas/tratamento farmacológico , Hepatopatias Alcoólicas/etiologia , Hepatopatias Alcoólicas/patologia , Etanol , Fígado Gorduroso/metabolismo , Cirrose Hepática/patologia , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/metabolismo , Fígado/metabolismoRESUMO
Alcohol use disorder (AUD) affects millions of people worldwide, causing extensive morbidity and mortality with limited pharmacological treatments. The liver is considered as the principal site for the detoxification of ethanol metabolite, acetaldehyde (AcH), by aldehyde dehydrogenase 2 (ALDH2) and as a target for AUD treatment, however, our recent data indicate that the liver only plays a partial role in clearing systemic AcH. Here we show that a liver-gut axis, rather than liver alone, synergistically drives systemic AcH clearance and voluntary alcohol drinking. Mechanistically, we find that after ethanol intake, a substantial proportion of AcH generated in the liver is excreted via the bile into the gastrointestinal tract where AcH is further metabolized by gut ALDH2. Modulating bile flow significantly affects serum AcH level and drinking behaviour. Thus, combined targeting of liver and gut ALDH2, and manipulation of bile flow and secretion are potential therapeutic strategies to treat AUD.
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Consumo de Bebidas Alcoólicas , Aldeído-Desidrogenase Mitocondrial , Etanol , Fígado , Fígado/metabolismo , Animais , Etanol/metabolismo , Aldeído-Desidrogenase Mitocondrial/metabolismo , Camundongos , Consumo de Bebidas Alcoólicas/metabolismo , Acetaldeído/metabolismo , Inativação Metabólica , Trato Gastrointestinal/metabolismo , Alcoolismo/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Masculino , Microbioma Gastrointestinal , Bile/metabolismoRESUMO
Excessive alcohol drinking can cause pathological changes including carcinogenesis in the digestive tract from mouth to large intestine, but the underlying mechanisms are not fully understood. In this review, we discuss the effects of alcohol on small and large intestinal functions, such as leaky gut, dysbiosis and alterations of intestinal epithelium and gut immune dysfunctions, commonly referred to as alcohol-associated bowel disease (ABD). To date, detailed mechanistic insights into ABD are lacking. Accumulating evidence suggests a pathogenic role of ethanol metabolism in dysfunctions of the intestinal tract. Ethanol metabolism generates acetaldehyde and acetate, which could potentially promote functional disruptions of microbial and host components of the intestinal barrier along the gastrointestinal tract. The potential involvement of acetaldehyde and acetate in the pathogenesis of the underlying ABD, including cancer, is discussed. We also highlight some gaps in knowledge existing in the field of ABD. Finally, we discuss future directions in exploring the role of acetaldehyde and acetate generated during chronic alcohol intake in various pathologies affecting different sites of the intestinal tract.
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BACKGROUND & AIMS: Binge drinking in patients with metabolic syndrome accelerates the development of alcohol-associated liver disease. However, the underlying mechanisms remain elusive. We investigated if oxidative and nonoxidative alcohol metabolism pathways, diet-induced obesity, and adipose tissues influenced the development of acute liver injury in a single ethanol binge model. METHODS: A single ethanol binge was administered to chow-fed or high-fat diet (HFD)-fed wild-type and genetically modified mice. RESULTS: Oral administration of a single dose of ethanol induced acute liver injury and hepatic endoplasmic reticulum (ER) stress in chow- or HFD-fed mice. Disruption of the Adh1 gene increased blood ethanol concentration and exacerbated acute ethanol-induced ER stress and liver injury in both chow-fed and HFD-fed mice, while disruption of the Aldh2 gene did not affect such hepatic injury despite high blood acetaldehyde levels. Mechanistic studies showed that alcohol, not acetaldehyde, promoted hepatic ER stress, fatty acid synthesis, and increased adipocyte death and lipolysis, contributing to acute liver injury. Increased serum fatty acid ethyl esters (FAEEs), which are formed by an enzyme-mediated esterification of ethanol with fatty acids, were detected in mice after ethanol gavage, with higher levels in Adh1 knockout mice than in wild-type mice. Deletion of the Ces1d gene in mice markedly reduced the acute ethanol-induced increase of blood FAEE levels with a slight but significant reduction of serum aminotransferase levels. CONCLUSIONS: Ethanol and its nonoxidative metabolites, FAEEs, not acetaldehyde, promoted acute alcohol-induced liver injury by inducing ER stress, adipocyte death, and lipolysis.
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Doença Hepática Induzida por Substâncias e Drogas , Estresse do Retículo Endoplasmático , Etanol , Lipólise , Animais , Camundongos , Acetaldeído/metabolismo , Adipócitos/metabolismo , Ésteres/metabolismo , Etanol/toxicidade , Ácidos Graxos/metabolismo , Fígado/metabolismoRESUMO
Background and aims: Vasoactive intestinal polypeptide type-I receptor (VIPR1) overexpression has been reported in numerous types of malignancies and utilized to develop novel target therapeutics and radiolabeled VIP analogue-based tumor imaging technology, but its role in liver carcinogenesis has not been explored. In the current study, we investigated the role of the VIP/VIPR1 signaling in controlling hepatocellular carcinoma (HCC) progression. Approach and results: By analyzing clinical samples, we found the expression level of VIPR1 was downregulated in human HCC tissues, which was correlated with advanced clinical stages, tumor growth, recurrence, and poor outcomes of HCC clinically. In vitro and in vivo studies revealed that activation of VIPR1 by VIP markedly inhibited HCC growth and metastasis. Intriguingly, transcriptome sequencing analyses revealed that activation of VIPR1 by VIP regulated arginine biosynthesis. Mechanistical studies in cultured HCC cells demonstrated that VIP treatment partially restored the expression of arginine anabolic key enzyme argininosuccinate synthase (ASS1), and to some extent, inhibited de novo pyrimidine synthetic pathway by downregulating the activation of CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase). VIP treatment upregulated ASS1 and subsequently suppressed CAD phosphorylation in an mTOR/p70S6K signaling dependent manner. Clinically, we found human HCC samples were associated with downregulation of ASS1 but upregulation of CAD phosphorylation, and that VIPR1 levels positively correlated with ASS1 levels and serum levels of urea, the end product of the urea cycle and arginine metabolism in HCC. Conclusions: Loss of VIPR1 expression in HCC facilitates CAD phosphorylation and tumor progression, and restoration of VIPR1 and treatment with the VIPR1 agonist may be a promising approach for HCC treatment.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Arginina/uso terapêutico , Argininossuccinato Sintase/metabolismo , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Humanos , Neoplasias Hepáticas/metabolismo , Pirimidinas/uso terapêutico , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo , Ureia/uso terapêuticoRESUMO
BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease, characterized by steatosis and hallmark liver neutrophil infiltration. NASH also is associated with adipose tissue inflammation, but the role of adipose tissue inflammation in NASH pathogenesis remains obscure. The aim of this study was to investigate the interplay between neutrophil recruitment in adipose tissue and the progression of NASH. METHODS: A mouse model of NASH was obtained by high-fat diet (HFD) feeding plus adenovirus-Cxcl1 overexpression (HFD+AdCxcl1). Genetic deletion of E-selectin (Sele) and treatment with an S100A9 inhibitor (Paquinimod) were investigated using this model. RESULTS: By analyzing transcriptomic data sets of adipose tissue from NASH patients, we found that E-selectin, a key adhesion molecule for neutrophils, is the highest up-regulated gene among neutrophil recruitment-related factors in adipose tissue of NASH patients compared with those in patients with simple steatosis. A marked up-regulation of Sele in adipose tissue also was observed in HFD+AdCxcl1 mice. The HFD+AdCxcl1-induced NASH phenotype was ameliorated in Sele knockout mice and was accompanied by reduced lipolysis and inflammation in adipose tissue, which resulted in decreased serum free fatty acids and proinflammatory adipokines. S100A8/A9, a major proinflammatory protein secreted by neutrophils, was highly increased in adipose tissue of HFD+AdCxcl1 mice. This increase was blunted in the Sele knockout mice. Therapeutically, treatment with the S100A9 inhibitor Paquinimod reduced lipolysis, inflammation, and adipokine production, ameliorating the NASH phenotype in mice. CONCLUSIONS: E-selectin plays an important role in inducing neutrophil recruitment in adipose tissue, which subsequently promotes inflammation and lipolysis via the production of S100A8/A9, thereby exacerbating the steatosis-to-NASH progression. Targeting adipose tissue inflammation therefore may represent a potential novel therapy for treatment of NASH.
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Hepatopatia Gordurosa não Alcoólica , Tecido Adiposo/metabolismo , Animais , Selectina E/metabolismo , Humanos , Inflamação/patologia , Lipólise , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/patologiaRESUMO
Background & Aims: Liver fibrosis is a common consequence of chronic liver injury and is characterized by the accumulation of extracellular matrix mainly generated from activated hepatic stellate cells (HSCs). At present, the mechanisms underlying liver fibrogenesis remain obscure and effective pharmacological therapies are lacking. Neutrophil-specific microRNA-223 (miR-223) plays an important role in controlling the development of various liver diseases; however, its role in HSC activation and liver fibrosis remains unclear. Methods: Liver fibrosis was induced by chronic carbon tetrachloride (CCl4) injection of miR-223 knockout (miR-223KO) mice and littermate wild-type controls. MiR-223 was overexpressed in cultured HSCs to determine its function and targets during HSC activation and proliferation. The expression of miR-223 and pri-miR-223 was examined in primary HSCs isolated from CCl4-treated mice and in cultured HSCs. The communication between HSCs and neutrophils was studied by performing in vitro co-culture experiments. Results: Genetic deletion of miR-223 exacerbated chronic CCl4-induced liver fibrosis. Administration of miR-223 inhibited liver fibrosis by inhibiting the transcriptional coactivator with PDZ-binding motif (TAZ)-Indian hedgehog (IHH)-GLI Family Zinc Finger 2 (GLI2) pathway via the crosstalk between hepatocytes and HSCs. Overexpression of miR-223 also directly attenuated Gli2 as well as platelet-derived growth factor receptor α/ß (Pdgfra/b) expression in HSCs, thereby suppressing HSC activation and proliferation. The expression of pri-miR-223 and miR-223 was downregulated during HSC activation in vitro. Expression of pri-miR-223 was also decreased in activated HSCs in vivo in fibrotic livers but mature miR-223 expression was not reduced. Finally, in co-culture experiments, activated HSCs were able to take up miR-223-enriched extracellular vesicles from neutrophils, resulting in elevation of miR-223. Conclusion: MiR-223 restricts liver fibrosis by targeting multiple genes in hepatocytes and HSCs, providing potential therapeutic targets for the treatment of liver fibrosis.
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Células Estreladas do Fígado/metabolismo , Hepatócitos/metabolismo , Cirrose Hepática/metabolismo , MicroRNAs/metabolismo , Aciltransferases/metabolismo , Animais , Intoxicação por Tetracloreto de Carbono/metabolismo , Linhagem Celular , Vesículas Extracelulares/metabolismo , Proteínas Hedgehog/metabolismo , Humanos , Camundongos Knockout , Receptor Cross-Talk , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais , Proteína Gli2 com Dedos de Zinco/metabolismoRESUMO
Neutrophil infiltration around lipotoxic hepatocytes is a hallmark of nonalcoholic steatohepatitis (NASH); however, how these 2 types of cells communicate remains obscure. We have previously demonstrated that neutrophil-specific microRNA-223 (miR-223) is elevated in hepatocytes to limit NASH progression in obese mice. Here, we demonstrated that this elevation of miR-223 in hepatocytes was due to preferential uptake of miR-223-enriched extracellular vesicles (EVs) derived from neutrophils as well other types of cells, albeit to a lesser extent. This selective uptake was dependent on the expression of low-density lipoprotein receptor (LDLR) on hepatocytes and apolipoprotein E (APOE) on neutrophil-derived EVs, which was enhanced by free fatty acids. Once internalized by hepatocytes, the EV-derived miR-223 acted to inhibit hepatic inflammatory and fibrogenic gene expression. In the absence of this LDLR- and APOE-dependent uptake of miR-223-enriched EVs, the progression of steatosis to NASH was accelerated. In contrast, augmentation of this transfer by treatment with an inhibitor of proprotein convertase subtilisin/kexin type 9, a drug used to lower blood cholesterol by upregulating LDLR, ameliorated NASH in mice. This specific role of LDLR and APOE in the selective control of miR-223-enriched EV transfer from neutrophils to hepatocytes may serve as a potential therapeutic target for NASH.
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Comunicação Celular , Vesículas Extracelulares/metabolismo , Hepatócitos/metabolismo , MicroRNAs/metabolismo , Neutrófilos/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores de LDL/metabolismo , Animais , Vesículas Extracelulares/genética , Vesículas Extracelulares/patologia , Hepatócitos/patologia , Camundongos , Camundongos Knockout , Camundongos Obesos , MicroRNAs/genética , Neutrófilos/patologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Receptores de LDL/genéticaRESUMO
Kupffer cells (KCs), which are liver-resident macrophages, originate from the fetal yolk sac and represent one of the largest macrophage populations in the body. However, the current data on the origin of the cells that restore macrophages during liver injury and regeneration remain controversial. Here, we address the question of whether liver macrophage restoration results from circulating monocyte infiltration or local KC proliferation in regenerating livers after partial hepatectomy (PHx) and uncover the underlying mechanisms. By using several strains of genetically modified mice and performing immunohistochemical analyses, we demonstrated that local KC proliferation mainly contributed to the restoration of liver macrophages after PHx. Peak KC proliferation was impaired in Il6-knockout (KO) mice and restored after the administration of IL-6 protein, whereas KC proliferation was not affected in Il4-KO or Csf2-KO mice. The source of IL-6 was identified using hepatocyte- and myeloid-specific Il6-KO mice and the results revealed that both hepatocytes and myeloid cells contribute to IL-6 production after PHx. Moreover, peak KC proliferation was also impaired in myeloid-specific Il6 receptor-KO mice after PHx, suggesting that IL-6 signaling directly promotes KC proliferation. Studies using several inhibitors to block the IL-6 signaling pathway revealed that sirtuin 1 (SIRT1) contributed to IL-6-mediated KC proliferation in vitro. Genetic deletion of the Sirt1 gene in myeloid cells, including KCs, impaired KC proliferation after PHx. In conclusion, our data suggest that KC repopulation after PHx is mainly driven by local KC proliferation, which is dependent on IL-6 and SIRT1 activation in KCs.
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Hepatectomia , Interleucina-6/metabolismo , Células de Kupffer , Animais , Proliferação de Células , Hepatectomia/métodos , Hepatócitos/metabolismo , Fígado/metabolismo , Regeneração Hepática/fisiologia , Camundongos , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Chemoresistance is a major obstacle to improving the survival rate of colorectal cancer (CRC) patients. Forkhead box protein C2 (FOXC2), a member of the forkhead box (Fox) transcription factor family, is reported to be an important regulator of epithelial-to-mesenchymal transition (EMT) and plays a key role in tumor progression. However, little is known about the effects of FOXC2 on oxaliplatin (OXA) resistance in CRC. METHODS: OXA-resistant cells were generated from HCT116 cells. CCK-8, colony formation, flow cytometry and Transwell assays were used to compare the characteristics of OXA-resistant HCT116/OXA cells and the corresponding parental HCT116 cells. The expression of FOXC2 was confirmed by qRT-PCR and Western blotting in HCT116/OXA and HCT116 cells. Gain- and loss-of-function assays were performed to evaluate the effects of FOXC2 on OXA sensitivity and EMT in HCT116/OXA and HCT116 cells both in vitro and in vivo, and the possible molecular mechanisms were investigated. RESULTS: The relative expression of FOXC2 was significantly increased in HCT116/OXA cells compared with the parental HCT116 cells. Upregulation of FOXC2 in HCT116 cells reduced OXA sensitivity and promoted EMT. However, knockdown of FOXC2 in HCT116/OXA cells markedly increased the in vitro and in vivo sensitivity of HCT116/OXA cells to OXA by regulating EMT progression. Furthermore, FOXC2 activated MAPK/ERK signaling, and blockade of ERK attenuated FOXC2-induced EMT and FOXC2-enhanced OXA resistance. CONCLUSION: FOXC2 induced EMT to promote oxaliplatin resistance by activating the MAPK/ERK signaling pathway. FOXC2 may be a potential therapeutic target for overcoming OXA resistance in human CRC.
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The rapid onset of resistance to cetuximab (CTX) limits its clinical utility in colorectal cancer (CRC) patients. This study aims to understand a potential role of mismatch repair gene mutL homolog 1 (MLH1) in CTX response. Functional analysis of MLH1 in Her-2/phosphoinositide 3-kinases (PI3K)/PKB protein kinase (AKT)-regulated CTX sensitivity is performed using human CRC specimens, CRC cell lines with different MLH1 expression levels, and a subcutaneous xenograft model. Overexpression, knockdown, small interfering RNA, and inhibitors are used to examine the role of MLH1 and HER-2 downstream signaling and apoptotic targets in CTX sensitivity. Reduced MLH1 expression is correlated with unfavorable prognosis in cetuximab-treated patients. MLH1 loss decreases CTX sensitivity through Her-2/PI3K/AKT signaling and apoptosis resistance in culture and in xenografts, while MLH1 overexpression increases CTX sensitivity. Blocking Her-2 signaling increases CTX sensitivity of microsatellite instability CRC in vitro and in vivo. MLH1 loss induces activation of Her-2/PI3K/AKT signaling and leads to cetuximab resistance in colon cancer.
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Objective: We aimed at analyzing the role of smoking in hepatic fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) and at exploring the related risk factors. Methods: This was a cross-sectional study that included a total of 225 patients with NAFLD. Among them, 127 were nonsmokers and 98 were smokers. Liver significant fibrosis was diagnosed when the liver stiffness (LS) value was higher than 7.4 kPa. The diagnostic criterion for NAFLD was a controlled attenuation parameter (CAP) value of >238 dB/m. The CAP and LS values were measured using FibroScan. Results: FibroScan showed that the LS value in the smokers was significantly higher than that in the nonsmokers (10.12 ± 10.38 kPa vs. 7.26 ± 6.42 kPa, P=0.013). The proportions of patients with liver significant fibrosis and advanced liver fibrosis among the smokers were significantly higher than those among the nonsmokers (P=0.046). Univariate analysis showed that age, weight, high AST level, low PLT level, and smoking were the risk factors associated with liver fibrosis in the smokers with NAFLD while multivariate analysis showed that age (OR = 1.029, P=0.021), high AST level (OR = 1.0121, P=0.025), and smoking (OR = 1.294, P=0.015) were the independent risk factors associated with liver fibrosis in the patients with NAFLD. Moreover, high AST level (OR = 1.040, P=0.029), smoking index (OR = 1.220, P=0.019), and diabetes mellitus (OR = 1.054, P=0.032) were the independent risk factors for liver fibrosis among the smokers with NAFLD. Conclusion: This study showed that smoking was closely associated with liver fibrosis among the patients with NAFLD. For patients with NAFLD who smoke, priority screening and timely intervention should be provided if they are at risk of liver fibrosis.
Assuntos
Cirrose Hepática/diagnóstico , Cirrose Hepática/epidemiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/psicologia , Fumar/efeitos adversos , Adulto , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Hepatocellular carcinoma (HCC) ranks the most common primary liver malignancy and the third leading cause of tumor-related mortality worldwide. Unfortunately, despite advances in HCC treatment, less than 40% of HCC patients are eligible for potentially curative therapies. Recently, cancer immunotherapy has emerged as one of the most promising approaches for cancer treatment. It has been proven therapeutically effective in many types of solid tumors, such as non-small cell lung cancer and melanoma. As an inflammation-associated tumor, it's well-evidenced that the immunosuppressive microenvironment of HCC can promote immune tolerance and evasion by various mechanisms. Triggering more vigorous HCC-specific immune response represents a novel strategy for its management. Pre-clinical and clinical investigations have revealed that various immunotherapies might extend current options for needed HCC treatment. In this review, we provide the recent progress on HCC immunology from both basic and clinical perspectives, and discuss potential advances and challenges of immunotherapy in HCC.