RESUMO
Metabolic reprogramming is a hallmark of cancer. However, mechanisms underlying metabolic reprogramming and how altered metabolism in turn enhances tumorigenicity are poorly understood. Here, we report that arginine levels are elevated in murine and patient hepatocellular carcinoma (HCC), despite reduced expression of arginine synthesis genes. Tumor cells accumulate high levels of arginine due to increased uptake and reduced arginine-to-polyamine conversion. Importantly, the high levels of arginine promote tumor formation via further metabolic reprogramming, including changes in glucose, amino acid, nucleotide, and fatty acid metabolism. Mechanistically, arginine binds RNA-binding motif protein 39 (RBM39) to control expression of metabolic genes. RBM39-mediated upregulation of asparagine synthesis leads to enhanced arginine uptake, creating a positive feedback loop to sustain high arginine levels and oncogenic metabolism. Thus, arginine is a second messenger-like molecule that reprograms metabolism to promote tumor growth.
Assuntos
Arginina , Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Humanos , Camundongos , Arginina/metabolismo , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Metabolismo dos Lipídeos , Neoplasias Hepáticas/metabolismoRESUMO
Hepatocellular carcinoma (HCC) is an aggressive malignancy with its global incidence and mortality rate continuing to rise, although early detection and surveillance are suboptimal. We performed serological profiling of the viral infection history in 899 individuals from an NCI-UMD case-control study using a synthetic human virome, VirScan. We developed a viral exposure signature and validated the results in a longitudinal cohort with 173 at-risk patients who had long-term follow-up for HCC development. Our viral exposure signature significantly associated with HCC status among at-risk individuals in the validation cohort (area under the curve: 0.91 [95% CI 0.87-0.96] at baseline and 0.98 [95% CI 0.97-1] at diagnosis). The signature identified cancer patients prior to a clinical diagnosis and was superior to alpha-fetoprotein. In summary, we established a viral exposure signature that can predict HCC among at-risk patients prior to a clinical diagnosis, which may be useful in HCC surveillance.
Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Viroses/patologia , Adulto , Idoso , Área Sob a Curva , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Estudos de Casos e Controles , Estudos de Coortes , Bases de Dados Genéticas , Feminino , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Curva ROC , Fatores de Risco , Viroses/complicações , Adulto Jovem , alfa-Fetoproteínas/análiseRESUMO
The fidelity of intracellular signaling hinges on the organization of dynamic activity architectures. Spatial compartmentation was first proposed over 30 years ago to explain how diverse G protein-coupled receptors achieve specificity despite converging on a ubiquitous messenger, cyclic adenosine monophosphate (cAMP). However, the mechanisms responsible for spatially constraining this diffusible messenger remain elusive. Here, we reveal that the type I regulatory subunit of cAMP-dependent protein kinase (PKA), RIα, undergoes liquid-liquid phase separation (LLPS) as a function of cAMP signaling to form biomolecular condensates enriched in cAMP and PKA activity, critical for effective cAMP compartmentation. We further show that a PKA fusion oncoprotein associated with an atypical liver cancer potently blocks RIα LLPS and induces aberrant cAMP signaling. Loss of RIα LLPS in normal cells increases cell proliferation and induces cell transformation. Our work reveals LLPS as a principal organizer of signaling compartments and highlights the pathological consequences of dysregulating this activity architecture.
Assuntos
Carcinogênese/metabolismo , Carcinoma Hepatocelular/genética , Compartimento Celular/genética , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Proteínas de Choque Térmico HSP40/genética , Neoplasias Hepáticas/genética , Transdução de Sinais , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinoma Hepatocelular/metabolismo , Compartimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , AMP Cíclico/farmacologia , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Citoplasma/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Camundongos , Oncogenes/genética , Domínios Proteicos , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes de Fusão , Espectroscopia de Infravermelho com Transformada de Fourier , Imagem com Lapso de Tempo/métodosRESUMO
The NRF2 transcription factor controls a cell stress program that is implicated in cancer and there is great interest in targeting NRF2 for therapy. We show that NRF2 activity depends on Fructosamine-3-kinase (FN3K)-a kinase that triggers protein de-glycation. In its absence, NRF2 is extensively glycated, unstable, and defective at binding to small MAF proteins and transcriptional activation. Moreover, the development of hepatocellular carcinoma triggered by MYC and Keap1 inactivation depends on FN3K in vivo. N-acetyl cysteine treatment partially rescues the effects of FN3K loss on NRF2 driven tumor phenotypes indicating a key role for NRF2-mediated redox balance. Mass spectrometry reveals that other proteins undergo FN3K-sensitive glycation, including translation factors, heat shock proteins, and histones. How glycation affects their functions remains to be defined. In summary, our study reveals a surprising role for the glycation of cellular proteins and implicates FN3K as targetable modulator of NRF2 activity in cancer.
Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Animais , Carcinoma Hepatocelular/patologia , Feminino , Técnicas de Silenciamento de Genes , Glucose/metabolismo , Glicosilação , Células HEK293 , Células Hep G2 , Xenoenxertos , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução GenéticaRESUMO
Identifying tumor-induced leukocyte subsets and their derived circulating factors has been instrumental in understanding cancer as a systemic disease. Nevertheless, how primary tumor-induced non-leukocyte populations in distal organs contribute to systemic spread remains poorly defined. Here, we report one population of tumor-inducible, erythroblast-like cells (Ter-cells) deriving from megakaryocyte-erythroid progenitor cells with a unique Ter-119+CD45-CD71+ phenotype. Ter-cells are enriched in the enlarged spleen of hosts bearing advanced tumors and facilitate tumor progression by secreting neurotrophic factor artemin into the blood. Transforming growth factor ß (TGF-ß) and Smad3 activation are important in Ter-cell generation. In vivo blockade of Ter-cell-derived artemin inhibits hepatocellular carcinoma (HCC) growth, and artemin deficiency abolishes Ter-cells' tumor-promoting ability. We confirm the presence of splenic artemin-positive Ter-cells in human HCC patients and show that significantly elevated serum artemin correlates with poor prognosis. We propose that Ter-cells and the secreted artemin play important roles in cancer progression with prognostic and therapeutic implications.
Assuntos
Progressão da Doença , Eritroblastos/citologia , Proteínas do Tecido Nervoso/sangue , Baço/citologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Apoptose , Carcinoma Hepatocelular/metabolismo , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Células Hep G2 , Humanos , Antígenos Comuns de Leucócito/metabolismo , Leucócitos/citologia , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Invasividade Neoplásica/genética , Transdução de SinaisRESUMO
Obesity is a major driver of cancer, especially hepatocellular carcinoma (HCC). The prevailing view is that non-alcoholic steatohepatitis (NASH) and fibrosis or cirrhosis are required for HCC in obesity. Here, we report that NASH and fibrosis and HCC in obesity can be dissociated. We show that the oxidative hepatic environment in obesity inactivates the STAT-1 and STAT-3 phosphatase T cell protein tyrosine phosphatase (TCPTP) and increases STAT-1 and STAT-3 signaling. TCPTP deletion in hepatocytes promoted T cell recruitment and ensuing NASH and fibrosis as well as HCC in obese C57BL/6 mice that normally do not develop NASH and fibrosis or HCC. Attenuating the enhanced STAT-1 signaling prevented T cell recruitment and NASH and fibrosis but did not prevent HCC. By contrast, correcting STAT-3 signaling prevented HCC without affecting NASH and fibrosis. TCPTP-deletion in hepatocytes also markedly accelerated HCC in mice treated with a chemical carcinogen that promotes HCC without NASH and fibrosis. Our studies reveal how obesity-associated hepatic oxidative stress can independently contribute to the pathogenesis of NASH, fibrosis, and HCC.
Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/patologia , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Carcinoma Hepatocelular/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Hepatócitos/metabolismo , Humanos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Estresse Oxidativo , Proteína Tirosina Fosfatase não Receptora Tipo 2/deficiência , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Proteína Tirosina Fosfatase não Receptora Tipo 2/metabolismo , Transdução de SinaisRESUMO
Metabolic reprogramming is an important feature of cancers that has been closely linked to post-translational protein modification (PTM). Lysine succinylation is a recently identified PTM involved in regulating protein functions, whereas its regulatory mechanism and possible roles in tumor progression remain unclear. Here, we show that OXCT1, an enzyme catalyzing ketone body oxidation, functions as a lysine succinyltransferase to contribute to tumor progression. Mechanistically, we find that OXCT1 functions as a succinyltransferase, with residue G424 essential for this activity. We also identified serine beta-lactamase-like protein (LACTB) as a main target of OXCT1-mediated succinylation. Extensive succinylation of LACTB K284 inhibits its proteolytic activity, resulting in increased mitochondrial membrane potential and respiration, ultimately leading to hepatocellular carcinoma (HCC) progression. In summary, this study establishes lysine succinyltransferase function of OXCT1 and highlights a link between HCC prognosis and LACTB K284 succinylation, suggesting a potentially valuable biomarker and therapeutic target for further development.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , beta-Lactamases , Humanos , beta-Lactamases/genética , beta-Lactamases/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Lisina/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/metabolismo , Processamento de Proteína Pós-TraducionalRESUMO
Chronic inflammation plays a central role in hepatocellular carcinoma (HCC), but the contribution of hepatocytes to tumor-associated inflammation is not clear. Here, we report that the zinc finger transcription factor Miz1 restricted hepatocyte-driven inflammation to suppress HCC, independently of its transcriptional activity. Miz1 was downregulated in HCC mouse models and a substantial fraction of HCC patients. Hepatocyte-specific Miz1 deletion in mice generated a distinct sub-group of hepatocytes that produced pro-inflammatory cytokines and chemokines, which skewed the polarization of the tumor-infiltrating macrophages toward pro-inflammatory phenotypes to promote HCC. Mechanistically, Miz1 sequestrated the oncoprotein metadherin (MTDH), preventing MTDH from promoting transcription factor nuclear factor κB (NF-κB) activation. A distinct sub-group of pro-inflammatory cytokine-producing hepatocytes was also seen in a subset of HCC patients. In addition, Miz1 expression inversely correated with disease recurrence and poor prognosis in HCC patients. Our findings identify Miz1 as a tumor suppressor that prevents hepatocytes from driving inflammation in HCC.
Assuntos
Carcinogênese/metabolismo , Carcinoma Hepatocelular/metabolismo , Hepatócitos/metabolismo , Inflamação/metabolismo , Neoplasias Hepáticas/metabolismo , Ativação de Macrófagos/fisiologia , Proteínas Inibidoras de STAT Ativados/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Carcinogênese/patologia , Carcinoma Hepatocelular/patologia , Linhagem Celular , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Regulação para Baixo/fisiologia , Feminino , Células HEK293 , Hepatócitos/patologia , Humanos , Inflamação/patologia , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Transdução de Sinais/fisiologia , Fatores de Transcrição/metabolismo , Dedos de Zinco/fisiologiaRESUMO
Type 2 diabetes mellitus is a major risk factor for hepatocellular carcinoma (HCC). Changes in extracellular matrix (ECM) mechanics contribute to cancer development1,2, and increased stiffness is known to promote HCC progression in cirrhotic conditions3,4. Type 2 diabetes mellitus is characterized by an accumulation of advanced glycation end-products (AGEs) in the ECM; however, how this affects HCC in non-cirrhotic conditions is unclear. Here we find that, in patients and animal models, AGEs promote changes in collagen architecture and enhance ECM viscoelasticity, with greater viscous dissipation and faster stress relaxation, but not changes in stiffness. High AGEs and viscoelasticity combined with oncogenic ß-catenin signalling promote HCC induction, whereas inhibiting AGE production, reconstituting the AGE clearance receptor AGER1 or breaking AGE-mediated collagen cross-links reduces viscoelasticity and HCC growth. Matrix analysis and computational modelling demonstrate that lower interconnectivity of AGE-bundled collagen matrix, marked by shorter fibre length and greater heterogeneity, enhances viscoelasticity. Mechanistically, animal studies and 3D cell cultures show that enhanced viscoelasticity promotes HCC cell proliferation and invasion through an integrin-ß1-tensin-1-YAP mechanotransductive pathway. These results reveal that AGE-mediated structural changes enhance ECM viscoelasticity, and that viscoelasticity can promote cancer progression in vivo, independent of stiffness.
Assuntos
Carcinoma Hepatocelular , Progressão da Doença , Elasticidade , Matriz Extracelular , Cirrose Hepática , Neoplasias Hepáticas , Animais , Humanos , beta Catenina/metabolismo , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células , Colágeno/química , Colágeno/metabolismo , Simulação por Computador , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Matriz Extracelular/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Integrina beta1/metabolismo , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Invasividade Neoplásica , Viscosidade , Proteínas de Sinalização YAP/metabolismo , Cirrose Hepática/complicações , Cirrose Hepática/metabolismo , Cirrose Hepática/patologiaRESUMO
The p53 tumor suppressor coordinates a series of antiproliferative responses that restrict the expansion of malignant cells, and as a consequence, p53 is lost or mutated in the majority of human cancers. Here, we show that p53 restricts expression of the stem and progenitor-cell-associated protein nestin in an Sp1/3 transcription-factor-dependent manner and that Nestin is required for tumor initiation in vivo. Moreover, loss of p53 facilitates dedifferentiation of mature hepatocytes into nestin-positive progenitor-like cells, which are poised to differentiate into hepatocellular carcinomas (HCCs) or cholangiocarcinomas (CCs) in response to lineage-specific mutations that target Wnt and Notch signaling, respectively. Many human HCCs and CCs show elevated nestin expression, which correlates with p53 loss of function and is associated with decreased patient survival. Therefore, transcriptional repression of Nestin by p53 restricts cellular plasticity and tumorigenesis in liver cancer.
Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Nestina/metabolismo , Animais , Carcinoma Hepatocelular/patologia , Transformação Celular Neoplásica , Hepatócitos/metabolismo , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Prognóstico , Fator de Transcrição Sp1/metabolismo , Fator de Transcrição Sp3/metabolismo , Transcrição Gênica , Proteína Supressora de Tumor p53/metabolismoRESUMO
Hepatocellular carcinoma (HCC) is a slowly developing malignancy postulated to evolve from premalignant lesions in chronically damaged livers. However, it was never established that premalignant lesions actually contain tumor progenitors that give rise to cancer. Here, we describe isolation and characterization of HCC progenitor cells (HcPCs) from different mouse HCC models. Unlike fully malignant HCC, HcPCs give rise to cancer only when introduced into a liver undergoing chronic damage and compensatory proliferation. Although HcPCs exhibit a similar transcriptomic profile to bipotential hepatobiliary progenitors, the latter do not give rise to tumors. Cells resembling HcPCs reside within dysplastic lesions that appear several months before HCC nodules. Unlike early hepatocarcinogenesis, which depends on paracrine IL-6 production by inflammatory cells, due to upregulation of LIN28 expression, HcPCs had acquired autocrine IL-6 signaling that stimulates their in vivo growth and malignant progression. This may be a general mechanism that drives other IL-6-producing malignancies.
Assuntos
Comunicação Autócrina , Regulação Neoplásica da Expressão Gênica , Interleucina-6/metabolismo , Neoplasias Hepáticas/patologia , Células-Tronco Neoplásicas/metabolismo , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Progressão da Doença , Hepacivirus , Hepatite C/genética , Hepatite C/metabolismo , Hepatite C/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Tumor-derived extracellular vesicles are important mediators of cell-to-cell communication during tumorigenesis. Here, we demonstrated that hepatocellular carcinoma (HCC)-derived ectosomes remodel the tumor microenvironment to facilitate HCC progression in an ectosomal PKM2-dependent manner. HCC-derived ectosomal PKM2 induced not only metabolic reprogramming in monocytes but also STAT3 phosphorylation in the nucleus to upregulate differentiation-associated transcription factors, leading to monocyte-to-macrophage differentiation and tumor microenvironment remodeling. In HCC cells, sumoylation of PKM2 induced its plasma membrane targeting and subsequent ectosomal excretion via interactions with ARRDC1. The PKM2-ARRDC1 association in HCC was reinforced by macrophage-secreted cytokines/chemokines in a CCL1-CCR8 axis-dependent manner, further facilitating PKM2 excretion from HCC cells to form a feedforward regulatory loop for tumorigenesis. In the clinic, ectosomal PKM2 was clearly detected in the plasma of HCC patients. This study highlights a mechanism by which ectosomal PKM2 remodels the tumor microenvironment and reveals ectosomal PKM2 as a potential diagnostic marker for HCC.
Assuntos
Proteínas de Transporte/metabolismo , Micropartículas Derivadas de Células/metabolismo , Proteínas de Membrana/metabolismo , Hormônios Tireóideos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proteínas de Transporte/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Micropartículas Derivadas de Células/genética , Micropartículas Derivadas de Células/patologia , Quimiocina CCL1/metabolismo , Progressão da Doença , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Macrófagos/metabolismo , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Monócitos/metabolismo , Prognóstico , Fator de Transcrição STAT3/metabolismo , Hormônios Tireóideos/genética , Microambiente Tumoral , Proteínas de Ligação a Hormônio da TireoideRESUMO
Hepatocellular carcinoma (HCC) formation is a multi-step pathological process that involves evolution of a heterogeneous immunosuppressive tumor microenvironment. However, the specific cell populations involved and their origins and contribution to HCC development remain largely unknown. Here, comprehensive single-cell transcriptome sequencing was applied to profile rat models of toxin-induced liver tumorigenesis and HCC patients. Specifically, we identified three populations of hepatic parenchymal cells emerging during HCC progression, termed metabolic hepatocytes (HCMeta ), Epcam+ population with differentiation potential (EP+Diff ) and immunosuppressive malignant transformation subset (MTImmu ). These distinct subpopulations form an oncogenic trajectory depicting a dynamic landscape of hepatocarcinogenesis, with signature genes reflecting the transition from EP+Diff to MTImmu . Importantly, GPNMB+ Gal-3+ MTImmu cells exhibit both malignant and immunosuppressive properties. Moreover, SOX18 is required for the generation and malignant transformation of GPNMB+ Gal-3+ MTImmu cells. Enrichment of the GPNMB+ Gal-3+ MTImmu subset was found to be associated with poor prognosis and a higher rate of recurrence in patients. Collectively, we unraveled the single-cell HCC progression atlas and uncovered GPNMB+ Gal-3+ parenchymal cells as a major subset contributing to the immunosuppressive microenvironment thus malignance in HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animais , Ratos , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Hepatócitos , Carcinogênese/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Terapia de Imunossupressão , Microambiente Tumoral , Fatores de Transcrição SOXF , Glicoproteínas de Membrana/genéticaRESUMO
Ectopic lymphoid-like structures (ELSs) are often observed in cancer, yet their function is obscure. Although ELSs signify good prognosis in certain malignancies, we found that hepatic ELSs indicated poor prognosis for hepatocellular carcinoma (HCC). We studied an HCC mouse model that displayed abundant ELSs and found that they constituted immunopathological microniches wherein malignant hepatocyte progenitor cells appeared and thrived in a complex cellular and cytokine milieu until gaining self-sufficiency. The egress of progenitor cells and tumor formation were associated with the autocrine production of cytokines previously provided by the niche. ELSs developed via cooperation between the innate immune system and adaptive immune system, an event facilitated by activation of the transcription factor NF-κB and abolished by depletion of T cells. Such aberrant immunological foci might represent new targets for cancer therapy.
Assuntos
Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/imunologia , Tecido Linfoide/imunologia , Células-Tronco Neoplásicas/imunologia , Nicho de Células-Tronco/imunologia , Imunidade Adaptativa/genética , Imunidade Adaptativa/imunologia , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Hibridização Genômica Comparativa , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Hepatócitos/imunologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Quinase I-kappa B/genética , Quinase I-kappa B/imunologia , Quinase I-kappa B/metabolismo , Imunidade Inata/genética , Imunidade Inata/imunologia , Immunoblotting , Hibridização In Situ , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Tecido Linfoide/metabolismo , Tecido Linfoide/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , NF-kappa B/genética , NF-kappa B/imunologia , NF-kappa B/metabolismo , Células-Tronco Neoplásicas/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Nicho de Células-Tronco/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transcriptoma/genética , Transcriptoma/imunologiaRESUMO
Hepatocellular carcinoma (HCC) is sexually dimorphic in both rodents and humans, with significantly higher incidence in males, an effect that is dependent on sex hormones. The molecular mechanisms by which estrogens prevent and androgens promote liver cancer remain unclear. Here, we discover that sexually dimorphic HCC is completely reversed in Foxa1- and Foxa2-deficient mice after diethylnitrosamine-induced hepatocarcinogenesis. Coregulation of target genes by Foxa1/a2 and either the estrogen receptor (ERα) or the androgen receptor (AR) was increased during hepatocarcinogenesis in normal female or male mice, respectively, but was lost in Foxa1/2-deficient mice. Thus, both estrogen-dependent resistance to and androgen-mediated facilitation of HCC depend on Foxa1/2. Strikingly, single nucleotide polymorphisms at FOXA2 binding sites reduce binding of both FOXA2 and ERα to their targets in human liver and correlate with HCC development in women. Thus, Foxa factors and their targets are central for the sexual dimorphism of HCC.
Assuntos
Carcinoma Hepatocelular/metabolismo , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Fator 3-beta Nuclear de Hepatócito/metabolismo , Neoplasias Hepáticas/metabolismo , Androgênios/metabolismo , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/patologia , Estrogênios/metabolismo , Feminino , Humanos , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/patologia , Masculino , Receptores Androgênicos/metabolismo , Receptores de Estrogênio/metabolismo , Fatores Sexuais , Transdução de SinaisRESUMO
Hepatocellular carcinoma (HCC)-the most common form of liver cancer-is an aggressive malignancy with few effective treatment options1. Lenvatinib is a small-molecule inhibitor of multiple receptor tyrosine kinases that is used for the treatment of patients with advanced HCC, but this drug has only limited clinical benefit2. Here, using a kinome-centred CRISPR-Cas9 genetic screen, we show that inhibition of epidermal growth factor receptor (EGFR) is synthetic lethal with lenvatinib in liver cancer. The combination of the EGFR inhibitor gefitinib and lenvatinib displays potent anti-proliferative effects in vitro in liver cancer cell lines that express EGFR and in vivo in xenografted liver cancer cell lines, immunocompetent mouse models and patient-derived HCC tumours in mice. Mechanistically, inhibition of fibroblast growth factor receptor (FGFR) by lenvatinib treatment leads to feedback activation of the EGFR-PAK2-ERK5 signalling axis, which is blocked by EGFR inhibition. Treatment of 12 patients with advanced HCC who were unresponsive to lenvatinib treatment with the combination of lenvatinib plus gefitinib (trial identifier NCT04642547) resulted in meaningful clinical responses. The combination therapy identified here may represent a promising strategy for the approximately 50% of patients with advanced HCC who have high levels of EGFR.
Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Compostos de Fenilureia/farmacologia , Quinolinas/farmacologia , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Feminino , Gefitinibe/farmacologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Receptores de Fatores de Crescimento de Fibroblastos , Transdução de Sinais , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. HCC incidence is on the rise, while treatment options remain limited. Thus, a better understanding of the molecular pathways involved in HCC development has become a priority to guide future therapies. While previous studies implicated the Activator Protein-1 (AP-1) (Fos/Jun) transcription factor family members c-Fos and c-Jun in HCC formation, the contribution of Fos-related antigens (Fra-) 1 and 2 is unknown. Here, we show that hepatocyte-restricted expression of a single chain c-Jun~Fra-2 protein, which functionally mimics the c-Jun/Fra-2 AP-1 dimer, results in spontaneous HCC formation in c-Jun~Fra-2hep mice. Several hallmarks of human HCC, such as cell cycle dysregulation and the expression of HCC markers are observed in liver tumors arising in c-Jun~Fra-2hep mice. Tumorigenesis occurs in the context of mild inflammation, low-grade fibrosis, and Pparγ-driven dyslipidemia. Subsequent analyses revealed increased expression of c-Myc, evidently under direct regulation by AP-1 through a conserved distal 3' enhancer. Importantly, c-Jun~Fra-2-induced tumors revert upon switching off transgene expression, suggesting oncogene addiction to the c-Jun~Fra-2 transgene. Tumors escaping reversion maintained c-Myc and c-Myc target gene expression, likely due to increased c-Fos. Interfering with c-Myc in established tumors using the Bromodomain and Extra-Terminal motif inhibitor JQ-1 diminished liver tumor growth in c-Jun~Fra-2 mutant mice. Thus, our data establish c-Jun~Fra-2hep mice as a model to study liver tumorigenesis and identify the c-Jun/Fra-2-Myc interaction as a potential target to improve HCC patient stratification and/or therapy.
Assuntos
Carcinoma Hepatocelular , Antígeno 2 Relacionado a Fos , Neoplasias Hepáticas , Proteínas Proto-Oncogênicas c-fos , Proteínas Proto-Oncogênicas c-jun , Proteínas Proto-Oncogênicas c-myc , Fator de Transcrição AP-1 , Animais , Fator de Transcrição AP-1/metabolismo , Fator de Transcrição AP-1/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Camundongos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Proteínas Proto-Oncogênicas c-jun/metabolismo , Antígeno 2 Relacionado a Fos/metabolismo , Antígeno 2 Relacionado a Fos/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Humanos , Hepatócitos/metabolismo , Multimerização Proteica , Regulação Neoplásica da Expressão Gênica , Camundongos TransgênicosRESUMO
Carnitine metabolism is thought to be negatively correlated with the progression of hepatocellular carcinoma (HCC) and the specific molecular mechanism is yet to be fully elucidated. Here, we report that little characterized cysteine-rich protein 1 (CRIP1) is upregulated in HCC and associated with poor prognosis. Moreover, CRIP1 promoted HCC cancer stem-like properties by downregulating carnitine energy metabolism. Mechanistically, CRIP1 interacted with BBOX1 and the E3 ligase STUB1, promoting BBOX1 ubiquitination and proteasomal degradation, and leading to the downregulation of carnitine. BBOX1 ubiquitination at lysine 240 is required for CRIP1-mediated control of carnitine metabolism and cancer stem-like properties. Further, our data showed that acetylcarnitine downregulation in CRIP1-overexpressing cells decreased beta-catenin acetylation and promoted nuclear accumulation of beta-catenin, thus facilitating cancer stem-like properties. Clinically, patients with higher CRIP1 protein levels had lower BBOX1 levels but higher nuclear beta-catenin levels in HCC tissues. Together, our findings identify CRIP1 as novel upstream control factor for carnitine metabolism and cancer stem-like properties, suggesting targeting of the CRIP1/BBOX1/ß-catenin axis as a promising strategy for HCC treatment.
Assuntos
Carcinoma Hepatocelular , Proteínas de Transporte/metabolismo , Proteínas com Domínio LIM/metabolismo , Neoplasias Hepáticas , gama-Butirobetaína Dioxigenase/metabolismo , Carcinoma Hepatocelular/metabolismo , Carnitina , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMO
The mechanisms underlying cancer metastasis remain poorly understood. Here, we report that TFAM deficiency rapidly and stably induced spontaneous lung metastasis in mice with liver cancer. Interestingly, unexpected polymerization of nuclear actin was observed in TFAM-knockdown HCC cells when cytoskeleton was examined. Polymerization of nuclear actin is causally linked to the high-metastatic ability of HCC cells by modulating chromatin accessibility and coordinating the expression of genes associated with extracellular matrix remodeling, angiogenesis, and cell migration. Mechanistically, TFAM deficiency blocked the TCA cycle and increased the intracellular malonyl-CoA levels. Malonylation of mDia2, which drives actin assembly, promotes its nuclear translocation. Importantly, inhibition of malonyl-CoA production or nuclear actin polymerization significantly impeded the spread of HCC cells in mice. Moreover, TFAM was significantly downregulated in metastatic HCC tissues and was associated with overall survival and time to tumor recurrence of HCC patients. Taken together, our study connects mitochondria to the metastasis of human cancer via uncovered mitochondria-to-nucleus retrograde signaling, indicating that TFAM may serve as an effective target to block HCC metastasis.
Assuntos
Carcinoma Hepatocelular , Proteínas de Ligação a DNA , Neoplasias Hepáticas , Proteínas Mitocondriais , Fatores de Transcrição , Actinas/metabolismo , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Coenzima A/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Grupo de Alta Mobilidade , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Metástase Neoplásica , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Hepatocyte nuclear factor 4α (HNF4α) is essential for liver development and hepatocyte function. Here, we show that transient inhibition of HNF4α initiates hepatocellular transformation through a microRNA-inflammatory feedback loop circuit consisting of miR-124, IL6R, STAT3, miR-24, and miR-629. Moreover, we show that, once this circuit is activated, it maintains suppression of HNF4α and sustains oncogenesis. Systemic administration of miR-124, which modulates inflammatory signaling, prevents and suppresses hepatocellular carcinogenesis by inducing tumor-specific apoptosis without toxic side effects. As we also show that this HNF4α circuit is perturbed in human hepatocellular carcinomas, our data raise the possibility that manipulation of this microRNA feedback-inflammatory loop has therapeutic potential for treating liver cancer.