RESUMEN
The early mechanisms of spontaneous tumor initiation that precede malignancy are largely unknown. We show that reduced aPKC levels correlate with stem cell loss and the induction of revival and metaplastic programs in serrated- and conventional-initiated premalignant lesions, which is perpetuated in colorectal cancers (CRCs). Acute inactivation of PKCλ/ι in vivo and in mouse organoids is sufficient to stimulate JNK in non-transformed intestinal epithelial cells (IECs), which promotes cell death and the rapid loss of the intestinal stem cells (ISCs), including those that are LGR5+. This is followed by the accumulation of revival stem cells (RSCs) at the bottom of the crypt and fetal-metaplastic cells (FMCs) at the top, creating two spatiotemporally distinct cell populations that depend on JNK-induced AP-1 and YAP. These cell lineage changes are maintained during cancer initiation and progression and determine the aggressive phenotype of human CRC, irrespective of their serrated or conventional origin.
Asunto(s)
Neoplasias Colorrectales , Células Epiteliales , Metaplasia , Proteína Quinasa C , Animales , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/genética , Proteína Quinasa C/metabolismo , Proteína Quinasa C/genética , Metaplasia/patología , Metaplasia/metabolismo , Ratones , Humanos , Células Epiteliales/metabolismo , Células Epiteliales/patología , Células Madre/metabolismo , Células Madre/patología , Factor de Transcripción AP-1/metabolismo , Factor de Transcripción AP-1/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Proteínas Señalizadoras YAP/metabolismo , Transformación Celular Neoplásica/patología , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Organoides/metabolismo , Organoides/patología , Linaje de la Célula , Isoenzimas/metabolismo , Isoenzimas/genética , Isoenzimas/deficiencia , Células Madre Neoplásicas/patología , Células Madre Neoplásicas/metabolismoRESUMEN
The metabolic and signaling pathways regulating aggressive mesenchymal colorectal cancer (CRC) initiation and progression through the serrated route are largely unknown. Although relatively well characterized as BRAF mutant cancers, their poor response to current targeted therapy, difficult preneoplastic detection, and challenging endoscopic resection make the identification of their metabolic requirements a priority. Here, we demonstrate that the phosphorylation of SCAP by the atypical PKC (aPKC), PKCλ/ι promotes its degradation and inhibits the processing and activation of SREBP2, the master regulator of cholesterol biosynthesis. We show that the upregulation of SREBP2 and cholesterol by reduced aPKC levels is essential for controlling metaplasia and generating the most aggressive cell subpopulation in serrated tumors in mice and humans. Since these alterations are also detected prior to neoplastic transformation, together with the sensitivity of these tumors to cholesterol metabolism inhibitors, our data indicate that targeting cholesterol biosynthesis is a potential mechanism for serrated chemoprevention.
Asunto(s)
Proteína Quinasa C , Transducción de Señal , Animales , Humanos , Ratones , Transformación Celular Neoplásica/genética , Colesterol , Células Epiteliales/metabolismo , Proteína Quinasa C/genética , Proteína Quinasa C/metabolismoRESUMEN
Mesenchymal activation, characterized by dense stromal infiltration of immune and mesenchymal cells, fuels the aggressiveness of colorectal cancers (CRC), driving progression and metastasis. Targetable molecules in the tumor microenvironment (TME) need to be identified to improve the outcome in CRC patients with this aggressive phenotype. This study reports a positive link between high thrombospondin-1 (THBS1) expression and mesenchymal characteristics, immunosuppression, and unfavorable CRC prognosis. Bone marrow-derived monocyte-like cells recruited by CXCL12 are the primary source of THBS1, which contributes to the development of metastasis by inducing cytotoxic T-cell exhaustion and impairing vascularization. Furthermore, in orthotopically generated CRC models in male mice, THBS1 loss in the TME renders tumors partially sensitive to immune checkpoint inhibitors and anti-cancer drugs. Our study establishes THBS1 as a potential biomarker for identifying mesenchymal CRC and as a critical suppressor of antitumor immunity that contributes to the progression of this malignancy with a poor prognosis.
Asunto(s)
Neoplasias Colorrectales , Monocitos , Humanos , Masculino , Animales , Ratones , Terapia de Inmunosupresión , Agresión , Inhibidores de Puntos de Control Inmunológico , Microambiente TumoralRESUMEN
Imaging organoid culture provides an excellent tool for studying complex diseases such as cancer. However, retaining the morphology of intact organoids for immunolabeling has been challenging. Here, we describe a protocol for immunofluorescence staining in intact colorectal cancer organoids derived from mice. We also describe additional steps for co-culture with mouse fibroblasts to enable the study of interactions with other cellular components of the tissue microenvironment. For complete details on the use and execution of this protocol, please refer to Martinez-Ordoñez et al. (2023).1.
RESUMEN
Mesenchymal colorectal cancer (mCRC) is microsatellite stable (MSS), highly desmoplastic, with CD8+ T cells excluded to the stromal periphery, resistant to immunotherapy, and driven by low levels of the atypical protein kinase Cs (aPKCs) in the intestinal epithelium. We show here that a salient feature of these tumors is the accumulation of hyaluronan (HA) which, along with reduced aPKC levels, predicts poor survival. HA promotes epithelial heterogeneity and the emergence of a tumor fetal metaplastic cell (TFMC) population endowed with invasive cancer features through a network of interactions with activated fibroblasts. TFMCs are sensitive to HA deposition, and their metaplastic markers have prognostic value. We demonstrate that in vivo HA degradation with a clinical dose of hyaluronidase impairs mCRC tumorigenesis and liver metastasis and enables immune checkpoint blockade therapy by promoting the recruitment of B and CD8+ T cells, including a proportion with resident memory features, and by blocking immunosuppression.
Asunto(s)
Neoplasias Colorrectales , Ácido Hialurónico , Microambiente Tumoral , Humanos , Linfocitos T CD8-positivos/patología , Neoplasias Colorrectales/patología , Ácido Hialurónico/metabolismo , Inmunoterapia , Sarcoma/patología , Microambiente Tumoral/fisiologíaRESUMEN
Air-liquid organotypic culture models enable the study of the cellular crosstalk in the tumor microenvironment. This 3D assay recapitulates the tumor niche more faithfully than 2D culture systems and represents a versatile platform that can be easily adapted to different types of cancer cells, stromal components, or ECM composition. Here, we detail the steps to build an organotypic culture including the preparation of the organotypic structure, organotypic gels, cell seeding, gel casting, membrane processing, and image and data analysis. For complete details on the use and execution of this protocol, please refer to Linares et al. (2022).
Asunto(s)
Neoplasias , Microambiente Tumoral , Línea Celular TumoralRESUMEN
Nononcogenic cancer drivers often impinge on complex signals that create new addictions and vulnerabilities. Protein kinase Cλ/ι (PKCλ/ι) suppresses tumorigenesis by blocking metabolic pathways that regulate fuel oxidation and create building blocks for the epigenetic control of cell differentiation. Reduced levels of PKCλ/ι unleash these pathways to promote tumorigenesis, but the simultaneous activation of the STING-driven interferon cascade prevents tumor initiation by triggering immunosurveillance mechanisms. However, depending on the context of other signaling pathways, such as WNT/ß-catenin or PKCζ, and timing, PKCλ/ι deletion can promote or inhibit tumorigenesis. In this review, we discuss in detail the molecular and cellular underpinnings of PKCλ/ι functions in cancer with the perspective of the crosstalk between metabolism and inflammation in the tumor microenvironment.
Asunto(s)
Isoenzimas , Neoplasias , Humanos , Isoenzimas/metabolismo , Proteína Quinasa C/genética , Proteína Quinasa C/metabolismo , Transducción de Señal/fisiología , Neoplasias/genética , Transformación Celular Neoplásica/patología , Microambiente TumoralRESUMEN
Reduced p62 levels are associated with the induction of the cancer-associated fibroblast (CAF) phenotype, which promotes tumorigenesis in vitro and in vivo through inflammation and metabolic reprogramming. However, how p62 is downregulated in the stroma fibroblasts by tumor cells to drive CAF activation is an unresolved central issue in the field. Here we show that tumor-secreted lactate downregulates p62 transcriptionally through a mechanism involving reduction of the NAD+/NADH ratio, which impairs poly(ADP-ribose)-polymerase 1 (PARP-1) activity. PARP-1 inhibition blocks the poly(ADP-ribosyl)ation of the AP-1 transcription factors, c-FOS and c-JUN, which is an obligate step for p62 downregulation. Importantly, restoring p62 levels in CAFs by NAD+ renders CAFs less active. PARP inhibitors, such as olaparib, mimick lactate in the reduction of stromal p62 levels, as well as the subsequent stromal activation both in vitro and in vivo, which suggests that therapies using olaparib would benefit from strategies aimed at inhibiting CAF activity.
Asunto(s)
Fibroblastos Asociados al Cáncer , Neoplasias , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos/metabolismo , Ácido Láctico/metabolismo , NAD/metabolismo , Neoplasias/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Poli(ADP-Ribosa) Polimerasas/metabolismoRESUMEN
Dysregulation of autophagic pathways leads to accumulation of abnormal proteins and damaged organelles in many neurodegenerative disorders, including Parkinson's disease (PD) and Lewy body dementia (LBD). Autophagy-related dysfunction may also trigger secretion and spread of misfolded proteins, such as α-synuclein (α-syn), the major misfolded protein found in PD/LBD. However, the mechanism underlying these phenomena remains largely unknown. Here, we used cell-based models, including human induced pluripotent stem cell-derived neurons, CRISPR/Cas9 technology, and male transgenic PD/LBD mice, plus vetting in human postmortem brains (both male and female). We provide mechanistic insight into this pathologic pathway. We find that aberrant S-nitrosylation of the autophagic adaptor protein p62 causes inhibition of autophagic flux and intracellular buildup of misfolded proteins, with consequent secretion resulting in cell-to-cell spread. Thus, our data show that pathologic protein S-nitrosylation of p62 represents a critical factor not only for autophagic inhibition and demise of individual neurons, but also for α-syn release and spread of disease throughout the nervous system.SIGNIFICANCE STATEMENT In Parkinson's disease and Lewy body dementia, dysfunctional autophagy contributes to accumulation and spread of aggregated α-synuclein. Here, we provide evidence that protein S-nitrosylation of p62 inhibits autophagic flux, contributing to α-synuclein aggregation and spread.
Asunto(s)
Células Madre Pluripotentes Inducidas , Enfermedad por Cuerpos de Lewy , Enfermedad de Parkinson , Proteínas de Unión al ARN , alfa-Sinucleína , Animales , Autofagia , Femenino , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Enfermedad por Cuerpos de Lewy/metabolismo , Enfermedad por Cuerpos de Lewy/patología , Masculino , Ratones , Ratones Transgénicos , Neuronas/metabolismo , Neuronas/patología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Proteína S/metabolismo , Proteínas de Unión al ARN/metabolismo , alfa-Sinucleína/metabolismoRESUMEN
The mechanisms controlling immunosurveillance and immunoevasion often operate simultaneously to the triggering of the oncogenic signaling that results in tumor initiation. The resolution of the balance between anti-cancer immune responses and pro-tumorigenic pathways determines if a tumor cell survives and can remodel the microenvironment to reinforce immunosuppression or is eliminated by the immune system. Cancer cells must endure a toxic and metabolically challenging milieu. In its various forms, autophagy provides a way for transformed cells to survive by promoting catabolism and detoxification. Mounting evidence suggests that the boundaries between cancer immunity and mitogenic and metabolic programs are diffuse, with the same molecules likely serving several diverse roles in immunity and metabolism during tumor initiation and progression. Our recent data provide mechanistic detail and functional relevance of a new paradigm whereby the same signaling elements control immunity and autophagy in cancer.
Asunto(s)
Interferones , Neoplasias , Autofagia/fisiología , Carcinogénesis , Transformación Celular Neoplásica , Humanos , Isoenzimas/metabolismo , Monitorización Inmunológica , Neoplasias/metabolismo , Proteína Quinasa C/metabolismo , Proteínas Serina-Treonina Quinasas , Transducción de Señal , Microambiente TumoralRESUMEN
The interferon (IFN) pathway is critical for cytotoxic T cell activation, which is central to tumor immunosurveillance and successful immunotherapy. We demonstrate here that PKCλ/ι inactivation results in the hyper-stimulation of the IFN cascade and the enhanced recruitment of CD8+ T cells that impaired the growth of intestinal tumors. PKCλ/ι directly phosphorylates and represses the activity of ULK2, promoting its degradation through an endosomal microautophagy-driven ubiquitin-dependent mechanism. Loss of PKCλ/ι results in increased levels of enzymatically active ULK2, which, by direct phosphorylation, activates TBK1 to foster the activation of the STING-mediated IFN response. PKCλ/ι inactivation also triggers autophagy, which prevents STING degradation by chaperone-mediated autophagy. Thus, PKCλ/ι is a hub regulating the IFN pathway and three autophagic mechanisms that serve to maintain its homeostatic control. Importantly, single-cell multiplex imaging and bioinformatics analysis demonstrated that low PKCλ/ι levels correlate with enhanced IFN signaling and good prognosis in colorectal cancer patients.
Asunto(s)
Neoplasias Colorrectales/metabolismo , Interferones/metabolismo , Isoenzimas/metabolismo , Proteína Quinasa C/metabolismo , Proteínas Serina-Treonina Quinasas/fisiología , Transducción de Señal , Adulto , Anciano , Anciano de 80 o más Años , Animales , Autofagia , Linfocitos T CD8-positivos/metabolismo , Carcinogénesis , Transformación Celular Neoplásica , Neoplasias Colorrectales/mortalidad , Cicloheximida/química , Femenino , Células HEK293 , Humanos , Inmunofenotipificación , Factor 3 Regulador del Interferón/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Persona de Mediana Edad , Trasplante de Neoplasias , Fosforilación , Pronóstico , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Factores de Transcripción , Regulación hacia ArribaRESUMEN
Activation of non-shivering thermogenesis is considered a promising approach to lower body weight in obesity. p62 deficiency in adipocytes reduces systemic energy expenditure but its role in sustaining mitochondrial function and thermogenesis remains unresolved. NBR1 shares a remarkable structural similarity with p62 and can interact with p62 through their respective PB1 domains. However, the physiological relevance of NBR1 in metabolism, as compared to that of p62, was not clear. Here we show that whole-body and adipocyte-specific ablation of NBR1 reverts the obesity phenotype induced by p62 deficiency by restoring global energy expenditure and thermogenesis in brown adipose tissue. Impaired adrenergic-induced browning of p62-deficient adipocytes is rescued by NBR1 inactivation, unveiling a negative role of NBR1 in thermogenesis under conditions of p62 loss. We demonstrate that upon p62 inactivation, NBR1 represses the activity of PPARγ, establishing an unexplored p62/NBR1-mediated paradigm in adipocyte thermogenesis that is critical for the control of obesity.
Asunto(s)
Adipocitos/metabolismo , Péptidos y Proteínas de Señalización Intracelular/deficiencia , PPAR gamma/metabolismo , Proteína Sequestosoma-1/deficiencia , Termogénesis , Tejido Adiposo Pardo/citología , Tejido Adiposo Pardo/metabolismo , Animales , Animales Recién Nacidos , Núcleo Celular/metabolismo , Células Cultivadas , Metabolismo Energético/genética , Células HEK293 , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , PPAR gamma/genética , Unión Proteica , Receptor alfa X Retinoide/genética , Receptor alfa X Retinoide/metabolismo , Proteína Sequestosoma-1/genéticaRESUMEN
Many cancers, including pancreatic ductal adenocarcinoma (PDAC), depend on autophagy-mediated scavenging and recycling of intracellular macromolecules, suggesting that autophagy blockade should cause tumor starvation and regression. However, until now autophagy-inhibiting monotherapies have not demonstrated potent anti-cancer activity. We now show that autophagy blockade prompts established PDAC to upregulate and utilize an alternative nutrient procurement pathway: macropinocytosis (MP) that allows tumor cells to extract nutrients from extracellular sources and use them for energy generation. The autophagy to MP switch, which may be evolutionarily conserved and not cancer cell restricted, depends on activation of transcription factor NRF2 by the autophagy adaptor p62/SQSTM1. NRF2 activation by oncogenic mutations, hypoxia, and oxidative stress also results in MP upregulation. Inhibition of MP in autophagy-compromised PDAC elicits dramatic metabolic decline and regression of transplanted and autochthonous tumors, suggesting the therapeutic promise of combining autophagy and MP inhibitors in the clinic.
Asunto(s)
Autofagia/fisiología , Carcinoma Ductal Pancreático/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Neoplasias Pancreáticas/metabolismo , Animales , Autofagia/genética , Carcinoma Ductal Pancreático/inmunología , Ratones , Factor 2 Relacionado con NF-E2/farmacología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Neoplasias Pancreáticas/inmunología , Pinocitosis/inmunología , Pinocitosis/fisiología , Proteína Sequestosoma-1/metabolismo , Transducción de Señal/inmunología , Transducción de Señal/fisiología , Neoplasias PancreáticasRESUMEN
In vivo interrogation of the functional role of genes implicated in colorectal cancer (CRC) is limited by the need for physiological models that mimic the disease. Here, we describe a protocol that provides the steps required for the orthotopic co-implantation of tumoral and stromal cells into the cecum and rectum to investigate the crosstalk between the tumor and its microenvironment. This protocol recapitulates metastases to the lymph nodes, liver, and lungs observed in human CRC. For complete details on the use and execution of this protocol, please refer to Kasashima et al. (2020).
Asunto(s)
Ciego/metabolismo , Neoplasias Colorrectales/metabolismo , Neoplasias Experimentales/metabolismo , Recto/metabolismo , Microambiente Tumoral , Animales , Ciego/patología , Línea Celular Tumoral , Neoplasias Colorrectales/patología , Humanos , Ratones , Neoplasias Experimentales/patología , Recto/patología , Células del Estroma/metabolismo , Células del Estroma/patologíaRESUMEN
Cancer-associated fibroblasts (CAFs) promote tumor malignancy, but the precise transcriptional mechanisms regulating the acquisition of the CAF phenotype are not well understood. We show that the upregulation of SOX2 is central to this process, which is repressed by protein kinase Cζ (PKCζ). PKCζ deficiency activates the reprogramming of colonic fibroblasts to generate a predominant SOX2-dependent CAF population expressing the WNT regulator Sfrp2 as its top biomarker. SOX2 directly binds the Sfrp1/2 promoters, and the inactivation of Sox2 or Sfrp1/2 in CAFs impaired the induction of migration and invasion of colon cancer cells, as well as their tumorigenicity in vivo. Importantly, recurrence-free and overall survival of colorectal cancer (CRC) patients negatively correlates with stromal PKCζ levels. Also, SOX2 expression in the stroma is associated with CRC T invasion and worse prognosis of recurrence-free survival. Therefore, the PKCζ-SOX2 axis emerges as a critical step in the control of CAF pro-tumorigenic potential.
Asunto(s)
Fibroblastos Asociados al Cáncer/metabolismo , Carcinogénesis/metabolismo , Neoplasias Colorrectales/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas de la Membrana/metabolismo , Proteína Quinasa C/deficiencia , Factores de Transcripción SOXB1/metabolismo , Animales , Fibroblastos Asociados al Cáncer/patología , Carcinogénesis/genética , Línea Celular Tumoral , Movimiento Celular/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Femenino , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Invasividad Neoplásica/genética , Organoides/metabolismo , Organoides/patología , Unión Proteica , Proteína Quinasa C/genética , Proteína Quinasa C/metabolismo , RNA-Seq , Recurrencia , Factores de Transcripción SOXB1/genética , Transducción de Señal/genética , Transducción de Señal/inmunología , Análisis de la Célula Individual , Regulación hacia Arriba , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
This protocol provides the steps required for a mouse liver orthotopic implantation model. The reliable pre-clinical animal models that have similar characteristics to hepatocellular carcinoma (HCC) are a powerful tool to unveil the mechanisms controlling tumor initiation and progression. Here, we describe a syngeneic orthotopic HCC model that recapitulates the role of a host pro-tumorigenic microenvironment by pre-conditioning mouse livers with a high-fat diet (HFD). For complete details on the use and execution of this protocol, please refer to Kudo et al. (2020).
Asunto(s)
Carcinoma Hepatocelular/patología , Hígado Graso/complicaciones , Neoplasias Hepáticas/patología , Animales , Modelos Animales de Enfermedad , Hígado/patología , Ratones Endogámicos C57BL , SuturasRESUMEN
Benign hepatosteatosis, affected by lipid uptake, de novo lipogenesis and fatty acid (FA) oxidation, progresses to non-alcoholic steatohepatitis (NASH) on stress and inflammation. A key macronutrient proposed to increase hepatosteatosis and NASH risk is fructose. Excessive intake of fructose causes intestinal-barrier deterioration and endotoxaemia. However, how fructose triggers these alterations and their roles in hepatosteatosis and NASH pathogenesis remain unknown. Here we show, using mice, that microbiota-derived Toll-like receptor (TLR) agonists promote hepatosteatosis without affecting fructose-1-phosphate (F1P) and cytosolic acetyl-CoA. Activation of mucosal-regenerative gp130 signalling, administration of the YAP-induced matricellular protein CCN1 or expression of the antimicrobial peptide Reg3b (beta) peptide counteract fructose-induced barrier deterioration, which depends on endoplasmic-reticulum stress and subsequent endotoxaemia. Endotoxin engages TLR4 to trigger TNF production by liver macrophages, thereby inducing lipogenic enzymes that convert F1P and acetyl-CoA to FA in both mouse and human hepatocytes.
Asunto(s)
Fructosa/farmacología , Inflamación/metabolismo , Lipogénesis/efectos de los fármacos , Acetilcoenzima A/farmacología , Animales , Endotoxemia/sangre , Femenino , Fructosafosfatos/farmacología , Microbioma Gastrointestinal , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Intestinos/efectos de los fármacos , Lipidómica , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Regeneración/efectos de los fármacos , Receptores Toll-Like/agonistasRESUMEN
Hepatocellular carcinoma (HCC) is the consequence of chronic liver damage caused by the excessive generation of reactive oxygen species (ROS). To mitigate the deleterious effects of ROS, cells activate the transcription factor NFE2L2/NRF2, which is constitutively degraded through its partner KEAP1. The inactivation of KEAP1 by ROS results in the upregulation of NFE2L2, which leads to the upregulation of critical detoxifying molecules that serve to keep ROS at tolerable levels in order to maintain cell viability. It is thought that this mechanism allows cells to accumulate mutations, which together with the additional pro-tumorigenic and pro-survival effects of NFE2L2 activation, promote cancer initiation and progression. Germane to this phenomenon is macroautophagy/autophagy, which under homeostatic conditions has also been proposed to serve as a detoxifying mechanism by clearing up toxic aggregates and damaged organelles. Our recent data establish a new paradigm for the role that autophagy plays in HCC development.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Autofagia , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Fosforilación Oxidativa , Estrés Oxidativo , Proteína Sequestosoma-1/metabolismoRESUMEN
Oxidative stress plays a critical role in liver tissue damage and in hepatocellular carcinoma (HCC) initiation and progression. However, the mechanisms that regulate autophagy and metabolic reprogramming during reactive oxygen species (ROS) generation, and how ROS promote tumorigenesis, still need to be fully understood. We show that protein kinase C (PKC) λ/ι loss in hepatocytes promotes autophagy and oxidative phosphorylation. This results in ROS generation, which through NRF2 drives HCC through cell-autonomous and non-autonomous mechanisms. Although PKCλ/ι promotes tumorigenesis in oncogene-driven cancer models, emerging evidence demonstrate that it is a tumor suppressor in more complex carcinogenic processes. Consistently, PKCλ/ι levels negatively correlate with HCC histological tumor grade, establishing this kinase as a tumor suppressor in liver cancer.