RESUMEN
Melanoma, arising from the malignant transformation of melanocytes, stands as the most lethal type of skin cancer. While significant strides have been made in targeted therapy and immunotherapy, substantially enhancing therapeutic efficacy, the prognosis for melanoma patients remains unoptimistic. SIRT7, a nuclear-localized deacetylase, plays a pivotal role in maintaining cellular homeostasis and adapting to external stressors in melanoma, with its activity closely tied to intracellular nicotinamide adenine dinucleotide (NAD+). However, its involvement in adaptive resistance to targeted therapy remains unclear. Herein, we unveil that up-regulated SIRT7 promotes mitochondrial biogenesis to render the adaptive resistance to MAPK inhibition in melanoma. Initially, we observed a significant increase of SIRT7 expression in publicly available datasets following targeted therapy within a short duration. In consistent, we found elevated SIRT7 expression in melanoma cells subjected to BRAF or MEK inhibitors in vitro. The up-regulation of SIRT7 expression was also confirmed in xenograft tumors in mice after targeted therapy in vivo. Furthermore, we proved that SIRT7 deficiency led to decreased cell viability upon prolonged exposure to BRAF or MEK inhibitors, accompanied by an increase in cell apoptosis. Mechanistically, SIRT7 deficiency restrained the upregulation of genes associated with mitochondrial biogenesis and intracellular ATP levels in response to targeted therapy treatment in melanoma cells. Ultimately, we proved that SIRT7 deficieny could sensitize BRAF-mutant melanoma cells to MAPK inhibition targeted therapy in vivo. In conclusion, our findings underscore the role of SIRT7 in fostering adaptive resistance to targeted therapy through the facilitation of mitochondrial biogenesis. Targeting SIRT7 emerges as a promising strategy to overcome MAPK inhibitor adaptive resistance in melanoma.
Asunto(s)
Resistencia a Antineoplásicos , Melanoma , Biogénesis de Organelos , Inhibidores de Proteínas Quinasas , Sirtuinas , Melanoma/metabolismo , Melanoma/patología , Melanoma/genética , Melanoma/tratamiento farmacológico , Humanos , Sirtuinas/metabolismo , Sirtuinas/genética , Animales , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Inhibidores de Proteínas Quinasas/farmacología , Ratones , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/tratamiento farmacológico , Ratones Desnudos , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidoresRESUMEN
BACKGROUND: Tumor cells frequently suffer from endoplasmic reticulum (ER) stress. Previous studies have extensively elucidated the role of tumorous unfolded protein response in melanoma cells, whereas the effect on tumor immunology and the underlying mechanism remain elusive. METHODS: Bioinformatics, biochemical assays and pre-clinical mice model were employed to demonstrate the role of tumorous inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α) in anti-tumor immunity and the underlying mechanism. RESULTS: We firstly found that IRE1α signaling activation was positively associated with the feature of tumor-infiltrating lymphocytes. Then, pharmacological ER stress induction by HA15 exerted prominent anti-tumor effect in immunocompetent mice and was highly dependent on CD8+T cells, paralleled with the reshape of immune cells in tumor microenvironment via tumorous IRE1α-XBP1 signal. Subsequently, tumorous IRE1α facilitated the expression and secretion of multiple chemokines and cytokines via XBP1-NF-κB axis, leading to increased infiltration and anti-tumor capacity of CD8+T cells. Ultimately, pharmacological induction of tumorous ER stress by HA15 brought potentiated therapeutic effect along with anti-PD-1 antibody on melanoma in vivo. CONCLUSIONS: Tumorous IRE1α facilitates CD8+T cells-dependent anti-tumor immunity and improves immunotherapy efficacy by regulating chemokines and cytokines via XBP1-NF-κB axis. The combination of ER stress inducer and anti-PD-1 antibody could be promising for increasing the efficacy of melanoma immunotherapy.
Asunto(s)
Melanoma , Animales , Ratones , Linfocitos T CD8-positivos/patología , Quimiocinas , Citocinas , Endorribonucleasas , Melanoma/patología , FN-kappa B , Proteínas Serina-Treonina Quinasas/metabolismo , Linfocitos T/metabolismo , Microambiente TumoralRESUMEN
Melanoma is the most lethal skin cancer originating from the malignant transformation of epidermal melanocyte. The dysregulation of cellular metabolism is a hallmark of cancer, including in melanoma. Aberrant branched-chain amino acids (BCAA) metabolism and related enzymes has been greatly implicated in the progression of multiple types of cancer, whereas remains far from understood in melanoma. Herein, we reported that the critical BCAA metabolism enzyme branched-chain amino acid transaminase 2 (BCAT2) is an oncogenic factor in melanoma by activating lipogenesis via the epigenetic regulation of fatty acid synthase (FASN) and ATP-citrate lyase (ACLY) expressions. Firstly, we found that BCAT2 expression was prominently increased in melanoma, and highly associated with clinical stage. Then, it was proved that the deficiency of BCAT2 led to impaired tumor cell proliferation, invasion and migration in vitro, and tumor growth and metastasis in vivo. Further, RNA sequencing technology and a panel of biochemical assays demonstrated that BCAT2 regulated de novo lipogenesis via the regulation of the expressions of both FASN and ACLY. Mechanistically, the inhibition of BCAT2 suppressed the generation of intracellular acetyl-CoA, mitigating P300-dependent histone acetylation at the promoter of FASN and ACLY, and thereby their transcription. Ultimately, zinc finger E-box binding homeobox 1 (ZEB1) was identified as the upstream transcriptional factor responsible for BCAT2 up-regulation in melanoma. Our results demonstrate that BCAT2 promotes melanoma progression by epigenetically regulating FASN and ACLY expressions via P300-dependent histone acetylation. Targeting BCAT2 could be exploited as a promising strategy to restrain tumor progression in melanoma.
Asunto(s)
Melanoma , Proteínas Gestacionales , Humanos , Lipogénesis/genética , ATP Citrato (pro-S)-Liasa/genética , ATP Citrato (pro-S)-Liasa/metabolismo , Histonas/metabolismo , Epigénesis Genética , Melanoma/genética , Transaminasas/genética , Proteínas Gestacionales/genética , Proteínas Gestacionales/metabolismo , Antígenos de Histocompatibilidad Menor/metabolismo , Acido Graso Sintasa Tipo I/genéticaRESUMEN
The dysregulation of branched-chain amino acid (BCAA) metabolism and related enzymes has been greatly implicated in the progression of multiple types of cancer, whereas remains far from understood in melanoma. Here, we explored the role of the BCAA metabolism enzyme BCKDHA in melanoma pathogenesis and elucidated the underlying mechanisms. In vitro cell biology experiments and in vivo pre-clinical mice model experiments were performed to investigate the role of BCKDHA in melanoma progression. RNA sequencing, immunohistochemical/immunofluorescence staining and bioinformatics analysis were used to examine the underlying mechanism. BCKDHA expression was prominently increased in both melanoma tissues and cell lines. The up-regulation of BCKDHA promoted long-term tumour cell proliferation, invasion and migration in vitro and tumour growth in vivo. Through RNA-sequencing technology, it was found that BCKDHA regulated the expressions of lipogenic fatty acid synthase (FASN) and ATP-citrate lyase (ACLY), which was thereafter proved to mediate the oncogenic role of BCKDHA in melanoma. Our results demonstrate that BCKDHA promotes melanoma progression by regulating FASN and ACLY expressions. Targeting BCKDHA could be exploited as a promising strategy to restrain tumour progression in melanoma.
Asunto(s)
ATP Citrato (pro-S)-Liasa , Melanoma , Animales , Ratones , ATP Citrato (pro-S)-Liasa/genética , ATP Citrato (pro-S)-Liasa/metabolismo , Línea Celular , Proliferación Celular , Lipogénesis , Melanoma/genéticaRESUMEN
BACKGROUND: The 2,940 nm erbium-doped yttrium aluminium garnet and 1,064 nm neodymium-doped yttrium aluminium garnet lasers have been widely applied in facial rejuvenation, but no randomized trials exist to evaluate the efficacy of the combination treatment. OBJECTIVE: The efficacy of the combined treatment for facial rejuvenation. MATERIALS AND METHODS: A total of 20 subjects with facial aging were enrolled and randomly assigned into 2 groups: one side of the face was treated with a 2,940 nm or 1,064 nm laser alone and the other side was treated with the combined lasers. The patients were treated by 3 sessions with 1-month intervals. The efficacies were quantitatively accessed by digitalized high-resolution photographs. RESULTS: The 1,064 nm laser alone showed significant improvements on indexes of skin texture, spore, brown spots, elasticity, and melanin as compared with the baseline (p < .05). The 2,940 nm laser alone showed significant improvements on indexes of wrinkle, texture, pore, and elasticity (p < .05). The combined treatments showed significant improvements on the abovementioned indexes as compared with either a 1,064 nm or 2,940 nm laser treatment (p < .05). CONCLUSION: A combination of 1,064 nm and 2,940 nm laser treatment renders significantly better efficacies for facial rejuvenation as compared with a 2,940 nm or 1,064 nm laser alone.
Asunto(s)
Técnicas Cosméticas , Láseres de Estado Sólido/uso terapéutico , Adulto , Cara , Femenino , Humanos , Masculino , Persona de Mediana Edad , Rejuvenecimiento , Resultado del TratamientoRESUMEN
Vitiligo is a depigmentation disorder that develops as a result of the progressive disappearance of epidermal melanocytes. The elevated level of amino acid metabolite homocysteine (Hcy) has been identified as circulating marker of oxidative stress and known as a risk factor for vitiligo. However, the mechanism underlying Hcy-regulated melanocytic destruction is currently unknown. The present study aims to elucidate the effect of Hcy on melanocytic destruction and its involvement in the pathogenesis of vitiligo. Our results showed that Hcy level was significantly elevated in the serum of progressive vitiligo patients. Notably, Hcy induced cell apoptosis in melanocytes via activating reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress protein kinase RNA-like ER kinase (PERK)-eukaryotic translation initiation factor 2α (eIF2α)-C/EBP homologous protein (CHOP) pathway. More importantly, folic acid, functioning in the transformation of Hcy, could lower the intracellular Hcy level and further reverse the apoptotic effect of Hcy on melanocytes. Additionally, Hcy disrupted melanogenesis whereas folic acid supplementation could reverse the melanogenesis defect induced by Hcy in melanocytes. Taken together, Hcy is highly increased in vitiligo patients at progressive stage, and our in vitro studies revealed that folic acid could protect melanocytes from Hcy-induced apoptosis and melanin synthesis inhibition, indicating folic acid as a potential benefit agent for patients with progressive vitiligo.
Asunto(s)
Apoptosis , Factor 2 Eucariótico de Iniciación/metabolismo , Homocisteína/metabolismo , Melanocitos/metabolismo , Melanocitos/patología , Factor de Transcripción CHOP/metabolismo , Vitíligo/metabolismo , eIF-2 Quinasa/metabolismo , Adulto , Apoptosis/efectos de los fármacos , Estudios de Casos y Controles , Proliferación Celular/efectos de los fármacos , Progresión de la Enfermedad , Estrés del Retículo Endoplásmico/efectos de los fármacos , Femenino , Ácido Fólico/farmacología , Homocisteína/sangre , Humanos , Masculino , Melaninas/biosíntesis , Melanocitos/efectos de los fármacos , Modelos Biológicos , Transducción de Señal/efectos de los fármacos , Vitíligo/sangreRESUMEN
Melanoma is an aggressive malignancy of melanocytes and most commonly arises in the skin. In 2002, BRAF gene mutations were identified in melanoma, and this finding resulted in the development of several small-molecule molecular inhibitors that specifically targeted the BRAF V600E mutation. The development of targeted therapies for advanced-stage melanoma, including tyrosine kinase inhibitors (TKIs) of the BRAF (V600E) kinase, vemurafenib and dabrafenib, have been approved for the treatment of advanced melanoma leading to improved clinical outcomes. However, the development of BRAF inhibitor (BRAFi) resistance has significantly reduced the therapeutic efficacy after prolonged treatment. Recent studies have identified the molecular mechanisms for BRAFi resistance. This review aims to describe the impact of BRAFi resistance on the pathogenesis of melanoma, the current status of molecular pathways involved in BRAFi resistance, including intrinsic resistance, adaptive resistance, and acquired resistance. This review will discuss how an understanding of the mechanisms associated with BRAFi resistance may aid the identification of useful strategies for overcoming the resistance to BRAF-targeted therapy in patients with advanced-stage melanoma.
Asunto(s)
Resistencia a Antineoplásicos/genética , Melanoma/genética , Proteínas Proto-Oncogénicas B-raf/genética , Antineoplásicos/farmacología , Femenino , Humanos , Imidazoles/farmacología , Masculino , Melanocitos/metabolismo , Melanoma/metabolismo , Terapia Molecular Dirigida , Mutación , Oximas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/metabolismo , Neoplasias Cutáneas/patología , Vemurafenib/farmacologíaRESUMEN
BACKGROUND: The diagnostic and prognostic significance of carcinoembryonic antigen (CEA), carbohydrate associated antigen 19-9 (CA19-9), alpha-fetoprotein (AFP) and cancer antigen 125 (CA125) in early gastric cancer have not been investigated yet. Thus, the present study aimed to explore the diagnostic and prognostic significance of the four tumor markers for early gastric cancer. METHODS: From September 2008 to March 2015, 587 early gastric cancer patients were given radical gastrectomy in our center. The clinicopathological characteristics were recorded. The association between levels of CEA and CA19-9 and clinicopathological characteristics and prognosis of patients were analyzed. RESULTS: There were 444 men (75.6%) and 143 women (24.4%). The median age was 57 years (ranged 21-85). The 1-, 3- and 5-year overall survival rate was 99.1%, 96.8% and 93.1%, respectively. The positive rate of CEA, CA19-9, AFP and CA125 was 4.3%, 4.8%, 1.5% and 1.9%, respectively. The positive rate of all markers combined was 10.4%. The associations between the clinicopathological features and levels of CEA and CA19-9 were analyzed. No significant association was found between CEA level and clinicopathological features. However, elevated CA19-9 level was correlated with female gender and presence of lymph node metastasis. Age > 60 years old, presence of lymph node metastasis and elevation of CEA level were independent risk factors for poor prognosis of early gastric cancer. CONCLUSIONS: The positive rates of CEA, CA19-9, APF and CA125 were relatively low for early gastric cancer. Elevation of CA19-9 level was associated with female gender and presence of lymph node metastasis. Elevation of CEA level was an independent risk factor for the poor prognosis of early gastric cancer.
Asunto(s)
Biomarcadores de Tumor/sangre , Antígeno Ca-125/sangre , Antígeno CA-19-9/sangre , Antígeno Carcinoembrionario/sangre , Neoplasias Gástricas/sangre , alfa-Fetoproteínas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Detección Precoz del Cáncer/métodos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/mortalidad , Tasa de Supervivencia/tendenciasRESUMEN
GOALS: The present study aimed to investigate the clinicopathologic features and prognosis of pancreatic gastrointestinal stromal tumor (GIST). BACKGROUND: Reports on clinicopathologic features and prognosis of pancreatic GIST are limited due to the extremely rare incidence. STUDY: One case of pancreatic GIST from our center and 44 cases reported in MEDLINE were enrolled in this study. Clinicopathologic features and prognosis of pancreatic GISTs were analyzed and compared with 297 gastric GISTs from our center. RESULTS: The most common location was head of pancreas (38.5%). The majority of pancreatic GISTs exceeded 5 cm (74.4%), displayed cystic or mixed imaging features (56.4%), and were high risk (85.7%). The 5-year disease-free survival (DFS) and disease-specific survival rates were 66.1% and 95.8%, respectively. Mitotic index was the only risk factor for DFS of pancreatic GISTs. The distribution of tumor size, histologic type and National Institutes of Health risk category were significantly different between pancreatic and gastric GISTs. The 5-year DFS rate of pancreatic GISTs was significantly lower than that of gastric GISTs. Multivariate analysis showed that location was an independent prognostic factor for DFS between pancreatic and gastric GISTs. CONCLUSIONS: The most common location was head of pancreas. The majority of pancreatic GISTs were large and highly malignant. Pancreatic GISTs differed significantly from gastric GISTs in respect to clinicopathologic features. The DFS of pancreatic GISTs was worse than that of gastric GISTs.
Asunto(s)
Tumores del Estroma Gastrointestinal/patología , Neoplasias Pancreáticas/patología , Neoplasias Gástricas/patología , Adulto , Anciano , Anciano de 80 o más Años , Distribución de Chi-Cuadrado , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Tumores del Estroma Gastrointestinal/mortalidad , Tumores del Estroma Gastrointestinal/terapia , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Índice Mitótico , Análisis Multivariante , Recurrencia Local de Neoplasia , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/terapia , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/terapia , Factores de Tiempo , Resultado del Tratamiento , Carga TumoralRESUMEN
BACKGROUND: The clinicopathological features and prognosis of gastric cancer in young patients are both limited and controversial. Therefore, the aim of this study was to define the clinicopathological features and prognosis of gastric cancer in young patients after curative resection. METHODS: From May 2008 to December 2014, 198 young patients (age ≤ 40 years) and 1096 middle-aged patients (55 ≤ age ≤ 64 years) were enrolled in this study. The clinicopathological features and prognosis of gastric cancer in these patients were analyzed. RESULTS: Compared with middle-aged patients, the proportion of females, lower third tumors, tumor size less than 5 cm, poorly differentiated tumors and T1 tumors were significantly higher in young patients (all P < 0.05). The proportions of comorbidity, upper third tumors, well and moderately differentiated tumors, T4 tumors, and positive carcinoembryonic antigen (CEA), alpha fetoprotein (AFP) and carbohydrate antigen (CA) 19-9 were significantly lower in young patients (all P < 0.05). The distributions of N status and CA125 were comparable between young and middle-aged patients (all P > 0.05). The five-year overall survival rates were comparable between young patients and middle-aged patients (62.8 vs 54.7 %, P = 0.307). The tumor location, T status, N status and CA125 were independent predictors of prognosis in young patients. The overall survival of patients with tumors located in the upper or middle third was significantly lower than for those located in the lower third (60.8 vs 50.6 % vs 68.4 %, P = 0.016). The overall survival of CA125-positive patients was significantly lower than CA125-negative patients (49.0 vs 64.4 %, P = 0.001). CONCLUSION: The clinicopathological features were significantly different between young and middle-aged patients. The prognosis of gastric cancer in young patients was equivalent to that of middle-aged patients. Tumor location, T status, N status and CA125 were independent risk factors for prognosis in young patients.
Asunto(s)
Adenocarcinoma Mucinoso/patología , Carcinoma de Células en Anillo de Sello/patología , Neoplasias Gástricas/patología , Adenocarcinoma Mucinoso/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células en Anillo de Sello/mortalidad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Neoplasias Gástricas/mortalidad , Adulto JovenRESUMEN
Melanoma is the most lethal type of skin cancer, originating from the malignant transformation of melanocyte. While the development of targeted therapy and immunotherapy has gained revolutionary advances in potentiating the therapeutic effect, the prognosis of patients with melanoma is still suboptimal. During tumor progression, melanoma frequently encounters stress from both endogenous and exogenous sources in tumor microenvironment. SIRT7 is a nuclear-localized deacetylase of which the activity is highly dependent on intracellular nicotinamide adenine dinucleotide (NAD+), with versatile biological functions in maintaining cell homeostasis. Nevertheless, whether SIRT7 regulates tumor cell biology and tumor immunology in melanoma under stressful tumor microenvironment remains elusive. Herein, we reported that SIRT7 orchestrates melanoma progression by simultaneously promoting tumor cell survival and immune evasion via the activation of unfolded protein response. We first identified that SIRT7 expression was the most significantly increased one in sirtuins family upon stress. Then, we proved that the deficiency of SIRT7 potentiated tumor cell death under stress in vitro and suppressed melanoma growth in vivo. Mechanistically, SIRT7 selectively activated the IRE1α-XBP1 axis to potentiate the pro-survival ERK signal pathway and the secretion of tumor-promoting cytokines. SIRT7 directly de-acetylated SMAD4 to antagonize the TGF-ß-SMAD4 signal, which relieved the transcriptional repression on IRE1α and induced the activation of the IRE1α-XBP1 axis. Moreover, SIRT7 up-regulation eradicated anti-tumor immunity by promoting PD-L1 expression via the IRE1α-XBP1 axis. Additionally, the synergized therapeutic effect of SIRT7 suppression and anti-PD-1 immune checkpoint blockade was also investigated. Taken together, SIRT7 can be employed as a promising target to restrain tumor growth and increase the effect of melanoma immunotherapy.
Asunto(s)
Melanoma , Sirtuinas , Humanos , Endorribonucleasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Supervivencia Celular/genética , Evasión Inmune , Línea Celular Tumoral , Melanoma/genética , Microambiente Tumoral , Sirtuinas/genéticaRESUMEN
DCs (dendritic cells) are the strongest professional APCs (antigen-presenting cells) to initiate immune responses against pathogens, but they are usually incompetent in initiating efficient immune responses in the progress of solid tumours. We have shown that Notch signalling plays a pivotal role in DC-dependent anti-tumour immunity. Compared with the control DCs, OP9-DL1 (Delta-like1) cell co-cultured DCs gained increased tumour suppression activity when inoculated together with tumour cells. This was probably due to the activation of Notch signalling in DCs enhancing their ability to evoke anti-tumour immune responses in solid tumours. Indeed, the OP9-DL1 cell co-cultured DCs expressed higher levels of MHC I, MHC II, CXCR4 (CXC chemokine receptor 4), CCR7 (CC chemokine receptor 7), IL-6 (interleukin 6), IL-12 and TNFα (tumour necrosis factor α), and a lower level of IL-10 than control DCs, resulting in more efficient DC migration and T-cell activation in vivo and in vitro. T-cells stimulated by OP9-DL1 cells co-cultured DCs more efficiently; and were cytotoxic against tumour cells, in contrast with control DCs. These results indicated that up-regulation of Notch signalling in DCs by co-culturing with OP9-DL1 cells enhances DC-dependent anti-tumour immune reactions, making the Notch signalling pathway a target for the establishment of the DC-based anti-tumour immunotherapies.
Asunto(s)
Células de la Médula Ósea/metabolismo , Células Dendríticas/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Neoplasias/inmunología , Animales , Células de la Médula Ósea/inmunología , Proteínas de Unión al Calcio , Técnicas de Cocultivo , Células Dendríticas/inmunología , Péptidos y Proteínas de Señalización Intercelular/inmunología , Interleucina-12/inmunología , Interleucina-12/metabolismo , Ratones , Neoplasias/patología , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia ArribaRESUMEN
Melanoma results from the malignant transformation of melanocytes and accounts for the most lethal type of skin cancers. In the pathogenesis of melanoma, disordered metabolism is a hallmark characteristic with multiple metabolic paradigms involved in, e.g., glycolysis, lipid metabolism, amino acid metabolism, oxidative phosphorylation, and autophagy. Under the driving forces of oncogenic mutations, melanoma metabolism is rewired to provide not only building bricks for macromolecule synthesis and sufficient energy for rapid proliferation and metastasis but also various metabolic intermediates for signal pathway transduction. Of note, metabolic alterations in tumor orchestrate tumor immunology by affecting the functions of surrounding immune cells, thereby interfering with their antitumor capacity, in addition to the direct influence on tumor cell intrinsic biological activities. In this review, we first introduced the epidemiology, clinical characteristics, and treatment proceedings of melanoma. Then, the components of the tumor microenvironment, especially different populations of immune cells and their roles in antitumor immunity, were reviewed. Sequentially, how metabolic rewiring contributes to tumor cell malignant behaviors in melanoma pathogenesis was discussed. Following this, the proceedings of metabolism- and metabolic intermediate-regulated tumor immunology were comprehensively dissertated. Finally, we summarized currently available drugs that can be employed to target metabolism to intervene tumor immunology and modulate immunotherapy.
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Melanoma , Neoplasias Cutáneas , Glucólisis , Humanos , Inmunoterapia , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/terapia , Microambiente TumoralRESUMEN
Melanoma is the most lethal form of skin cancer, resulting from the malignant transformation of epidermal melanocytes. Recent revolutionary progress in targeted therapy and immunotherapy has prominently improved the treatment outcome, but the survival of melanoma patients remains suboptimal. Ferroptosis is greatly involved in cancer pathogenesis and can execute the outcome of immunotherapy. However, the detailed regulatory mechanisms of melanoma cell ferroptosis remain elusive. Herein, we report that Wnt/ß-catenin signaling regulates ferroptosis and melanoma immunotherapy efficacy via the regulation of MITF. First of all, we found that Wnt/ß-catenin signaling was prominently suppressed in melanoma cell ferroptosis. Then, we proved that targeting ß-catenin exacerbated melanoma cell ferroptosis by promoting the generation of lipid peroxidation both in vitro and in vivo. Subsequent mechanistic studies revealed that MITF mediated the effect of Wnt/ß-catenin signaling on melanoma cell ferroptosis, and PGC1α and SCD1 were documented as two main effectors downstream of Wnt/ß-catenin-MITF pathway. Ultimately, pharmacological inhibition of ß-catenin or MITF increased the efficacy of anti-PD-1 immunotherapy in preclinical xenograft tumor model by promoting ferroptosis. Taken together, Wnt/ß-catenin signaling deficiency exacerbates ferroptosis in melanoma via the regulation of MITF. Targeting Wnt/ß-catenin-MITF pathway could be a promising strategy to potentiate ferroptosis and increase the efficacy of anti-PD-1 immunotherapy.
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Ferroptosis , Melanoma , Humanos , beta Catenina/metabolismo , Proteínas Wnt/metabolismo , Melanoma/patología , Vía de Señalización Wnt , Inmunoterapia , Factor de Transcripción Asociado a Microftalmía/metabolismoRESUMEN
BACKGROUND: Although anti-programmed cell death protein 1 (PD-1) immunotherapy is greatly effective in melanoma treatment, low response rate and treatment resistance significantly hinder its efficacy. Tumor cell ferroptosis triggered by interferon (IFN)-γ that is derived from tumor-infiltrating CD8+ T cells greatly contributes to the effect of immunotherapy. However, the molecular mechanism underlying IFN-γ-mediated ferroptosis and related potentially promising therapeutic strategy warrant further clarification. MicroRNAs (miRNAs) participate in ferroptosis execution and can be delivered systemically by multiple carriers, which have manifested obvious therapeutic effects on cancer. METHODS: MiRNAs expression profile in IFN-γ-driven ferroptosis was obtained by RNA sequencing. Biochemical assays were used to clarify the role of miR-21-3p in IFN-γ-driven ferroptosis and the underlying mechanism. MiR-21-3p-loaded gold nanoparticles were constructed and systemically applied to analyze the role of miR-21-3p in anti-PD-1 immunotherapy in preclinical transplanted tumor model. RESULTS: MiRNAs expression profile of melanoma cells in IFN-γ-driven ferroptosis was first obtained. Then, upregulated miR-21-3p was proved to facilitate IFN-γ-mediated ferroptosis by potentiating lipid peroxidation. miR-21-3p increased the ferroptosis sensitivity by directly targeting thioredoxin reductase 1 (TXNRD1) to enhance lipid reactive oxygen species (ROS) generation. Furthermore, miR-21-3p overexpression in tumor synergized with anti-PD-1 antibody by promoting tumor cell ferroptosis. More importantly, miR-21-3p-loaded gold nanoparticles were constructed, and the systemic delivery of them increased the efficacy of anti-PD-1 antibody without prominent side effects in preclinical mice model. Ultimately, ATF3 was found to promote miR-21-3p transcription in IFN-γ-driven ferroptosis. CONCLUSIONS: MiR-21-3 p upregulation contributes to IFN-γ-driven ferroptosis and synergizes with anti-PD-1 antibody. Nanoparticle delivery of miR-21-3 p is a promising therapeutic approach to increase immunotherapy efficacy without obvious systemic side effects.
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Ferroptosis , Melanoma , Nanopartículas del Metal , MicroARNs , Animales , Linfocitos T CD8-positivos , Línea Celular Tumoral , Oro , Humanos , Inmunoterapia , Melanoma/tratamiento farmacológico , Melanoma/genética , Ratones , MicroARNs/genética , MicroARNs/metabolismoRESUMEN
Tachykinins such as SP (substance P) may be involved in the progression of gastric adenocarcinoma through binding to NK-1 receptor. However, the existence and relationship between SP and gastric cancer progression and differentiation remained unknown. We have studied the NK-1 receptor in human gastric cancer tissue and MKN45 cell line and found SP-containing nerve fibres in human gastric cancer and found that the amounts of SP-positive nerves were related to gastric cancer differentiation. SP could promote proliferation, adhesion, migration and invasion of MKN45 cells in vitro. In addition, the intracellular calcium level of MKN45 cells was elevated after SP stimulation, and administration of CRACs (calcium release-activated calcium channels) inhibitor SKF-96365 could partially abolish these effects induced by SP. These results demonstrated that NK-1 receptor and SP-containing nerves existed in human gastric cancer; SP positive nerves may play an important role in human gastric cancer progression, and calcium is critically significant among SP-induced biological effects.
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Fibras Nerviosas/metabolismo , Neoplasias Gástricas/metabolismo , Sustancia P/metabolismo , Calcio/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio/química , Canales de Calcio/metabolismo , Diferenciación Celular , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Humanos , Imidazoles/farmacología , Fibras Nerviosas/inmunología , Unión Proteica , Receptores de Neuroquinina-1/metabolismo , Transducción de Señal , Neoplasias Gástricas/patología , Sustancia P/inmunologíaRESUMEN
Melanoma cells are relatively resistant to endoplasmic reticulum (ER) stress, which contributes to tumor progression under stressful conditions and renders tolerance to ER stressâinducing therapeutic agents. Mitochondria are tightly interconnected with ER. However, whether mitochondria play a role in regulating ER stress resistance in melanoma remains elusive. In this study, we reported that the XBP1âMARCH5âMFN2 axis conferred ER stress resistance by coordinating mitochondrial fission and mitophagy in melanoma. Our integrative bioinformatics first revealed that the downregulation of mitochondrial genes was highly correlated with unfolded protein response activation in melanoma. Then we proved that mitochondrial fission and mitophagy were prominently induced to contribute to ER stress resistance both in vitro and in vivo by maintaining mitochondrial function. Mechanistically, the activation of IRE1α/ATF6-XBP1 branches of unfolded protein response promoted the transcription of E3 ligase MARCH5 to facilitate the ubiquitination and degradation of MFN2, which thereby triggered mitochondrial fission and mitophagy under ER stress. Together, our findings show a regulatory axis that links mitochondrial fission and mitophagy to the resistance to ER stress. Targeting mitochondrial quality control machinery can be exploited as an approach to reinforce the efficacy of ER stressâinducing agents against cancer.
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Estrés del Retículo Endoplásmico/fisiología , GTP Fosfohidrolasas/fisiología , Melanoma/metabolismo , Proteínas de la Membrana/fisiología , Dinámicas Mitocondriales/fisiología , Proteínas Mitocondriales/fisiología , Mitofagia/fisiología , Ubiquitina-Proteína Ligasas/fisiología , Proteína 1 de Unión a la X-Box/fisiología , Animales , Línea Celular Tumoral , Femenino , Humanos , Ratones , Respuesta de Proteína DesplegadaRESUMEN
Age-related human trabecular meshwork (HTM) cell loss is suggested to affect its ability to regulate aqueous humor outflow in the eye. In addition, disease-related HTM cell loss is suggested to lead to elevated intraocular pressure in glaucoma. Induced pluripotent stem cell (iPSC)-derived trabecular meshwork (TM) cells are promising autologous cell sources that can be used to restore the declining TM cell population and function. Previously, an in vitro HTM model is bioengineered for understanding HTM cell biology and screening of pharmacological or biological agents that affect trabecular outflow facility. In this study, it is demonstrated that human iPSC-derived TM cells cultured on SU-8 scaffolds exhibit HTM-like cell morphology, extracellular matrix deposition, and drug responsiveness to dexamethasone treatment. These findings suggest that iPSC-derived TM cells behave like primary HTM cells and can thus serve as reproducible and scalable cell sources when using this in vitro system for glaucoma drug screening and further understanding of outflow pathway physiology, leading to personalized medicine.
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Células Madre Pluripotentes Inducidas , Modelos Biológicos , Malla Trabecular , Biomimética , Técnicas de Cultivo de Célula/métodos , Glaucoma/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Malla Trabecular/citología , Malla Trabecular/metabolismoRESUMEN
Human Schlemm's canal (HSC) cells are critical for understanding outflow physiology and glaucoma etiology. However, primary donor cells frequently used in research are difficult to isolate. HSC cells exhibit both vascular and lymphatic markers. Human adipose-derived stem cells (ADSCs) represent a potential source of HSC due to their capacity to differentiate into both vascular and lymphatic endothelial cells, via VEGF-A and VEGF-C. Shear stress plays a critical role in maintaining HSC integrity, function, and PROX1 expression. Additionally, the human trabecular meshwork (HTM) microenvironment could provide cues for HSC-like differentiation. We hypothesize that subjecting ADSCs to VEGF-A or VEGF-C, shear stress, and co-culture with HTM cells could provide biological, mechanical, and cellular cues necessary for HSC-like differentiation. To test this hypothesis, effects of VEGF-A, VEGF-C, and shear stress on ADSC differentiation were examined and compared to primary HSC cells in terms of cell morphology, and HSC marker expression using qPCR, immunoblotting, and immunocytochemistry analysis. Furthermore, the effect of co-culture with HTM cells on porous scaffolds on ADSC differentiation was studied. Treatment with VEGF-C under shear stress is effective in differentiating ADSCs into PROX1-expressing HSC-like cells. Co-culture with HTM cells on porous scaffolds leads to HTM/ADSC-derived HSC-like constructs that regulate through-flow and respond as expected to dexamethasone. STATEMENT OF SIGNIFICANCE: We successfully generated human Schlemm's canal (HSC) like cells from adipocyte-derived stem cells induced by biochemical and biomechanical cues as well as bioengineered human trabecular meshwork (HTM) on micropatterned, porous SU8 scaffolds. These stem cell-derived HSC-like cells co-cultured with HTM cells on SU8 scaffolds can regulate through-flow, and in particular, are responsive to steroid treatment as expected. These findings show that ADSC-derived HSC-like cells have the potential to recreate the ocular outflow pathway for in vitro glaucoma drug screening. To the best of our knowledge, it is the very first time to demonstrate derivation of Schlemm's canal-like cells from stem cells. It provides an important alternative source to primary Schlemm's canal cells that are very difficult to be isolated and cultured from human donors.
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Bioingeniería , Diferenciación Celular , Evaluación Preclínica de Medicamentos , Glaucoma/tratamiento farmacológico , Células Madre/citología , Tejido Adiposo/citología , Biomarcadores/metabolismo , Diferenciación Celular/efectos de los fármacos , Técnicas de Cocultivo , Dexametasona/farmacología , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Glaucoma/patología , Humanos , Imagen Óptica , Perfusión , Células Madre/efectos de los fármacos , Malla Trabecular/citologíaRESUMEN
Retinal pigment epithelial (RPE) cells are highly specialized neural cells that have several functions essential for vision. Progressive deterioration of RPE cells in elderly individuals can result in visual impairment and ultimately the blinding disease age-related macular degeneration. Subretinal transplantation of stem cell-derived RPE cell suspensions is being explored as a strategy to recover the damaged retina and improve vision. This approach may be improved by developing a vehicle that increases postinjection cell viability and distribution and integration of RPE cells. In this study, Food and Drug Administration-approved natural polymers, including alginate, methylcellulose, and hyaluronic acid (HA), were examined for performance as cell vehicles for adult human RPE stem cells (RPESCs). We compared the effect of RPESC storage as a cell suspension in these delivery vehicles for 1-96 hr at different temperatures on subsequent cell performance in a cell culture model. RPESC survival, attachment, distribution, proliferation, and differentiation into RPE cells were monitored by microscopy over the course of 8 weeks. Our in vitro results demonstrate that RPESC suspension in a 0.2% HA solution promotes better initial cell distribution, proliferation, cobblestone formation, and expression of RPE cell markers (microphthalmia-associated transcription factor and orthodenticle homeobox 2) after 96 hr of storage. These data suggest that HA addition to the vehicle can significantly enhance RPESC performance in vitro and is a promising strategy to pursue an improved delivery vehicle supporting in vivo RPE cell transplantation.