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A one-pot step-economic tandem process involving (5 + 2)-cycloaddition and Nazarov cyclization reactions has been reported for the facile synthesis of indanone-fused benzo[cd]azulenes from (E)-2-arylidene-3-hydroxyindanones and conjugated eneynes. This highly regio- and stereoselective bisannulation reaction is enabled by dual silver and Brønsted acid catalysis and opens up a new avenue for the construction of important bicyclo[5.3.0]decane skeletons.
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This study describes the preparation of a lignin-based expandable flame retardant (Lignin-N-DOPO) using grafting melamine and covering 9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide (DOPO) using the Mannich reaction. Then, through in situ growth, a metal-organic framework (MOF) HKUST-1 (e.g., Cu3(BTC)2, BTC = benzene-1,3,5-tricarboxylate)/lignin-based expandable flame retardant (F-lignin@HKUST-1) was created. Before that, lignin epoxy resin containing phosphorus (P) and nitrogen (N) components had been created by combining epoxy resin (EP) with F-lignin@HKUST-1. Thermogravimetric analysis was used to examine the thermal characteristics of epoxy resin (EP) composite. The findings indicate that the thermal stability of EP is significantly affected by the presence of F-lignin@HKUST-1. Last but not least, the activation energy (E) of EP/15% F-lignin@HKUST-1 was examined using four different techniques, including the Kissinger-SY iteration method, the Ozawa-SY iteration method, the Lee-Beck approximation-iteration method, and the Gorbatchev approximation-iteration method. It was discovered that the activation energy was significantly higher than that of lignin. Higher activation energy suggests that F-lignin@HKUST-1 pyrolysis requires more energy from the environment, which will be significant about the application of lignin-based flame retardants.
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Effective fault-diagnosis strategies have been the focus of research on multi-agent systems (MASs). In this paper, the belief rule base (BRB)-based distributed fault-diagnosis problem for MASs is investigated, and a topology-switching strategy is developed to increase the reliability of fault-diagnosis model. Firstly, a BRB-based distributed fault-diagnosis model is constructed for the MAS with multiple faults, then expert knowledge is used to judge whether the agent is faulty. Then, considering that the system may be influenced by the fault or some other factors and thus leading to a decrease in the accuracy of the fault-diagnosis results, a topology-switching strategy based on the average distance of the output diagnosis accuracy is proposed to update the topology of the agent so that the fault-diagnosis results can be more reliable. Note that the topology-switching threshold is designed based on the average distance between the accuracy of the fault diagnosis of each agent. The method proposed in this paper can solve the problem when the fault-diagnosis accuracy of the model is affected by some common factors and thus decreases, and can improve the reliability of the fault-diagnosis model very well. Finally, the effectiveness of the BRB-based distributed fault-diagnosis model and the proposed topology-switching strategy to improve the fault-diagnosis accuracy is verified by simulation examples.
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High-mobility group protein A2 (HMGA2) is highly expressed in hepatocellular carcinoma (HCC) cells and contributes to tumor metastasis and poor patient survival. However, the molecular mechanism through which HMGA2 is transcriptionally regulated in HCC cells remains largely unclear. Here, we showed that the expression HMGA2 was upregulated in HCC, and that elevated HMGA2 could promote tumor metastasis. Incubation of HCC cells with epidermal growth factor (EGF) could promote the expression of HMGA2 mRNA and protein. Mechanistic studies suggested that EGF can phosphorylate p300 at Ser1834 residue through the PI3K/Akt signaling pathway in HCC cells. Knockdown of p300 can reverse EGF-induced HMGA2 expression and histone H3-K9 acetylation, whereas a phosphorylation-mimic p300 S1834D mutant can stimulate HMGA2 expression as well as H3-K9 acetylation in HCC cells. Furthermore, we identified that p300-mediated H3-K9 acetylation participates in EGF-induced HMGA2 expression in HCC. In addition, the levels of H3-K9 acetylation positively correlated with the expression levels of HMGA2 in a chemically induced HCC model in rats and human HCC specimens.
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Carcinoma Hepatocelular/patologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Proteína HMGA2/biossíntese , Histonas/metabolismo , Neoplasias Hepáticas/patologia , Acetilação , Animais , Carcinoma Hepatocelular/metabolismo , Receptores ErbB/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ratos , Ratos Sprague-Dawley , Transcrição Gênica , Fatores de Transcrição de p300-CBP/metabolismoRESUMO
Cisplatin has been reported to promote the expression of programmed cell death ligand-1 (PD-L1) in some cancer cells. However, the underlying mechanism through which PD-L1 is transcriptionally regulated by cisplatin in hepatocellular carcinoma (HCC) cells remains largely unknown. In the present study, we found that the expression of hepatocyte growth factor (HGF), p-Akt, p-ERK, and PD-L1 was increased in cisplatin-treated SNU-368 and SNU-739 cells. HGF stimulation also increased PD-L1 expression in these cells. Moreover, Inhibition of HGF/c-MET, PI3K/Akt, and MEK/ERK signaling pathways can dramatically block cisplatin or HGF-induced PD-L1 expression in SNU-368 and SNU-739 cells. In vivo, combination PHA665752 with cisplatin significantly reduced tumor weight with increased infiltration of CD8+ T cells in the tumor. Taken together, our study suggested that HGF/c-Met axis-induced the activation of PI3K/Akt and MEK/ERK pathways contributes to cisplatin-mediated PD-L1 expression. These findings may provide an alternative avenue for the treatment of HCC.
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Antígeno B7-H1/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Cisplatino/farmacologia , Fator de Crescimento de Hepatócito/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Myocardial ischaemia (MI) remains a major cause of death and disability worldwide. Accumulating evidence suggests a significant role for innate immunity, in which the family of toll-like receptors (TLRs) acts as an essential player. We previously reported and reviewed the changes of Tlr expression in models of MI. However, the underlying mechanisms regulating Tlr expression in MI remain unclear. The present study first screened transcription factors (TFs) that potentially regulate Tlr gene transcription based on in silico analyses followed by experimental verification, using both in vivo and in vitro models. Forkhead box C1 (FOXC1) was identified as a putative TF, which was highly responsive to MI. Next, by focusing on two representative TLR subtypes, an intracellular subtype TLR3 and a cell-surface subtype TLR4, the regulation of FOXC1 on Tlr expression was investigated. The overexpression or knockdown of FoxC1 was observed to up- or down-regulate Tlr3/4 mRNA and protein levels, respectively. A dual-luciferase assay showed that FOXC1 trans-activated Tlr3/4 promoter, and a ChIP assay showed direct binding of FOXC1 to Tlr3/4 promoter. Last, a functional study of FOXC1 was performed, which revealed the pro-inflammatory effects of FOXC1 and its destructive effects on infarct size and heart function in a mouse model of MI. The present study for the first time identified FOXC1 as a novel regulator of Tlr expression and described its function in MI.
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Fatores de Transcrição Forkhead/metabolismo , Isquemia Miocárdica/genética , Receptores Toll-Like/genética , Regulação para Cima/genética , Animais , Animais Recém-Nascidos , Citocinas/metabolismo , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Humanos , Inflamação/genética , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Camundongos , Regiões Promotoras Genéticas , Ligação Proteica/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Receptores Toll-Like/metabolismoRESUMO
Persistent cardiac hypertrophy eventually leads to deterioration of heart function and changes to normal morphology. Decreased nitric oxide (NO) production plays a critical role in modulating cardiac hypertrophy. Interleukin enhancement binding factor 3 (ILF3), a member of the double-stranded RNA-binding protein family, is known to regulate the transcription and stability of mRNA. Therefore, the major aim of the present study was to determine the role of ILF3 in reduction of NO production in cardiac hypertrophy. Cardiac hypertrophy models of neonatal rat cardiomyocytes (NRCMs) and adult rats were induced by angiotensin II (Ang II) in this study. First, it was found that ILF3 expression, NO production, and nitric oxide synthase (NOS) activity was decreased in cultured cardiomyocytes and adult rats treated with Ang II, compared with NRCMs treated with vehicle and rats treated with saline infusion, respectively. These effects induced by Ang II were significantly exacerbated by specific ILF3 knockdown. Moreover, the level of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS, was increased significantly in the Ang II-induced hypertrophic NRCMs and adult rats. Additionally, decreased protein expression and mRNA level of dimethylarginine dimethylaminohydrolases 1 (DDAH1, which degrades ADMA) were observed. Furthermore, specific ILF3 knockdown further aggravated these effects, but didn't reduce the expression level of NOS isoforms. In conclusion, our data show that ADMA accumulation-mediated decrease in NO production plays an important role in cardiomyocyte remodeling, which may be associated with ILF3-mediated DDAH1 reduction.
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Arginina/análogos & derivados , Cardiomegalia/metabolismo , Óxido Nítrico/metabolismo , Proteínas do Fator Nuclear 90/metabolismo , Amidoidrolases/metabolismo , Angiotensina II , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Arginina/metabolismo , Cardiomegalia/induzido quimicamente , Cardiomegalia/etiologia , Regulação para Baixo , Técnicas de Silenciamento de Genes , Losartan/farmacologia , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Proteínas do Fator Nuclear 90/genética , Ratos Sprague-DawleyRESUMO
The rich blood supply of the bone marrow provides favorable conditions for tumor cell proliferation and growth. In the disease's early stages, circulating tumor cells can escape to the bone marrow and form imperceptible micro metastases. These tumor cells may be reactivated to regain the ability to grow aggressively and eventually develop into visible metastases. Symptomatic bone marrow metastases with abnormal hematopoiesis solid tumor metastases are rare and have poor prognoses. Treatment options are carefully chosen because of the suppression of bone marrow function. In this review, we summarized the mechanisms involved in developing bone marrow metastases from tumor cells and the clinical features, treatment options, and prognosis of patients with symptomatic bone marrow metastases from different solid tumors reported in the literature.
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Given the serious harm caused by dietary intake of diethylstilbestrol (DES), it is urgent to explore rapid and sensitive DES sensing methods. In this work, a photothermal DES immunochromatography sensor based on covalent organic framework (COF) was constructed. The performance of COF in the field of photothermal sensing was systematically investigated for the first time. A donor-acceptor type of COF with a photothermal conversion rate of 51.17 % was synthesized. The logarithm of the DES concentrations-temperature change value standard curve was plotted. The intensity of the photothermal sensing signal was inversely proportional to the sample concentration. The detection limit of the proposed photothermal method (0.24 µg·L-1) was 10 times higher than that of visual detection (3 µg·L-1). This work not only constructed a novel detection method for DES sensing, but also provided a feasible demonstration for the application of COF in photothermal sensing and expanded the application of their photothermal properties.
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Estruturas Metalorgânicas , Cromatografia de AfinidadeRESUMO
Autophagy is a dynamic self-renovation biological process that maintains cell homeostasis and is responsible for the quality control of proteins, organelles, and energy metabolism. The E1-like ubiquitin-activating enzyme autophagy-related gene 7 (ATG7) is a critical factor that initiates classic autophagy reactions by promoting the formation and extension of autophagosome membranes. Recent studies have identified the key functions of ATG7 in regulating the cell cycle, apoptosis, and metabolism associated with the occurrence and development of multiple diseases. This review summarizes how ATG7 is precisely programmed by genetic, transcriptional, and epigenetic modifications in cells and the relationship between ATG7 and aging-related diseases.
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Autofagossomos , Autofagia , Proteína 7 Relacionada à Autofagia/genética , Autofagossomos/metabolismo , Autofagia/genética , Enzimas Ativadoras de Ubiquitina/metabolismo , Enzimas de Conjugação de Ubiquitina/metabolismoRESUMO
p53 regulates multiple signaling pathways and maintains cell homeostasis under conditions of DNA damage and oxidative stress. Although USP7 has been shown to promote p53 stability via deubiquitination, the USP7-p53 activation mechanism has remained unclear. Here, we propose that DNA damage induces reactive oxygen species (ROS) production and activates ATM-CHK2, and CHK2 then phosphorylates USP7 at S168 and T231. USP7 phosphorylation is essential for its deubiquitination activity toward p53. USP7 also deubiquitinates CHK2 at K119 and K131, increasing CHK2 stability and creating a positive feedback loop between CHK2 and USP7. Compared to peri-tumor tissues, thyroid cancer and colon cancer tissues show higher CHK2 and phosphorylated USP7 (S168, T231) levels, and these levels are positively correlated. Collectively, our results uncover a phosphorylation-deubiquitination positive feedback loop involving the CHK2-USP7 axis that supports the stabilization of p53 and the maintenance of cell homeostasis.
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Quinase do Ponto de Checagem 2 , Estresse Oxidativo , Proteína Supressora de Tumor p53 , Peptidase 7 Específica de Ubiquitina , Ubiquitinação , Quinase do Ponto de Checagem 2/metabolismo , Peptidase 7 Específica de Ubiquitina/metabolismo , Humanos , Proteína Supressora de Tumor p53/metabolismo , Fosforilação , Retroalimentação Fisiológica , Dano ao DNA , Espécies Reativas de Oxigênio/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Transdução de Sinais , Linhagem Celular Tumoral , Estabilidade Proteica , AnimaisRESUMO
This article studies the tracking problem of a class of heterogeneous linear minimum-phase discrete-time multiagent systems (MASs) with unknown agent parameters in the presence of bounded disturbances. By introducing a distributed adaptive observer and a reference model, a novel framework is proposed to convert the complicated cooperative tracking problem of unknown heterogeneous MASs into a cooperative tracking problem of the reference models to the leader and a local robust model reference adaptive control problem. It is shown that under the adaptive controller designed based on the proposed framework, the tracking errors between the outputs of all the agents and the output of the leader converge to a residual set. It is also shown that the tracking errors will converge to zero asymptotically when the disturbances are absent. Compared with the existing related works, our main contribution is that the proposed framework could deal with the unknown MASs with arbitrary individual relative degrees and do not rely on any global graph information. Finally, the effectiveness of the proposed controller is illustrated by an example.
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Purpose: The lungs are a common metastatic organ in breast cancer, mainly due to blood metastasis. On imaging, most metastatic lesions show a peripheral round mass in the lung, occasionally with a hilar mass as the primary manifestation, showing burr and lobulation signs. This study aimed to investigate breast cancer patient's clinical characteristics and prognosis with two different metastatic sites in the lung. Methods: We retrospectively analyzed patients admitted to the First Hospital of Jilin University between 2016 and 2021 diagnosed with breast cancer lung metastases. Forty breast cancer patients with hilar metastases (HM) and 40 patients with peripheral lung metastases (PLM) were matched 1:1 using a pairing method. To analyze the patient's prognosis, the clinical characteristics of patients with two different metastatic sites were compared using the chi-square test, Kaplan-Meier curve, and Cox proportional hazards model. Results: The median follow-up time was 38 months (2-91 months). The median age of patients with HM was 56 years (25-75 years), and that of patients with PLM was 59 years (44-82 years). The median overall survival (mOS) was 27 months in the HM group and 42 months in the PLM group (p = 0.001). The results of the Cox proportional hazards model showed that the histological grade (hazard ratio = 2.741, 95% confidence interval 1.442-5.208, p = 0.002) was a prognostic factor in the HM group. Conclusion: The number of young patients in the HM group was higher than that in the PLM group, with higher Ki-67 indexes and histological grades. Most patients had mediastinal lymph node metastasis, with shorter DFI and OS and poor prognosis.
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Fibrinolysis is a bleeding disorder characterized by hypofibrinogenemia caused by abnormal activation of fibrinolytic system function. Patients with cancer are prone to hypercoagulable and should be vigilant for the risk of venous thrombosis. However, patients with tumors in which bleeding is the first manifestation are relatively rare. The present study reports the case of a 52-year-old woman with metastatic breast cancer with acquired hyperfibrinolysis as the first manifestation. Hyperfibrinolysis is an important sign and manifestation of disease progression. In this case, fibrinogen was used as a sensitive biomarker of tumor burden to specifically predict the efficacy of the antitumor therapy. Effective antitumor therapy can improve the hyperfibrinolysis of patients, and so the fibrinogen levels gradually increased. In conclusion, the present case showed acquired hyperfibrinolysis with bleeding symptoms, which is an uncommon paraneoplastic phenomenon in breast cancer, especially when combined with bone marrow metastasis, as in the present case. Timely diagnosis and treatment of the primary disease is the fundamental way to improve hyperfibrinolysis. As an effective biomarker, fibrinogen level predicts the changes in a patient's illness and guides the clinical diagnosis and treatment process.
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Spinal cord injury (SCI) has considerable impact on patient physical, mental, and financial health. Secondary SCI is associated with inflammation, vascular destruction, and subsequent permanent damage to the nervous system. Mesenchymal stem cells (MSCs) have anti-inflammatory properties, promoting vascular regeneration and the release neuro-nutrients, and are a promising strategy for the treatment of SCI. Preclinical studies have shown that MSCs promote sensory and motor function recovery in rats. In clinical trials, MSCs have been reported to improve the American Spinal Injury Association (ASIA) sensory and motor scores. However, the effectiveness of MSCs in treating patients with SCI remains controversial. MSCs promote tumorigenesis and ensuring the survival of MSCs in the hostile environment of SCI is challenging. In this article we examine the evidence on the pathophysiological changes occurring after SCI. We then review the underlying mechanisms of MSCs in the treatment of SCI and summarize the potential application of MSCs in clinical practice. Finally, we highlight the challenges surrounding the use of MSCs in the treatment of SCI and discuss future applications.
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Células-Tronco Mesenquimais , Traumatismos da Medula Espinal , Ratos , Animais , Traumatismos da Medula Espinal/terapia , Células-Tronco Mesenquimais/fisiologiaRESUMO
Objective: The surgical treatment of the primary site has been a subject of controversy in patients with de novo metastatic breast cancer. In recent years, studies using large databases and retrospective analyses have provided evidence of the survival benefits of localized surgery for these patients. However, due to the improved prognosis associated with novel antitumor agents and the widespread use of anti-HER2 therapy, it is important to investigate the role of primary site surgery in the context of new drug treatments for stage IV HER2-positive breast cancer. Methods: This retrospective analysis included patients with metastatic breast cancer at diagnosis who were consulted at the First Hospital of Jilin University between 2016 and 2022. We compared the patients' clinical and pathological characteristics, treatment regimens, and prognosis between the surgery and non-surgery groups. Results: A total of 96 patients with stage IV HER2-positive breast cancer were included in the study, with 24 patients (25%) undergoing surgery for the primary lesion. Patients with lower Eastern Cooperative Oncology Group (ECOG) scores, earlier T-stage, metastases confined to one organ/site, and fewer metastases were more likely to undergo surgery. Patients in the surgical group had longer progression-free survival (median 25.7 vs. 15.9 months, p=0.073) and overall survival (median 79.1 vs. 48 months, p=0.073) compared to patients in the non-surgical group, however, there was no statistical difference. Univariate and multivariate Cox regression analysis suggested that the choice of first-line targeted therapy regimens rather than surgical treatment influenced the patients' prognoses. In the subgroup of patients receiving first-line targeted therapy with trastuzumab plus pertuzumab, the decision to undergo surgery on the primary site did not have a statistically significant effect on prognosis. Conclusion: Primary site surgery does not improve the prognosis of de novo stage IV HER2-positive breast cancer. In the era of anti-HER2 therapy, primary surgery is not recommended, except in exceptional circumstances.
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Intervertebral disc degeneration (IVDD) is one of the leading causes of lower back pain. Although IVDD cannot directly cause death, it can cause pain, psychological burdens, and economic burdens to patients. Current conservative treatments for IVDD can relieve pain but cannot reverse the disease. Patients who cannot tolerate pain usually resort to a strategy of surgical resection of the degenerated disc. However, the surgical removal of IVDD can affect the stability of adjacent discs. Furthermore, the probability of the reherniation of the intervertebral disc (IVD) after surgery is as high as 21.2%. Strategies based on tissue engineering to deliver stem cells for the regeneration of nucleus purposes (NP) and annulus fibrosus (AF) have been extensively studied. The developed biomaterials not only locally withstand the pressure of the IVD but also lay the foundation for the survival of stem cells. However, the structure of IVDs does not provide sufficient nutrients for delivered stem cells. The role of immune mechanisms in IVDD has recently become clear. In IVDD, the IVD that was originally in immune privilege prevents the attack of immune cells (mainly effector T cells and macrophages) and aggravates the disease. Immune regulatory and inflammatory factors released by effector T cells, macrophages, and the IVD further aggravate IVDD. Reversing IVDD by regulating the inflammatory microenvironment is a potential approach for the treatment of the disease. However, the biological factors modulating the inflammatory microenvironment easily degrade in vivo. It makes it possible for different biomaterials to modulate the inflammatory microenvironment to repair IVDD. In this review, we have discussed the structures of IVDs and the immune mechanisms underlying IVDD. We have described the immune mechanisms elicited by different biological factors, including tumor necrosis factors, interleukins, transforming growth factors, hypoxia-inducible factors, and reactive oxygen species in IVDs. Finally, we have discussed the biomaterials used to modulate the inflammatory microenvironment to repair IVDD and their development.
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Degeneração do Disco Intervertebral , Disco Intervertebral , Humanos , Materiais Biocompatíveis/metabolismo , Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/patologia , Dor/metabolismo , Fatores Biológicos/metabolismoRESUMO
Gastric cancer has a high incidence rate, significantly threatening patients' health. Gastric histopathology images can reliably diagnose related diseases. Still, the data volume of histopathology images is too large, making misdiagnosis or missed diagnosis easy. The classification model based on deep learning has made some progress on gastric histopathology images. However, traditional convolutional neural networks (CNN) generally use pooling operations, which will reduce the spatial resolution of the image, resulting in poor prediction results. The image feature in previous CNN has a poor perception of details. Therefore, we design a dilated CNN with a late fusion strategy (DCNNLFS) for gastric histopathology image classification. The DCNNLFS model utilizes dilated convolutions, enabling it to expand the receptive field. The dilated convolutions can learn the different contextual information by adjusting the dilation rate. The DCNNLFS model uses a late fusion strategy to enhance the classification ability of DCNNLFS. We run related experiments on a gastric histopathology image dataset to verify the excellence of the DCNNLFS model, where the three metrics Precision, Accuracy, and F1-Score are 0.938, 0.935, and 0.959.
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Understanding the mechanisms regulating PD-L1 expression in hepatocellular carcinoma (HCC) is important to improve the response rate to PD-1/PD-L1 blockade therapy. Here, we show that DKK1 expression is positively associated with PD-L1 expression and inversely correlated with CD8+ T cell infiltration in human HCC tumor specimens. In a subcutaneous xenograft tumor model, overexpression of DKK1 significantly promotes tumor growth, tumoral PD-L1 expression, but reduces tumoral CD8+ T cell infiltration; whereas knockdown of DKK1 has opposite effects. Moreover, enforced expression of DKK1 dramatically promotes PD-L1 expression, Akt activation, ß-catenin phosphorylation and total protein expression in HCC cells. By contrast, knockdown of DKK1 inhibits all, relative to controls. In addition, CKAP4 depletion, Akt inhibition, or ß-catenin depletion remarkably abrogates DKK1 overexpression-induced transcriptional expression of PD-L1 in HCC cells. Reconstituted expression of the active Akt1 largely increased PD-L1 transcriptional expression in HCC cells. Similarly, expression of WT ß-catenin, but not the phosphorylation-defective ß-catenin S552A mutant, significantly promotes PD-L1 expression. Correlation analysis of human HCC tumor specimens further revealed that DKK1 and PD-L1 expression were positively correlated with p-ß-catenin expression. Together, our findings revealed that DKK1 promotes PD-L1 expression through the activation of Akt/ß-catenin signaling, providing a potential strategy to enhance the clinical efficacy of PD-1/PD-L1 blockade therapy in HCC patients.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , beta Catenina/metabolismo , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Neoplasias Hepáticas/metabolismo , Receptor de Morte Celular Programada 1 , Proteínas Proto-Oncogênicas c-akt , Evasão TumoralRESUMO
Oxidative stress-induced autophagy helps to prevent cellular damage and to maintain homeostasis. However, the regulatory pathway that initiates autophagy remains unclear. We previously showed that reactive oxygen species (ROS) function as signaling molecules to activate the ATM-CHK2 pathway and promote autophagy. Here, we find that the E3 ubiquitin ligase TRIM32 functions downstream of ATM-CHK2 to regulate ATG7 ubiquitination. Under metabolic stress, ROS induce ATM phosphorylation at S1981, which in turn phosphorylates CHK2 at T68. We show that CHK2 binds and phosphorylates TRIM32 at the S55 site, which then mediates K63-linked ubiquitination of ATG7 at the K45 site to initiate autophagy. In addition, Chk2-/- mice show an aggravated infarction phenotype and reduced phosphorylation of TRIM32 and ubiquitination of ATG7 in a stroke model. We propose a molecular mechanism for autophagy initiation by ROS via the ATM-CHK2-TRIM32-ATG7 axis to maintain intracellular homeostasis and to protect cells exposed to pathological conditions from stress-induced tissue damage.