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Despite the success of immunotherapy in treating hepatocellular carcinoma (HCC), HCC remains a severe threat to health. Here, a crucial transcription factor, SOX12, is revealed that induces the immunosuppression of liver tumor microenvironment. Overexpressing SOX12 in HCC syngeneic models increases intratumoral regulatory T-cell (Treg) infiltration, decreases CD8+T-cell infiltration, and hastens HCC metastasis. Hepatocyte-specific SOX12 knockout attenuates DEN/CCl4-induced HCC progression and metastasis, whereas hepatocyte-specific SOX12 knock-in accelerates these effects. Mechanistically, SOX12 transcriptionally activates C-C motif chemokine ligand 22 (CCL22) expression to promote the recruitment and suppressive activity of Tregs. Moreover, SOX12 transcriptionally upregulates CD274 expression to suppress CD8+T-cell infiltration. Either knockdown of CCL22 or PD-L1 dampens SOX12-mediated HCC metastasis. Blocking of CC chemokine receptor 4 (CCR4), a receptor for CCL22, by inhibitor C-021 or Treg-specific knockout of CCR4 inhibits SOX12-mediated HCC metastasis. Transforming growth factor-ß1 (TGF-ß1)/TGFßR1-Smad2/3/4 is identified as a key upstream signaling for SOX12 overexpression in HCC cells. Combining C-021 or TGFßR1 inhibitor galunisertib with anti-PD-L1 exhibits an enhanced antitumor effect in two HCC models. Collectively, the findings demonstrate that SOX12 contributes to HCC immunosuppression through the CCL22/CCR4-Treg and PD-L1-CD8+T axes. Blocking of CCR4 or TGFßR1 improves the efficacy of anti-PD-L1 in SOX12-mediated HCC.
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BACKGROUND AND AIMS: RNA splicing is an essential step in regulating the gene posttranscriptional expression. Serine/arginine-rich splicing factors (SRSFs) are splicing regulators with vital roles in various tumors. Nevertheless, the expression patterns and functions of SRSFs in hepatocellular carcinoma (HCC) are not fully understood. METHODS: Flow cytometry and immunofluorescent staining were used to determine the CD8+T cell infiltration. Orthotopic HCC model, lung metastasis model, DEN/CCl4 model, Srsf10â³hep model, and Srsf10HepOE model were established to evaluate the role of SRSF10 in HCC and the efficacy of combination treatment. RESULTS: SRSF10 was one of the most survival-relevant genes among SRSF members and was an independent prognostic factor for HCC. SRSF10 facilitated HCC growth and metastasis by suppressing CD8+T cell infiltration. Mechanistically, SRSF10 down-regulated the p53 protein by preventing the exon 6 skipping (exon 7 in mouse) mediated degradation of MDM4 transcript, thus inhibiting CD8+T cell infiltration. Elimination of CD8+T cells or overexpression of MDM4 removed the inhibitory role of SRSF10 knockdown in HCC growth and metastasis. SRSF10 also inhibited the IFNα/γ signaling pathway and promoted the HIF1α-mediated up-regulation of PD-L1 in HCC. Hepatocyte-specific SRSF10 deficiency alleviated the DEN/CCl4-induced HCC progression and metastasis, whereas hepatocyte-specific SRSF10 overexpression deteriorated these effects. Finally, SRSF10 knockdown enhanced the anti-PD-L1-mediated anti-tumor activity. CONCLUSIONS: SRSF10 promoted HCC growth and metastasis by repressing CD8+T cell infiltration mediated by the MDM4-p53 axis. Furthermore, SRSF10 suppressed the IFNα/γ signaling pathway and induced the HIF1α signal mediated PD-L1 up-regulation. Targeting SRSF10 combined with anti-PD-L1 therapy showed promising efficacy.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Camundongos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Fatores de Processamento de Serina-Arginina/genética , Fatores de Processamento de Serina-Arginina/metabolismo , Proteínas Repressoras/metabolismo , Proteínas de Ciclo Celular/metabolismoRESUMO
Food safety is a pressing concern for human society, as it directly impacts people's lives, while food freshness serves as one of the most crucial indicators in ensuring food safety. There exist diverse techniques for monitoring food freshness, among which intelligent packaging based on artificial intelligence technology boasts the advantages of low cost, high efficiency, fast speed and wide applicability; however, it is currently underutilized. By analyzing the current research status of intelligent packaging both domestically and internationally, this paper provides a clear classification of intelligent packaging technology. Additionally, it outlines the advantages and disadvantages of using intelligent packaging technology for food freshness detection methods, while summarizing the latest research progress in applying artificial intelligence-based technologies to food freshness detection through intelligent packaging. Finally, the author points out the limitations of the current research, and anticipates future developments in artificial intelligence technology for assisting freshness detection in intelligent packaging. This will provide valuable insights for the future development of intelligent packaging in the field of food freshness detection.
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This study reported the production of pH-responsive films based on 8 wt% polyvinyl alcohol solution/0.2 wt% agar solution incorporated with cochineal-loaded starch particles (CSN) (2, 4, 6 and 8 wt% on agar basis) by a casting process. Results revealed that CSN presented obvious color changes over the pH range of 2-12. FTIR, XRD spectra and SEM micrographs presented that the incorporation of CSN formed new hydrogen bonds with a matrix and a tighter network structure. A certain improvement was observed in the color stability, swelling index and functional properties (antimicrobial and antioxidant activities) but water solubility, water vapor permeability and water contact angle of the pH-responsive films were decreased by the addition of CSN. The release of cochineal was a rate-limiting step following the Korsmeyer-Peppas model. The agar/polyvinyl alcohol film containing 6% CSN (PVA/GG-6) exhibited the best sensitivity for ammonia detection and its limit of detection was 35.4 ppm (part per million) for ammonia. The application trials showed that the PVA/GG-6 film presented different color changes for pork freshness. Hence, these pH-responsive films can be used as potential packaging materials for tracking the freshness of protein-rich fresh food in a non-destructive way.
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BACKGROUND & AIMS: Metastasis remains the major reason for the high mortality of patients with hepatocellular carcinoma (HCC). This study was designed to investigate the role of E-twenty-six-specific sequence variant 4 (ETV4) in promoting HCC metastasis and to explore a new combination therapy strategy for ETV4-mediated HCC metastasis. METHODS: PLC/PRF/5, MHCC97H, Hepa1-6, and H22 cells were used to establish orthotopic HCC models. Clodronate liposomes were used to clear macrophages in C57BL/6 mice. Gr-1 monoclonal antibody was used to clear myeloid-derived suppressor cells (MDSCs) in C57BL/6 mice. Flow cytometry and immunofluorescence were used to detect the changes of key immune cells in the tumour microenvironment. RESULTS: ETV4 expression was positively related to higher tumour-node-metastasis (TNM) stage, poor tumour differentiation, microvascular invasion, and poor prognosis in human HCC. Overexpression of ETV4 in HCC cells transactivated PD-L1 and CCL2 expression, which increased tumour-associated macrophage (TAM) and MDSC infiltration and inhibited CD8+ T-cell accumulation. Knockdown of CCL2 by lentivirus or CCR2 inhibitor CCX872 treatment impaired ETV4-induced TAM and MDSC infiltration and HCC metastasis. Furthermore, FGF19/FGFR4 and HGF/c-MET jointly upregulated ETV4 expression through the ERK1/2 pathway. Additionally, ETV4 upregulated FGFR4 expression, and downregulation of FGFR4 decreased ETV4-enhanced HCC metastasis, which created a FGF19-ETV4-FGFR4 positive feedback loop. Finally, anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib prominently inhibited FGF19-ETV4 signalling-induced HCC metastasis. CONCLUSIONS: ETV4 is a prognostic biomarker, and anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib may be effective strategies to inhibit HCC metastasis. IMPACT AND IMPLICATIONS: Here, we reported that ETV4 increased PD-L1 and chemokine CCL2 expression in HCC cells, which resulted in TAM and MDSC accumulation and CD8+ T-cell inhibition to facilitate HCC metastasis. More importantly, we found that anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib markedly inhibited FGF19-ETV4 signalling-mediated HCC metastasis. This preclinical study will provide a theoretical basis for the development of new combination immunotherapy strategies for patients with HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Camundongos , Animais , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Camundongos Endogâmicos C57BL , Transdução de Sinais , Macrófagos/metabolismo , Linhagem Celular Tumoral , Microambiente Tumoral , Proteínas Proto-Oncogênicas c-ets/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Quimiocina CCL2 , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/metabolismoRESUMO
A novel colorimetric film was developed from polyvinyl alcohol/sodium carboxymethyl cellulose (PVA/CMC-Na, CPA) incorporated with anthocyanins (AHO) or betacyanins (BTA) or AHO and BTA mixtures (in the mass ratios of 2:2, 3:1, 1:3) for intelligent packaging. Fourier transform infrared (FTIR) and scanning electron microscope (SEM) illustrated that AHO/BTA were immobilized into CPA network and improved compatibility of PVA and CMC-Na. The incorporation of AHO/BTA increased the tensile strength (TS), elongation at break (EAB), thickness and water solubility (WS) of the sample but decreased the crystallinity and swelling index (SI) of the sample. Furthermore, the colorimetric films presented antioxidant activity besides antibacterial activity against Escherichia coli and Staphylococcus aureus. The colorimetric film incorporated with AHO and BTA at a mass ratio of 3:1 indicated different colors to represent the freshness of pork. The novel colorimetric film possesses great potential in intelligent packaging for monitoring the real-time freshness of pork products.
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Carne de Porco , Carne Vermelha , Animais , Suínos , Álcool de Polivinil , Antocianinas , Carboximetilcelulose Sódica , Betacianinas , Colorimetria , Embalagem de Alimentos , Escherichia coli , Sódio , Concentração de Íons de HidrogênioRESUMO
Introduction: Necroptosis, a type of programmed cell death, has recently been extensively studied as an important pathway regulating tumor development, metastasis, and immunity. However, the expression patterns of necroptosis-related genes (NRGs) in colorectal cancer (CRC) and their potential roles in the tumor microenvironment (TME) have not been elucidated. Methods: We explored the expression patterns of NRGs in 1247 colorectal cancer samples from genetics and transcriptional perspective. Based on a consensus clustering algorithm, we identified NRG molecular subtypes and gene subtypes, respectively. Furthermore, we constructed a necroptosis-related signature for predicting overall survival time and verified the predictive ability of the model. Using the ESTIMATE, CIBERSORT, and ssGSEA algorithms, we assessed the association between the above subtypes, scores and immune infiltration. Results: Most NRGs were differentially expressed between CRC tissues and normal tissues. We found that distinct subtypes exhibited different NRGs expression, patients' prognosis, immune checkpoint gene expression, and immune infiltration characteristics. The scores calculated from the necroptosis-related signature can be used to classify patients into high-risk and low-risk groups, with the high-risk group corresponding to reduced immune cell infiltration and immune function, and a greater risk of immune dysfunction and immune escape. Discussion: Our comprehensive analysis of NRGs in CRC demonstrated their potential role in clinicopathological features, prognosis, and immune infiltration in the TME. These findings help us deepen our understanding of NRGs and the tumor microenvironment landscape, and lay a foundation for effectively assessing patient outcomes and promoting more effective immunotherapy.
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Neoplasias Colorretais , Necroptose , Humanos , Necroptose/genética , Algoritmos , Apoptose , Análise por Conglomerados , Neoplasias Colorretais/genética , Microambiente Tumoral/genéticaRESUMO
BACKGROUND: Metastasis is a major determinant of death in patients with hepatocellular carcinoma (HCC). Dissecting key molecular mediators that promote this malignant feature may help yield novel therapeutic insights. Here, we investigated the role of E-twenty-six transformation-specific variant 1 (ETV1), a member of the E-twenty-six transformation-specific (ETS) family, in HCC metastasis. METHODS: The clinical significance of ETV1 and its target genes in two independent cohorts of HCC patients who underwent curative resection were assessed by Kaplan-Meier analysis and Multivariate Cox proportional hazards model. Luciferase reporter assay and chromatin immunoprecipitation assay were used to detect the transcriptional regulation of target gene promoters by ETV1. The effect of ETV1 on invasiveness and metastasis of HCC were detected by transwell assays and the orthotopically metastatic model. RESULTS: ETV1 expression was frequently elevated in human HCC specimens. Increased ETV1 expression was associated with the malignant biological characteristics and poor prognosis of HCC patients. ETV1 facilitated invasion and metastasis of HCC cells in vitro and in vivo. Mechanistically, ETV1 promoted HCC metastasis via upregulating metastasis-related genes, including protein tyrosine kinase 2 (PTK2) and MET. Down-regulated the expression of PTK2 or tyrosine protein kinase Met (c-MET) decreased ETV1-mediated HCC metastasis. Hepatocyte growth factor (HGF) upregulated ETV1 expression through activating c-MET-ERK1/2-ELK1 pathway. Notably, in two independent cohorts, patients with positive coexpression of ETV1/PTK2 or ETV1/c-MET had worse prognosis. Furthermore, the combination of PTK2 inhibitor defactinib and c-MET inhibitor capmatinib significantly suppressed HCC metastasis induced by ETV1. CONCLUSION: This study uncovers functional and prognostic roles for ETV1 in HCC and exposes a positive feedback loop of HGF-ERK1/2-ETV1-c-MET. Targeting this pathway may provide a potential therapeutic intervention for ETV1-overexpressing HCC.
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Carcinoma Hepatocelular , Proteínas de Ligação a DNA , Neoplasias Hepáticas , Fatores de Transcrição , Carcinoma Hepatocelular/patologia , Proteínas de Ligação a DNA/genética , Quinase 1 de Adesão Focal/genética , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Neoplasias Hepáticas/patologia , Prognóstico , Fatores de Transcrição/genéticaRESUMO
RNA-binding protein (RBP) dysregulation is functionally linked to several human diseases, including neurological disorders, cardiovascular disease, and cancer. Heterogeneous nuclear ribonucleoproteins (hnRNPs) are a diverse family of RBPs involved in nucleic acid metabolism. A growing body of studies has shown that the dysregulated hnRNPs play important roles in tumorigenesis. Here, we found that heterogeneous nuclear ribonucleoprotein C (C1/C2) (HNRNPC) had good performance in distinguishing between hepatocellular carcinoma (HCC) and normal liver tissues through bioinformatics analysis. Further investigation revealed that HNRNPC was significantly correlated with multiple malignant characteristics of HCC, including tumor size, microvascular invasion, tumor differentiation, and TNM stage. Patients with HCC with positive HNRNPC expression exhibited decreased overall survival and increased recurrence rate. HNRNPC downregulation inhibited HCC invasion and metastasis. The decreased expression of hypoxia inducible factor 1 subunit alpha (HIF1A) was identified as the molecular mechanism underlying HNRNPC downregulation-inhibited HCC metastasis by RNA sequencing. Mechanistically, HNRNPC downregulation decreased HIF1A expression by destabilizing HIF1A mRNA. HIF1A overexpression rescued the decrease in invasiveness and metastasis of HCC induced by HNRNPC downregulation. Additionally, interleukin (IL)-6/STAT3 signaling upregulated HNRNPC expression in HCC cells, and knockdown of HNRNPC significantly inhibited IL-6/STAT3-enhanced HCC metastasis. Furthermore, anti-IL-6 antibody siltuximab significantly inhibited IL-6-mediated HCC metastasis. In summary, our research revealed the clinical value, functional role, and molecular mechanism of HNRNPC in HCC and showed the potential of HNRNPC as a biomarker for diagnosis, prognosis, and further therapeutic targets for HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas Grupo C/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo C/metabolismo , Humanos , Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Interleucina-6/metabolismo , Neoplasias Hepáticas/patologia , Metástase Neoplásica , RNA Mensageiro , Proteínas de Ligação a RNA/genética , Fator de Transcrição STAT3/metabolismoRESUMO
Recently, due to the enhancement in consumer awareness of food safety, considerable attention has been paid to intelligent packaging that displays the quality status of food through color changes. Natural food colorants show useful functionalities (antibacterial and antioxidant activities) and obvious color changes due to their structural changes in different acid and alkali environments, which could be applied to detect these acid and alkali environments, especially in the preparation of intelligent packaging. This review introduces the latest research on the progress of pH-responsive freshness indicators based on natural food colorants and biodegradable polymers for monitoring packaged food quality. Additionally, the current methods of detecting food freshness, the preparation methods for pH-responsive freshness indicators, and their applications for detecting the freshness of perishable food are highlighted. Subsequently, this review addresses the challenges and prospects of pH-responsive freshness indicators in food packaging, to assist in promoting their commercial application.
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The effect of targeted therapy for metastatic hepatocellular carcinoma (HCC) is still unsatisfactory. Exploring the underlying mechanism of HCC metastasis is favorable to provide new therapeutic strategies. T-box (TBX) transcription factor family genes, which are crucial regulators in embryo and organ development, are vital for regulating tumor initiation, growth and metastasis. Here we explored the role of TBX19 in HCC metastasis, which is one of the most upregulated TBX family genes in human HCC tissues. TBX19 expression was markedly upregulated in HCC tissues and elevated TBX19 expression predicted poor prognosis. Overexpression of TBX19 enhanced HCC metastasis through upregulating epidermal growth factor receptor (EGFR) and Rac family small GTPase 1 (RAC1) expression. Downregulation of EGFR and RAC1 inhibited TBX19-mediated HCC metastasis, while upregulation of EGFR and RAC1 restored inhibition of HCC metastasis mediated by TBX19 knockdown. Furthermore, epidermal growth factor (EGF)/EGFR signaling upregulated TBX19 expression via the extracellular signal-regulated kinase (ERK)/nuclear factor (NF)-kB axis. Besides, the combined application of EGFR inhibitor Erlotinib and RAC1 inhibitor NSC23766 markedly inhibited TBX19-mediated HCC metastasis. In HCC cohorts, TBX19 expression was positively associated with EGFR and RAC1 expression. Patients with positive coexpression of TBX19/EGFR or TBX19/RAC1 displayed the poorest prognosis. In conclusion, EGF/EGFR signaling upregulated TBX19 expression via ERK/NF-kB pathway and TBX19 fostered HCC metastasis by enhancing EGFR and RAC1 expression, which formed an EGF-TBX19-EGFR positive feedback loop. Targeting this signaling pathway may offer a potential therapeutic strategy to efficiently restrain TBX19-mediated HCC metastasis.
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Carcinoma Hepatocelular , Receptores ErbB , Neoplasias Hepáticas , Proteínas rac1 de Ligação ao GTP , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Fator de Crescimento Epidérmico/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Neoplasias Hepáticas/patologia , Metástase Neoplásica , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismoRESUMO
Metastasis is the predominant reason for high mortality of hepatocellular carcinoma (HCC) patients. It is critical to explore the molecular mechanism underlying HCC metastasis. Here, we reported that transcription factor One Cut homeobox 2 (ONECUT2) functioned as an oncogene to facilitate HCC metastasis. Elevated ONECUT2 expression was positively correlated with increased tumor number, tumor encapsulation loss, microvascular invasion, poor tumor differentiation, and advanced TNM stage. Mechanistically, ONECUT2 directly bound to the promoters of fibroblast growth factor 2 (FGF2) and ATP citrate lyase (ACLY) and transcriptionally upregulated their expression. Knockdown of FGF2 and ACLY inhibited ONECUT2-mediated HCC metastasis, whereas upregulation of FGF2 and ACLY rescued ONECUT2 knockdown-induced suppression of HCC metastasis. ONECUT2 expression was positively correlated with FGF2 and ACLY expression in human HCC tissues. HCC patients with positive coexpression of ONECUT2/FGF2 or ONECUT2/ACLY exhibited the worst prognosis. In addition, FGF2 upregulated ONECUT2 expression through the FGFR1/ERK/ELK1 pathway, which formed an FGF2-FGFR1-ONECUT2 positive feedback loop. Knockdown of ONECUT2 inhibited FGF2-induced HCC metastasis. Furthermore, the combination of FGFR1 inhibitor PD173074 with ACLY inhibitor ETC-1002 markedly suppressed ONECUT2-mediated HCC metastasis. In summary, ONECUT2 was a potential prognostic biomarker in HCC and targeting this oncogenic signaling pathway may provide an efficient therapeutic strategy against HCC metastasis.
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ATP Citrato (pro-S)-Liase/metabolismo , Carcinoma Hepatocelular/genética , Fator 2 de Crescimento de Fibroblastos/metabolismo , Proteínas de Homeodomínio/genética , Neoplasias Hepáticas/genética , Oncogenes/genética , Fatores de Transcrição/genética , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Pessoa de Meia-Idade , Metástase Neoplásica , Regulação para CimaRESUMO
The Coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an international public health emergency. Although respiratory symptoms predominate the clinical manifestations of COVID-19, gastrointestinal symptoms have been observed in a subset of patients. Notably, some patients have nausea/vomiting as the first clinical manifestation of COVID-19, which is often overlooked by people. It is now clear that not only the lungs, the gastrointestinal tract could also be attacked by SARS-CoV-2. Its host receptor angiotensin-converting enzyme 2 (ACE2), which acts as a gateway to infection, has been found to be highly expressed in the gastrointestinal epithelium and may lead to the development of nausea/vomiting. Raise awareness of these symptoms and take timely intervention would help people combat the pandemic. This review discussed epidemiology, mechanisms, management, and prevention of COVID-19 related nausea and vomiting.
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COVID-19/fisiopatologia , Náusea/virologia , SARS-CoV-2/fisiologia , Vômito/virologia , Enzima de Conversão de Angiotensina 2 , COVID-19/complicações , COVID-19/terapia , COVID-19/virologia , Humanos , Náusea/epidemiologia , Vômito/epidemiologiaRESUMO
BACKGROUND AND AIMS: Because of a paucity of effective treatment options, metastasis is still a major cause for HCC-associated mortality. The molecular mechanism of inflammation-induced HCC metastasis is open for study. Here, we characterized the function of solute carrier family 7 member 11 (SLC7A11) in inflammation-related HCC metastasis and probed therapy strategies for this subpopulation of patients. APPROACH AND RESULTS: Elevated expression of SLC7A11 was positively correlated with poor tumor differentiation, and higher tumor-nodule-metastasis stage, and indicated poor prognosis in human HCC. SLC7A11 increased HIF1α expression through reducing α-ketoglutarate (αKG) level by exporting glutamate. SLC7A11 up-regulated programmed death ligand 1 (PD-L1) and colony-stimulating factor 1 (CSF1) expression through αKG-HIF1α cascade. SLC7A11 overexpression in HCC cells promoted intratumoral tumor-associated macrophage (TAM) and myeloid-derived suppressor cell (MDSC) infiltration through the CSF1/colony-stimulating factor 1 receptor (CSF1R) axis, whereas knockdown of CSF1 attenuated SLC7A11-mediated intratumoral TAM and MDSC infiltration and HCC metastasis. Depletion of either TAMs or MDSCs decreased SLC7A11-mediated HCC metastasis. Furthermore, the combination of CSF1R inhibitor BZL945 and anti-PD-L1 antibody blocked SLC7A11-induced HCC metastasis. In addition, IL-1ß up-regulated SLC7A11 expression through the interleukin-1 receptor type 1 (IL-1R1)/extracellular signal-regulated kinase/specificity protein 1 pathway. SLC7A11 knockdown impaired IL-1ß-promoted HCC metastasis. Anakinra, an IL-1R1 antagonist, reversed IL-1ß-promoted HCC metastasis. In human HCC tissues, SLC7A11 expression was positively associated with HIF1α, PD-L1, and CSF1 expression and intratumoral TAM and MDSC infiltration. CONCLUSIONS: IL-1ß-induced SLC7A11 overexpression up-regulated PD-L1 and CSF1 through the αKG/HIF1α axis, which promoted TAM and MDSC infiltration. Interruption of this oncogenic loop may provide a promising therapy strategy for the inhibition of SLC7A11-mediated HCC metastasis.
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Sistema y+ de Transporte de Aminoácidos/genética , Carcinoma Hepatocelular/imunologia , Interleucina-1beta/metabolismo , Neoplasias Hepáticas/imunologia , Sistema y+ de Transporte de Aminoácidos/metabolismo , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/terapia , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Seguimentos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Técnicas de Silenciamento de Genes , Hepatectomia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Ácidos Cetoglutáricos/metabolismo , Fígado/imunologia , Fígado/patologia , Fígado/cirurgia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/terapia , Fator Estimulador de Colônias de Macrófagos/metabolismo , Células Supressoras Mieloides/imunologia , Prognóstico , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/imunologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologiaRESUMO
Metastasis is the major reason for the high mortality of colorectal cancer (CRC) patients and its molecular mechanism remains unclear. Here, we report a novel role of Homeobox A13 (HOXA13), a member of the Homeobox (HOX) family, in promoting CRC metastasis. The elevated expression of HOXA13 was positively correlated with distant metastasis, higher AJCC stage, and poor prognosis in two independent CRC cohorts. Overexpression of HOXA13 promoted CRC metastasis whereas downregulation of HOXA13 suppressed CRC metastasis. Mechanistically, HOXA13 facilitated CRC metastasis by transactivating ATP-citrate lyase (ACLY) and insulin-like growth factor 1 receptor (IGF1R). Knockdown of ACLY and IGFIR inhibited HOXA13-medicated CRC metastasis, whereas ectopic overexpression of ACLY and IGFIR rescued the decreased CRC metastasis induced by HOXA13 knockdown. Furthermore, Insulin-like growth factor 1 (IGF1), the ligand of IGF1R, upregulated HOXA13 expression through the PI3K/AKT/HIF1α pathway. Knockdown of HOXA13 decreased IGF1-mediated CRC metastasis. In addition, the combined treatment of ACLY inhibitor ETC-1002 and IGF1R inhibitor Linsitinib dramatically suppressed HOXA13-mediated CRC metastasis. In conclusion, HOXA13 is a prognostic biomarker in CRC patients. Targeting the IGF1-HOXA13-IGF1R positive feedback loop may provide a potential therapeutic strategy for the treatment of HOXA13-driven CRC metastasis.
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ATP Citrato (pro-S)-Liase/metabolismo , Neoplasias Colorretais/metabolismo , Proteínas de Homeodomínio/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Fatores de Transcrição/metabolismo , ATP Citrato (pro-S)-Liase/antagonistas & inibidores , Idoso , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Ácidos Dicarboxílicos/farmacologia , Ácidos Graxos/farmacologia , Feminino , Células HEK293 , Xenoenxertos , Proteínas de Homeodomínio/antagonistas & inibidores , Humanos , Fator de Crescimento Insulin-Like I/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Metástase Neoplásica , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/metabolismo , Proteínas Recombinantes/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Regulação para CimaRESUMO
Background: Since metastasis remains the main reason for HCC-associated death, a better understanding of molecular mechanism underlying HCC metastasis is urgently needed. Here, we elucidated the role of Homeobox B5 (HOXB5), a member of the HOX transcriptional factor family, in promoting HCC metastasis. Method: The expression of HOXB5 and its functional targets fibroblast growth factor receptor 4 (FGFR4) and C-X-C motif chemokine ligand 1 (CXCL1) were detected by immunohistochemistry. Luciferase reporter and chromatin immunoprecipitation assays were performed to measure the transcriptional regulation of target genes by HOXB5. The effects of FGFR4 and CXCL1 on HOXB5-mediated metastasis were analyzed by an orthotopic metastasis model. Results: Elevated expression of HOXB5 had a positive correlation with poor tumour differentiation, higher TNM stage, and indicated unfavorable prognosis. Overexpression of HOXB5 promoted HCC metastasis through transactivating FGFR4 and CXCL1 expression, whereas knockdown of FGFR4 and CXCL1 decreased HOXB5-enhanced HCC metastasis. Moreover, HOXB5 overexpression in HCC cells promoted myeloid derived suppressor cells (MDSCs) infiltration through CXCL1/CXCR2 axis. Either depletion of MDSCs by anti-Gr1 or blocking CXCL1-CXCR2 axis by CXCR2 inhibitor impaired HOXB5-mediated HCC metastasis. In addition, fibroblast growth factor 19 (FGF19) contributed to the HOXB5 upregulation through PI3K/AKT/HIF1α pathway. Overexpression of FGF15 (an analog of FGF19 in mouse) promoted HCC metastasis, whereas knockdown of HOXB5 significantly inhibited FGF15-enhanced HCC metastasis in immunocompetent mice. HOXB5 expression was positively associated with CXCL1 expression and intratumoral MDSCs accumulation in human HCC tissues. Patients who co-expressed HOXB5/CXCL1 or HOXB5/CD11b exhibited the worst prognosis. Furthermore, the combination of FGFR4 inhibitor BLU-554 and CXCR2 inhibitor SB265610 dramatically decreased HOXB5-mediated HCC metastasis. Conclusion: HOXB5 was a potential prognostic biomarker in HCC patients and targeting this loop may provide a promising treatment strategy for the inhibition of HOXB5-mediated HCC metastasis.
Assuntos
Carcinoma Hepatocelular/genética , Quimiocina CXCL1/genética , Proteínas de Homeodomínio/genética , Neoplasias Hepáticas/genética , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/genética , Regulação para Cima/genética , Animais , Carcinoma Hepatocelular/patologia , Diferenciação Celular/genética , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Fosfatidilinositol 3-Quinases/genética , Prognóstico , Transdução de Sinais/genéticaRESUMO
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, ranking third in cancer deaths worldwide. Over the last decade, several studies have emphasized the development of tyrosine kinase inhibitors (TKIs) to target the aberrant pathways in HCC. However, the outcomes are far from satisfactory due to the increasing resistance and adverse effects. The family of fibroblast growth factor (FGF) and its receptors (FGFR) are involved in various biological processes, including embryogenesis, morphogenesis, wound repair, and cell growth. The aberrant FGF/FGFR signaling is also observed in multiple cancers, including HCC. Anti-FGF/FGFR provides delightful benefits for cancer patients, especially those with FGF signaling alteration. More and more multi-kinase inhibitors targeting FGF signaling, pan-FGFR inhibitors, and selective FGFR inhibitors are now under preclinical and clinical investigation. This review summarizes the aberrant FGF/FGFR signaling in HCC initiating, development and treatment status, and provide new insights into the treatment of HCC.
RESUMO
The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global public health challenge. Most patients do not experience severe complications, but approximately 25% of patients progress to acute respiratory distress syndrome (ARDS), and the mortality rate is approximately 5-7%. Clinical findings have determined several risk factors for severe complications and mortality in COVID-19 patients, such as advanced age, smoking, obesity, and chronic diseases. Obesity is a common and serious health problem worldwide that initiates a cascade of disorders, including hypertension, cardiovascular disease (CVD), diabetes mellitus, and chronic kidney disease (CKD). The presence of these disorders is linked to a more severe course of COVID-19. Given the "epidemic" of obesity worldwide and the importance of obesity in the progression of COVID-19, we investigated the mechanisms through which obesity increases the susceptibility to and severity of COVID-19 to support the selection of more appropriate therapies for individuals with obesity.