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Poly(ADP-ribosyl)ation (PARylation) is a critical posttranslational modification that plays a vital role in maintaining genomic stability via a variety of molecular mechanisms, including activation of replication stress and the DNA damage response. The nudix hydrolase NUDT16 was recently identified as a phosphodiesterase that is responsible for removing ADP-ribose units and that plays an important role in DNA repair. However, the roles of NUDT16 in coordinating replication stress and cell cycle progression remain elusive. Here, we report that SETD3, which is a member of the SET-domain containing protein (SETD) family, is a novel substrate for NUDT16, that its protein levels fluctuate during cell cycle progression, and that its stability is strictly regulated by NUDT16-mediated dePARylation. Moreover, our data indicated that the E3 ligase CHFR is responsible for the recognition and degradation of endogenous SETD3 in a PARP1-mediated PARylation-dependent manner. Mechanistically, we revealed that SETD3 associates with BRCA2 and promotes its recruitment to stalled replication fork and DNA damage sites upon replication stress or DNA double-strand breaks, respectively. Importantly, depletion of SETD3 in NUDT16-deficient cells did not further exacerbate DNA breaks or enhance the sensitivity of cancer cells to IR exposure, suggesting that the NUDT16-SETD3 pathway may play critical roles in the induction of tolerance to radiotherapy. Collectively, these data showed that NUDT16 functions as a key upstream regulator of SETD3 protein stability by reversing the ADP-ribosylation of SETD3, and NUDT16 participates in the resolution of replication stress and facilitates HR repair.
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ADP-Ribosilación , Neoplasias , Roturas del ADN de Doble Cadena , Daño del ADN , Reparación del ADN , Neoplasias/genética , Neoplasias/radioterapia , Poli(ADP-Ribosa) Polimerasa-1/genética , Procesamiento Proteico-Postraduccional , Humanos , Línea Celular , Pirofosfatasas/genética , Pirofosfatasas/metabolismo , Histona Metiltransferasas/genética , Histona Metiltransferasas/metabolismoRESUMEN
Drug resistance in cancer remains a major challenge in oncology, impeding the effectiveness of various treatment modalities. The nuclear factor-kappa B (NF-κB) signaling pathway has emerged as a critical player in the development of drug resistance in cancer cells. This comprehensive review explores the intricate relationship between NF-κB and drug resistance in cancer. We delve into the molecular mechanisms through which NF-κB activation contributes to resistance against chemotherapeutic agents, targeted therapies, and immunotherapies. Additionally, we discuss potential strategies to overcome this resistance by targeting NF-κB signaling, such as small molecule inhibitors and combination therapies. Understanding the multifaceted interactions between NF-κB and drug resistance is crucial for the development of more effective cancer treatment strategies. By dissecting the complex signaling network of NF-κB, we hope to shed light on novel therapeutic approaches that can enhance treatment outcomes, ultimately improving the prognosis for cancer patients. This review aims to provide a comprehensive overview of the current state of knowledge on NF-κB and its role in drug resistance, offering insights that may guide future research and therapeutic interventions in the fight against cancer.
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FN-kappa B , Neoplasias , Humanos , FN-kappa B/genética , FN-kappa B/metabolismo , Transducción de Señal , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Resistencia a Medicamentos , Resistencia a Antineoplásicos/genética , Línea Celular TumoralRESUMEN
This review aims to provide insight into the role of N6-methyladenosine (m6A) modification in neoplastic immunity and subsequent tumorigenesis. m6A modification, which is catalyzed by methyltransferases, demethylases and reader proteins, has emerged as a widespread regulatory mechanism that controls immune-related gene expression and immune reactions during tumorigenesis. Aberrant m6A modification changes the neoplastic immune response in multiple cancers by regulating immune cell infiltration, tumor-promoting inflammation, immunosuppression, immune surveillance, and antitumor immune responses. m6A modification affects immune cell recruitment and cancer-promoting inflammation in hepatocellular carcinoma (HCC) to alter the progression of HCC. m6A modification has been implicated in the infiltration of immune cells and the activation of immune pathways, changing the proliferation and metastasis of gastric cancer. Immune surveillance and the antitumor immune response in breast cancer were enhanced via m6A modification, which inhibited tumor proliferation. m6A modification participates in neoplastic immunoregulation to influence tumor progression.
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Adenosina , Neoplasias/inmunología , Adenosina/análogos & derivados , Adenosina/metabolismo , Animales , Carcinogénesis , Transformación Celular Neoplásica , Humanos , Inmunidad , Inflamación , Neoplasias/genética , Neoplasias/patología , Microambiente TumoralRESUMEN
B7 homolog 3 (B7-H3) has been proven to be involved in tumorigenesis. An elucidation of its role and underlying mechanisms is essential to an understanding of tumorigenesis and the development of effective clinical applications. B7-H3 is abnormally overexpressed in many types of cancer and is generally associated with a poor clinical prognosis. B7-H3 inhibits the initiation of the "caspase cascade" by the Janus kinase/signal transducers and activators of transcription pathway to resist tumor cell apoptosis. B7-H3 accelerates malignant proliferation by attacking the checkpoint mechanism of the tumor cell cycle through the phosphatidylinositol 3-kinase and protein kinase B pathway. B7-H3 reprograms the metabolism of glucose and lipids and transforms the metabolic flux of tumor cells to promote tumorigenesis. B7-H3 induces abnormal angiogenesis by recruiting vascular endothelial growth factor and matrix metalloproteinase to tumor lesions. B7-H3 strongly promotes tumorigenesis through antiapoptotic, pro-proliferation, metabolism reprogramming, and pro-angiogenesis.
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Carcinogénesis/genética , Transformación Celular Neoplásica/genética , Regulación Neoplásica de la Expresión Génica/genética , Factor de Transcripción STAT3/genética , Proliferación Celular/genética , Resistencia a Antineoplásicos/genética , Humanos , Factor de Transcripción STAT3/metabolismoRESUMEN
CDK8 is an important member of the cyclin-dependent kinase family associated with transcription and acts as a key "molecular switch" in the Mediator complex. CDK8 regulates gene expression by phosphorylating transcription factors and can control the transcription process through Mediator complex. Previous studies confirmed that CDK8 is an important oncogenic factor, making it a potential tumor biomarker and a promising target for tumor therapy. However, CDK8 has also been confirmed to be a tumor suppressor, indicating that it not only promotes the development of tumors but may also be involved in tumor suppression. Therefore, the dual role of CDK8 in the process of tumor development is worth further exploration and summary. This comprehensive review delves into the intricate involvement of CDK8 in transcription-related processes, as well as its role in signaling pathways related to tumorigenesis, with a focus on its critical part in driving cancer progression.
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Circular RNAs (circRNAs) have been recognized as pivotal regulators in tumorigenesis, yet the biological functions as well as molecular mechanisms of the majority of circRNAs in hepatocellular carcinoma (HCC) remain elusive. We sought to unveil the expression profile and biological role of circMYBL2 in HCC. Initial microarray analyses were conducted to probe the expression profile of circMYBL2 in HCC cells, and qRTâPCR analysis was then performed in HCC cell lines and tissues, revealing significant upregulation of circMYBL2. Subsequent experiments were conducted to evaluate the biological function of circMYBL2 in HCC progression. Furthermore, bioinformatics analysis, qRTâPCR analysis, luciferase reporter assays, and western blot analysis were employed to investigate the interplay among circMYBL2, miR-1205, and E2F1. CircMYBL2 was found to exhibit marked upregulation in tumor tissues as well as HCC cell lines. Elevated expression of circMYBL2 increased the proliferation and migration of HCC cells, whereas circMYBL2 knockdown elicited contrasting effects. Mechanistically, our results indicated that circMYBL2 promoted E2F1 expression and facilitated HCC progression by sponging miR-1205. Our findings revealed that circMYBL2 contributed to HCC progression through the circMYBL2/miR-1205/E2F1 axis, suggesting the potential of circMYBL2 as a novel target for HCC treatment or a prognostic biomarker for HCC.
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Carcinoma Hepatocelular , Movimiento Celular , Proliferación Celular , Progresión de la Enfermedad , Factor de Transcripción E2F1 , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas , MicroARNs , ARN Circular , Humanos , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Factor de Transcripción E2F1/genética , Factor de Transcripción E2F1/metabolismo , ARN Circular/genética , Proliferación Celular/genética , Línea Celular Tumoral , MicroARNs/genética , Movimiento Celular/genética , Ratones , PronósticoRESUMEN
Aggressive triple-negative breast cancer (TNBC) still lacks approved targeted therapies, requiring more exploration of its underlying mechanisms. Previous studies have suggested a potential role of SAT1 (Spermidine/Spermine N1-acetyltransferase 1) in cancer, which needs to be further elucidated in breast cancer. In this study, highly expressed SAT1 in TNBC signified worse patient prognoses. And SAT1 knockdown effectively inhibited the proliferation and migration abilities of TNBC cells in vitro and in vivo. In terms of mechanism, the transcription factor JUN enhanced SAT1 transcriptional activity by binding to its promoter region. Then, SAT1 protein in the cytoplasm engaged in directly binding with YBX1 for sustaining YBX1 protein stability via deubiquitylation mediated by the E3 ligase HERC5. Further, SAT1 was found to suppress autophagy remarkably via stabilization of mTOR mRNA with the accumulation of YBX1-mediated methyl-5-cytosine (m5C) modification. These findings proved that SAT1 drives TNBC progression through the SAT1/YBX1/mTOR axis, which may provide a potential candidate for targeted therapy in advanced TNBC.
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Disruption of disulfide homeostasis during biological processes can have fatal consequences. Excess disulfides induce cell death in a novel manner, termed as "disulfidptosis." However, the specific mechanism of disulfidptosis has not yet been elucidated. To determine the cancer types sensitive to disulfidptosis and outline the corresponding treatment strategies, we firstly investigated the crucial functions of disulfidptosis regulators pan-cancer at multi-omics levels. We found that different tumor types expressed dysregulated levels of disulfidptosis regulators, most of which had an impact on tumor prognosis. Moreover, we calculated the disulfidptosis activity score in tumors and validated it using multiple independent datasets. Additionally, we found that disulfidptosis activity was correlated with classic biological processes and pathways in various cancers. Disulfidptosis activity was also associated with tumor immune characteristics and could predict immunotherapy outcomes. Notably, the disulfidptosis regulator, glycogen synthase 1 (GYS1), was identified as a promising target for triple-negative breast cancer and validated via in vitro and in vivo experiments. In conclusion, our study elucidated the complex molecular phenotypes and clinicopathological correlations of disulfidptosis regulators in tumors, laying a solid foundation for the development of disulfidptosis-targeting strategies for cancer treatment.
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The discovery of induced pluripotent stem cells(iPSCs) is a promising advancement in the field of regenerative medicine. Previous studies have indicated that the teratoma-forming propensity of iPSCs is variable; however, the relationship between tumorigenic potential and genomic instability in human iPSCs (HiPSCs) remains to be fully elucidated. Here, we evaluated the malignant potential of HiPSCs by using both colony formation assays and tumorigenicity tests. We demonstrated that HiPSCs formed tumorigenic colonies when grown in cancer cell culture medium and produced malignancies in immunodeficient mice. Furthermore, we analyzed genomic instability in HiPSCs using whole-genome copy number variation analysis and determined that the extent of genomic instability was related with both the cells' propensity to form colonies and their potential for tumorigenesis. These findings indicate a risk for potential malignancy of HiPSCs derived from genomic instability and suggest that quality control tests, including comprehensive tumorigenicity assays and genomic integrity validation, should be rigorously executed before the clinical application of HiPSCs. In addition, HiPSCs should be generated through the use of combined factors or other approaches that decrease the likelihood of genomic instability.
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Carcinogénesis , Variaciones en el Número de Copia de ADN , Inestabilidad Genómica , Células Madre Pluripotentes Inducidas , Teratoma/etiología , Animales , Células Cultivadas , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/trasplante , Ratones , Ratones SCID , Células 3T3 NIH , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Teratocarcinoma/etiología , Ensayo de Tumor de Célula MadreRESUMEN
Background: Necroptosis is progressively becoming an important focus of research because of its role in the pathogenesis of cancer and other inflammatory diseases. Our study is designed to anticipate the survival time of kidney renal clear cell carcinoma (KIRC) by constructing a prognostic signature of necroptosis-related genes. Materials: Clinical information and RNA-seq data were acquired from Renal Cell Cancer-European Union (RECA-EU) and The Cancer Genome Atlas- (TCGA-) KIRC, respectively. ConsensusClusterPlus was used to identify molecular subtypes, and the distribution of immune cell infiltration, anticancer drug sensitivity, and somatic gene mutations was studied in these subtypes. Subsequently, LASSO-Cox regression and univariate Cox regression were also carried out to construct a necroptosis-related signature. Cox regression, survival analysis, clinicopathological characteristic correlation analysis, nomogram, cancer stem cell analysis, and receiver operating characteristic (ROC) curve were some tools employed to study the prognostic power of the signature. Results: Based on the expression patterns of 66 survival-related necroptosis genes, we classified the KIRC into three subtypes (C1, C2, and C3) that are associated with necroptosis, which had significantly different tumor stem cell components. Among these, C2 patients had a longer survival time and enhanced immune status and were more sensitive to conventional chemotherapeutic drugs. Moreover, in order to predict the prognosis of KIRC patients, five genes (BMP8A, TLCD1, CLGN, GDF7, and RARB) were used to develop a necroptosis-related prognostic signature, which had an acceptable predictive potency. The results from Cox regression and stratified survival analysis revealed that the signature was an independent prognostic factor, whereas the nomogram and calibration curve demonstrated satisfactory survival time prediction based on the risk score. Conclusions: Three molecular subtypes and five necroptosis-related genes were discovered in KIRC using data from TCGA-KIRC and RECA-EU. Thus, a new biomarker and a potentially effective therapeutic approach for KIRC patients were provided in the current study.
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Cytoskeleton-associated protein 4 (CKAP4) acts as a key transmembrane protein that connects the endoplasmic reticulum (ER) to microtubule dynamics. Researchers have not examined the roles of CKAP4 in nasopharyngeal carcinoma (NPC). The study aimed at evaluating the prognostic value and metastasis-regulating effect of CKAP4 in NPC. CKAP4 protein could be observed in 86.36% of 557 NPC specimens but not in normal nasopharyngeal epithelial tissue. According to immunoblot assays, NPC cell lines presented high CKAP4 expression relative to NP69 immortalized nasopharyngeal epithelial cells. Moreover, CKAP4 was highly expressed at the NPC tumor front and in matched liver, lung, and lymph node metastasis samples. Furthermore, high CKAP4 expression reported poor overall survival (OS) and presented a positive relevance to tumor (T) classification, recurrence, and metastasis. According to multivariate analysis, CKAP4 could independently and negatively predict patients' prognosis. Stable knockdown of CKAP4 expression in NPC cells inhibited cell migration, invasion and metastasis in vitro and in vivo. Moreover, CKAP4 promoted epithelial-mesenchymal transition (EMT) in NPC cells. CKAP4 knockdown was followed by the downregulation of the interstitial marker vimentin, and upregulation of the epithelial marker E-cadherin. In NPC tissues, high CKAP4 expression exhibited a positive relevance to vimentin expression and a negative relevance to E-cadherin expression. In conclusion, CKAP4 is an independent predictor of NPC, and CKAP4 might contribute NPC progression and metastasis, which may be involved in EMT with vimentin and E-cadherin.
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Neoplasias Nasofaríngeas , Humanos , Cadherinas/metabolismo , Línea Celular Tumoral , Movimiento Celular , Citoesqueleto/metabolismo , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/patología , Invasividad Neoplásica/genética , VimentinaRESUMEN
BACKGROUND: The aim of the present study was to analyse the expression of Secreted protein acidic and rich in cysteine (SPARC) in nasopharyngeal carcinoma (NPC) specimens, and to evaluate its correlation with clinicopathologic features, including survival of patients with NPC. METHODS: NPC tissue microarrays (TMAs) were constructed from Sun Yat-sen University Cancer Center (SYSUCC), another three centers on mainland China, Singapore and Hong Kong. Using quantitative RT-PCR and Western-blotting techniques, we detected mRNA and protein expression of SPARC in NPC cell lines and immortalized nasopharyngeal epithelial cells (NPECs) induced by Bmi-1 (NPEC2 Bmi-1). The difference of SPARC expression in the cell lines was tested using a t-test method. The relationship between the SPARC expression and clinicopathological data was assessed by chi-square. Survival analysis was estimated using the Kaplan-Meier approach with log-rank test. Univariate and multivariate analyses of clinical variables were performed using Cox proportional hazards regression models. RESULTS: The expression levels of SPARC mRNA and protein were markedly higher in NPC cell lines than in NPEC2 Bmi-1. Especially, the expression levels of SPARC mRNA and protein were much lower in the 6-10B than in the 5-8 F (P = 0.002, P = 0.001). SPARC immunostaining revealed cytoplasmic localization in NPC cells and no staining in the stroma and epithelium. In addition, high level of SPARC positively correlated with the status of distant metastasis (P = 0.001) and WHO histological classification (P = 0.023). NPC patients with high SPARC expression also had a significantly poorer prognosis than patients with low SPARC expression (log-rank test, P < 0.001), especially patients with advanced stage disease (log-rank, P < 0.001). Multivariate analysis suggested that the level of SPARC expression was an independent prognostic indicator for the overall survival of patients with NPC (P < 0.001). CONCLUSIONS: SPARC expression is common in NPC patients. Our data shows that elevated SPARC expression is a potential unfavorable prognostic factor for patients with NPC.
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Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/patología , Osteonectina/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma , Línea Celular Tumoral , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/genética , Metástasis de la Neoplasia , Osteonectina/genética , Pronóstico , Modelos de Riesgos Proporcionales , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Adulto JovenRESUMEN
BACKGROUND: The secretory small GTPase Rab27b was recently identified as an oncogene in breast cancer (BC) in vivo and in vitro studies. This research was designed to further explore the clinical and prognostic significance of Rab27B in BC patients. METHODS: The mRNA/protein expression level of Rab27B was examined by performing Real-time PCR, western blot, and immunohistochemistry (IHC) assays in 12 paired BC tissues and matched adjacent noncancerous tissues (NAT). Then we carried out IHC assay in a large cohort of 221 invasive BC tissues, 22 normal breast tissues, 40 fibroadenoma (FA), 30 ductual carcinoma in situ (DCIS) and 40 metastatic lymph nodes (LNs). The receiver operating characteristic curve method was applied to obtain the optimal cutoff value for high Rab27B expression. Epithelial-mesenchymal transition (EMT) marker expression levels were detected in relation to Rab27B expression. RESULTS: We observed that the increased expression of Rab27B was dependent upon the magnitude of cancer progression (P < 0.001). The elevated expression of Rab27B was closely correlated with lymph node metastasis, advanced clinical stage, ascending pathology classification, and positive ER status. Furthermore, patients with high expression of Rab27B had inferior survival outcomes. Multivariate Cox regression analysis proved that Rab27B was a significantly independent risk factor for patients' survival (P < 0.001). Furthermore, a significant positive relationship was observed between Rab27B expression and elevated mesenchymal EMT markers. CONCLUSION: Our findings suggest that overexpression of Rab27B in BC coincides with lymph node metastasis and acquisition of a poor prognostic phenotype.
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Neoplasias de la Mama/metabolismo , Metástasis Linfática , Proteínas de Unión al GTP rab/metabolismo , Secuencia de Bases , Western Blotting , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/patología , Estudios de Cohortes , Cartilla de ADN , Transición Epitelial-Mesenquimal , Femenino , Humanos , Inmunohistoquímica , Pronóstico , Reacción en Cadena en Tiempo Real de la Polimerasa , Tasa de SupervivenciaRESUMEN
BACKGROUND: Heat shock protein 70, a stress protein, has been implicated in tumor progression. However, its role in nasopharyngeal carcinoma (NPC) progression has not yet been clearly investigated. METHODS: Immunohistochemistry (IHC) was employed to examine the expression patterns of Hsp70, human leukocyte antigen -A (HLA-A) in NPC tissue samples. RESULTS: The expression of Hsp70 exhibited different spatial patterns among nuclear, membrane and cytoplasm in 507 NPC tumor tissues. Kaplan-Meier survival analysis demonstrated that different Hsp70 expression patterns are correlated with different patient outcomes. High membranal and cytoplasmic levels of Hsp70 predicted good survival of patients. In contrast, high nuclear abundance of Hsp70 correlated with poor survival. Moreover, the membranal and cytoplasmic levels of Hsp70 were positively correlated with levels of the MHC I molecule HLA-A. CONCLUSIONS: Different Hsp70 expression patterns had distinct predictive values. The different spatial abundance of Hsp70 may imply its important role in NPC development and provide insight for the development of novel therapeutic strategies involving immunotherapy for NPC.
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Proteínas HSP70 de Choque Térmico/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Adulto , Anciano , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Neoplasias Nasofaríngeas/patología , Pronóstico , Curva ROC , Análisis de Supervivencia , Análisis de Matrices TisularesRESUMEN
BACKGROUND: Esophagus cancer (ESCA) is the sixth most frequent cancer in males, with 5-year overall survival of 15%-25%. RNA modifications function critically in cancer progression, and m6A regulators are associated with ESCA prognosis. This study further revealed correlations between m6A and ESCA development. METHODS: Univariate Cox regression analysis and consensus clustering were applied to determine molecular subtypes. Functional pathways and gene ontology terms were enriched by gene set enrichment analysis. Protein-protein interaction (PPI) analysis on differentially expressed genes (DEGs) was conducted for hub gene screening. Public drug databases were employed to study the interactions between hub genes and small molecules. RESULTS: Three molecular subtypes related to ESCA prognosis were determined. Based on multiple analyses among molecular subtypes, 146 DEGs were screened, and a PPT network of 15 hub genes was visualized. Finally, 8 potential small-molecule drugs (BMS-754807, gefitinib, neratinib, zuclopenthixol, puromycin, sulfasalazine, and imatinib) were identified for treating ESCA. CONCLUSIONS: This study applied a new approach to analyzing the relation between m6A and ESCA prognosis, providing a reference for exploring potential targets and drugs for ESCA treatment.
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Background: Colorectal cancer (CRC) frequently has a dysregulated epigenome causing aberrant up-regulation of oncogenes such as c-MYC. Bromodomain and extra-terminal domain (BET) proteins and histone acetyltransferases (HAT) are epigenetic regulatory proteins that create and maintain epigenetic states supporting oncogenesis. BET inhibitors and HAT inhibitors are currently being investigated as cancer therapeutics due to their ability to suppress cancer-promoting epigenetic modifiers. Due to the extensive molecular crosstalk between BET proteins and HAT proteins, we hypothesized that dual inhibition of BET and HAT could more potently inhibit CRC cells than inhibition of each individual protein. Methods: We investigated the activity and mechanisms of a dual BET and HAT inhibitor, NEO2734, in CRC cell lines and mouse xenografts. MTS, flow cytometry, and microscopy were used to assess cell viability. qPCR, Western blotting, and immunofluorescent staining were used to assess mechanisms of action. Results: We found that NEO2734 more potently suppresses CRC cell growth than first generation BET inhibitors, regardless of the status of common CRC driver mutations. We previously showed that BET inhibitors upregulate DR5 to induce extrinsic apoptosis. In the current study, we show that NEO2734 treatment induces CRC cell apoptosis via both the intrinsic and extrinsic apoptosis pathways. NEO2734 increases p53 expression and subsequently increased expression of the p53-upregulated mediator of apoptosis (PUMA), which is a critical mechanism for activating intrinsic apoptosis. We demonstrate that inhibition of either the intrinsic or extrinsic branches of apoptosis partially rescues CRC cells from NEO2734 treatment, while the dual inhibition of both branches of apoptosis more strongly rescues CRC cells from NEO2734 treatment. Finally, we show that NEO2734 monotherapy is able to suppress tumor growth in CRC xenografts by inducing apoptosis. Conclusions: Our study demonstrates NEO2734 potently suppresses CRC cells in vitro and in vivo by simultaneously upregulating PUMA and DR5 to induce cell death. Further studies of NEO2734 for treating CRC are warranted.
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Growing evidence indicates a connection between cancer-associated fibroblasts (CAFs) and tumor microenvironment (TME) remodeling and tumor progression. Nevertheless, how patterns of CAFs impact TME and immunotherapy responsiveness in triple-negative breast cancer (TNBC) remains unclear. Here, we systematically investigate the relationship between TNBC progression and patterns of CAFs. By using unsupervised clustering methods in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset, we identified two distinct CAF-associated clusters that were related to clinical features, characteristics of TME, and prognosis of patients. Then, we established a CAF-related prognosis index (CPI) by the least absolute shrinkage and selection operator (LASSO)-Cox regression method. CPI showed prognostic accuracy in both training and validation cohorts (METABRIC, GSE96058, and GSE21653). Consequently, we constructed a nomogram with great predictive performance. Moreover, the CPI was verified to be correlated with the responsiveness of immunotherapy in three independent cohorts (GSE91061, GSE165252, and GSE173839). Taken together, the CPI might help us improve our recognition of the TME of TNBC, predict the prognosis of TNBC patients, and offer more immunotherapy strategies in the future.
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Fibroblastos Asociados al Cáncer , Neoplasias de la Mama Triple Negativas , Humanos , Fibroblastos Asociados al Cáncer/patología , Pronóstico , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Microambiente TumoralRESUMEN
Background: Although immune checkpoint inhibitors have opened a new mode of treatment for solid tumors, their efficacy in nasopharyngeal carcinoma (NPC) needs to be further investigated. Inhibitors of the PD-1/PD-L1 immune checkpoint are one of the hot topics in tumor immunotherapy. Programmed death ligand-2 (PD-L2) is a less studied ligand of PD-1 and has not yet been fully explored, especially in NPC. Understanding the clinical significance of PD-L2 expression, together with immune cell infiltration, might provide clues for biomarker screening in NPC immunotherapy. This study aimed to evaluate the role of PD-L2 as a prognostic factor for NPC patients as well as its role in immune regulation. Methods: Immunohistochemistry (IHC) was performed on a tissue microarray including 557 NPC specimens using PD-L2 antibody. The immune cell markers CD4, FOXP3 and CD68 were also stained and quantified. The expression of PD-L2 exhibited different spatial patterns among NPC tumor and stromal tissues. Results: A total of 90.8% of the cases showed membranous PD-L2 expression in tumors, and 80.8% showed membranous PD-L2 expression in stromal tissue. High stromal expression of PD-L2 predicted favorable overall and disease-free survival of NPC patients and was negatively correlated with tumor size, recurrence or metastasis and clinical stage. In contrast, high tumor abundance of PD-L2 correlated with poor disease-free survival, but had no obvious correlation with clinicopathological parameters. Multivariate analysis indicated that stromal PD-L2 was an independent and favorable prognostic factor. Furthermore, we found a positive correlation between stromal PD-L2 expression and the infiltration of CD68+ macrophages and CD4+Foxp3+ Treg cells in NPC stromal tissues (Pearson correlation=0.181 and 0.098, respectively). Conclusions: Our results suggest that different PD-L2 expression patterns have distinct predictive values. PD-L2 expressed on stromal cells might play a role in the regulation of NPC progression, and involve in immune activation in the tissue microenvironment and have an independent good prognosis for NPC patients.
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To develop a minipig model of type 2 diabetes that simulates the common manifestations of the metabolic abnormalities and resembles the kidney pathology of type 2 diabetes in the human population, male Chinese Bama minipigs were divided into 2 groups (5 in each) and fed with a control diet (CD) or high-fat/ high-sucrose/ high-cholesterol diet (HFSCD) for 5 months. The biochemical parameters of blood and urine, and the oral glucose tolerance test were monitored after the feeding program. The insulin resistance was estimated by the HOMA-IR index and the glucose elimination constant (K(G)), and beta-cell function by the HOMA-beta index and the acute insulin response (AIR). Glomerulosclerosis index (GSI) was semi-quantitated by the degree of glomerular lesions in kidney sections stained with Masson trichrome. Extracellular matrix deposition in the kidney was examined by the protein expression of type IV collagen, connective tissue growth factor (CTGF) and matrix metalloproteinases 2 (MMP-2) using immunohistochemistry. Feeding HFSCD to minipigs markedly caused hyperglycaemia, hyperinsulinaemia and dyslipidaemia. HOMA-IR was significantly increased while HOMA-beta, AIR and K(G) were obviously decreased in the HFSCD group compared with control group. Microalbuminuria, glucosuria and moderate glomerulosclerosis were exhibited in HFSCD-fed minipigs. The expression of type IV collagen and CTGF was elevated whereas that of MMP-2 was reduced in the kidneys of HFSCD group compared with the CD group. We concluded that feeding HFSCD to Chinese Bama minipigs for 5 months can induce humanoid type 2 diabetes and early-stage diabetic nephropathy, and accelerate extracellular matrix deposition and glomerulosclerosis.
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Colesterol en la Dieta/efectos adversos , Diabetes Mellitus Tipo 2/etiología , Nefropatías Diabéticas/etiología , Carbohidratos de la Dieta/efectos adversos , Grasas de la Dieta/efectos adversos , Modelos Animales de Enfermedad , Resistencia a la Insulina , Sacarosa/efectos adversos , Porcinos Enanos , Animales , Matriz Extracelular/metabolismo , Humanos , Riñón/metabolismo , Masculino , Índice de Severidad de la Enfermedad , PorcinosRESUMEN
Inflammation, closely associated with obesity, is emerging as an important risk factor for the pathophysiological development of atherosclerosis and diabetes mellitus. Fat balance is critical in the aetiology of obesity. Lipoprotein lipase is an important enzyme in lipid metabolism. The aim of this study was to investigate the long-term effect of the lipoprotein lipase activator, NO-1886, on inflammation cytokines, adiposity and related diseases in miniature pigs fed a high-fat/high-sucrose/high-cholesterol diet (HFSC diet). Chinese Bama-miniature pigs were fed a control diet or HFSC diet with or without NO-1886 for 5 months. The levels of inflammation-associated cytokines were determined using the antibody arrays. Feeding of the HFSC diet to miniature pigs markedly increased the expression of inflammatory cytokines. On the other hand, supplementation of NO-1886 to HFSC diet decreased the expression of inflammatory cytokines significantly, protecting against the development of atherosclerosis and diabetes mellitus. NO-1886 may have a beneficial effect on the most inflammation-associated cytokines, and this effect may contribute to improving atherosclerosis and diabetes mellitus.