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BACKGROUND: As the most lethal gynecologic cancer, ovarian cancer (OV) holds the potential of being immunotherapy-responsive. However, only modest therapeutic effects have been achieved by immunotherapies such as immune checkpoint blockade. This study aims to propose a generalized stroma-immune prognostic signature (SIPS) to identify OV patients who may benefit from immunotherapy. METHODS: The 2097 OV patients included in the study were significant with high-grade serous ovarian cancer in the III/IV stage. The 470 immune-related signatures were collected and analyzed by the Cox regression and Lasso algorithm to generalize a credible SIPS. Correlations between the SIPS signature and tumor microenvironment were further analyzed. The critical immunosuppressive role of stroma indicated by the SIPS was further validated by targeting the major suppressive stroma component (CAFs, Cancer-associated fibroblasts) in vitro and in vivo. With four machine-learning methods predicting tumor immune subtypes, the stroma-immune signature was upgraded to a 23-gene signature. RESULTS: The SIPS effectively discriminated the high-risk individuals in the training and validating cohorts, where the high SIPS succeeded in predicting worse survival in several immunotherapy cohorts. The SIPS signature was positively correlated with stroma components, especially CAFs and immunosuppressive cells in the tumor microenvironment, indicating the critical suppressive stroma-immune network. The combination of CAFs' marker PDGFRB inhibitors and frontline PARP inhibitors substantially inhibited tumor growth and promoted the survival of OV-bearing mice. The stroma-immune signature was upgraded to a 23-gene signature to improve clinical utility. Several drug types that suppress stroma-immune signatures, such as EGFR inhibitors, could be candidates for potential immunotherapeutic combinations in ovarian cancer. CONCLUSIONS: The stroma-immune signature could efficiently predict the immunotherapeutic sensitivity of OV patients. Immunotherapy and auxiliary drugs targeting stroma could enhance immunotherapeutic efficacy in ovarian cancer.
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Síndrome de DiGeorge , Neoplasias Ováricas , Femenino , Animales , Ratones , Humanos , Receptor beta de Factor de Crecimiento Derivado de Plaquetas , Pronóstico , Neoplasias Ováricas/tratamiento farmacológico , Inmunosupresores , Inmunoterapia , Microambiente TumoralRESUMEN
Pulmonary hypertension (PH) is a chronic vascular disease characterized by elevated pulmonary arterial resistance and vascular remodeling, and chronic hypoxia plays an important role in PH. Milk fat globule-EGF factor 8 (MFG-E8) is a glycoprotein that regulates cell proliferation and apoptosis, but its role in hypoxia-induced PH is unknown. The current study aimed to determine the function and fundamental mechanisms of MFG-E8 in hypoxia-induced PH. Herein, we exposed mice to hypoxia for 5 weeks, and MFG-E8 was found to be elevated in mouse lung tissues, arteries, and plasma. Compared with wild-type littermates, mice lacking MFG-E8 showed a significant increase in the ratio of pulmonary artery acceleration time to ejection time (PAT/PET), while they showed decreases in right ventricular systolic pressure, the Fulton's Index, percent medial wall thickness (%WT), and vascular muscularization in pulmonary arteries. In addition, MFG-E8 protein levels were also increased in the serum of patients with chronic PH. Similarly, we observed a higher expression of MFG-E8 in human pulmonary artery smooth muscle cells (PASMCs) in the presence of hypoxic stimulation than MFG-E8 in cells in normoxic conditions. Furthermore, MFG-E8 silencing resulted in partial inhibition of proliferation, migration and cell cycle progression in human PASMCs, and the possible mechanisms might involve the interaction between MFG-E8 and the p-Akt/cyclin D1 pathway. Collectively, our study suggests that the absence of MFG-E8 can attenuate the development of hypoxia-induced PH and vascular remodeling. MFG-E8 can be a potential therapeutic target or a biomarker for PH.
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Antígenos de Superficie/genética , Hipertensión Pulmonar/genética , Hipoxia/genética , Proteínas de la Leche/genética , Animales , Apoptosis/genética , Proliferación Celular/genética , Células Cultivadas , Glicoproteínas/genética , Humanos , Hipertensión Pulmonar/patología , Hipoxia/patología , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/patología , Arteria Pulmonar/patología , Transducción de Señal/genética , Remodelación Vascular/genéticaRESUMEN
Persistent fibroblast activation is a predominant feature of idiopathic pulmonary fibrosis (IPF), but the transcriptional and epigenetic mechanisms controlling this process are not well understood. Silent information regulator type-1 (Sirt1) is a member of class â ¢ histone deacetylase with important regulatory roles in a variety of pathophysiologic processes, but its role in fibrotic lung diseases is not clearly elucidated. Sirt1 expression in lung tissues of IPF patients and in a mouse model of bleomycin (BLM)-induced lung fibrosis were evaluated by immunofluorescence. The function of Sirt1 in BLM-induced lung fibrosis in the mouse model or transforming growth factor ß1 (TGF-ß1)-mediated lung fibroblast cellular model was investigated by Sirt1 activation, overexpression and knockdown of Sirt1. Finally, the involvement of p300 signaling pathways was assessed. In this study, we found up-regulation of Sirt1 in BLM-induced lung fibrosis, as well as in the lungs of IPF patients, including in the aggregated pulmonary fibroblasts of fibrotic foci. Activation or overexpression of Sirt1 attenuated TGF-ß1-mediated lung fibroblast differentiation and activation and diminished the severity of experimental lung fibrosis in mice. Whereas knockdown of Sirt1 promoted the pro-fibrogenic activity of TGF-ß1 in lung fibroblasts. A potential mechanism for the role of Sirt1 in lung fibrosis was through regulating the expression of p300. Thus, we characterized Sirt1 as an important regulator of lung fibrosis and provides a proof of principle for activation or overexpression of Sirt1 as a potential novel therapeutic strategy for IPF.
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Proteína p300 Asociada a E1A/inmunología , Fibroblastos/inmunología , Fibrosis Pulmonar/inmunología , Sirtuina 1/inmunología , Animales , Fibroblastos/patología , Humanos , Ratones , Ratones Endogámicos C57BL , Regulación hacia Arriba/inmunologíaRESUMEN
BACKGROUND: The association between MBL2 gene polymorphisms and the risk of asthma has been evaluated in multiple studies; however, the results are inconsistent. OBJECTIVE: To perform a meta-analysis to explore whether MBL2 gene polymorphisms were associated with the risk of asthma. METHODS: We searched PubMed, Web of Science, and Cochrane Library to find relevant articles published up to March 2016. Nine studies, including 2066 cases and 2183 controls, were included in the meta-analysis. The strength of association was evaluated by odds ratio (OR) with 95% confidence interval (CI). RESULTS: The results reveal that MBL2 gene polymorphisms (codon 54 A/B, -550 H/L or -221 X/Y) were not associated with the risk of asthma (codon 54 A/B: BB+AB vs AA: OR, 1.02; 95% CI, 0.85-1.23; -550 H/L: LL+HL vs HH: OR, 0.81; 95% CI, 0.63-1.03; -221 X/Y: XX+YX vs YY: OR, 0.85; 95% CI, 0.69-1.04). Subgroup analysis by ethnicity implied that the MBL2 codon 54 A/B polymorphism was not significantly associated with the risk of asthma in Asians (BB+AB vs AA: OR, 0.95; 95% CI, 0.70-1.29) or whites (BB+AB vs AA: OR, 1.07; 95% CI, 0.84-1.35). CONCLUSION: The results indicated that MBL2 gene polymorphisms (codon 54 A/B, -550 H/L or -221 X/Y) may be not associated with the risk of asthma.
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Asma/genética , Lectina de Unión a Manosa/genética , Pueblo Asiatico/genética , Predisposición Genética a la Enfermedad , Humanos , Oportunidad Relativa , Polimorfismo Genético , Factores de RiesgoRESUMEN
Targeting ferroptosis for cancer therapy has slowed because of an incomplete understanding of ferroptosis mechanisms under specific pathological contexts such as tumorigenesis and cancer treatment. Here, we identify TRPML1-mediated lysosomal exocytosis as a potential anti-ferroptotic process through genome-wide CRISPR-Cas9 activation and kinase inhibitor library screening. AKT directly phosphorylated TRPML1 at Ser343 and inhibited K552 ubiquitination and proteasome degradation of TRPML1, thereby promoting TRPML1 binding to ARL8B to trigger lysosomal exocytosis. This boosted ferroptosis defense of AKT-hyperactivated cancer cells by reducing intracellular ferrous iron and enhancing membrane repair. Correlation analysis and functional analysis revealed that TRPML1-mediated ferroptosis resistance is a previously unrecognized feature of AKT-hyperactivated cancers and is necessary for AKT-driven tumorigenesis and cancer therapeutic resistance. TRPML1 inactivation or blockade of the interaction between TRPML1 and ARL8B inhibited AKT-driven tumorigenesis and cancer therapeutic resistance in vitro and in vivo by promoting ferroptosis. A synthetic peptide targeting TRPML1 inhibited AKT-driven tumorigenesis and enhanced the sensitivity of AKT-hyperactivated tumors to ferroptosis inducers, radiotherapy, and immunotherapy by boosting ferroptosis in vivo. Together, our findings identified TRPML1 as a therapeutic target in AKT-hyperactivated cancer.
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Ferroptosis , Neoplasias , Proteínas Proto-Oncogénicas c-akt , Animales , Humanos , Ratones , Factores de Ribosilacion-ADP/metabolismo , Carcinogénesis/patología , Carcinogénesis/genética , Línea Celular Tumoral , Ferroptosis/efectos de los fármacos , Lisosomas/metabolismo , Neoplasias/patología , Neoplasias/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , UbiquitinaciónRESUMEN
Background: Protein-energy malnutrition (PEM) has been recognized as a poor prognostic factor in many clinical issues. However, nationwide population studies concerning the impact of PEM on outcomes after major cancer surgery (MCS) are lacking. We aimed to evaluate the postoperative outcomes associated with PEM following MCS. Methods: By using the Nationwide Inpatient Sample database, data of patients undergoing MCS including colectomy, cystectomy, esophagectomy, gastrectomy, hysterectomy, lung resection, pancreatectomy, or prostatectomy were analyzed retrospectively from 2009 to 2015, resulting in a weighted estimate of 1,335,681 patients. The prevalence trend of PEM, as well as mortality and major complications after MCS were calculated. Multivariable regression analysis was applied to estimate the impact of PEM on postoperative outcomes after MCS. Results: PEM showed an estimated annual percentage increase of 7.17% (95% confidence interval (CI): 4-10.44%) from 2009 to 2015, which contrasts with a 4.52% (95% CI: -6.58-2.41%) and 1.21% (95% CI: -1.85-0.56%) annual decrease in mortality and major complications in patients with PEM after MCS. PEM was associated with increased risk of mortality (odds ratio (OR)=2.26; 95% CI: 2.08-2.44; P < 0.0001), major complications (OR=2.46; 95% CI: 2.36-2.56; P < 0.0001), higher total cost ($35814 [$22292, $59579] vs. $16825 [$11393, $24164], P < 0.0001), and longer length of stay (14 [9-21] days vs. 4 [2-7] days, P < 0.0001), especially in patients underwent prostatectomy, hysterectomy and lung resection. Conclusions: PEM was associated with increased worse outcomes after major cancer surgery. Early identification and timely medical treatment of PEM for patients with cancer are crucial for improving postoperative outcomes.
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Background: The mechanistic aspects of the involvement of long noncoding RNAs (lncRNAs) in NETosis, the process of neutrophil extracellular trap (NET) formation in head and neck squamous cell carcinoma (HNSCC), lack comprehensive elucidation. The involvement of these molecules in the immune microenvironment and plausible HNSCC prognosis remain to see the light of the day. The plausible functioning of NETosis-related lncRNAs with their plausible prognostic impact in HNSCC was probed in this work. Methods: The scrutiny of lncRNAs linked to NETosis entailed the probing of twenty-four genes associated with the process employing Pearson's correlation analysis on HNSCC patients' RNA sequencing data from The Cancer Genome Atlas (TCGA) database. The application of univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analyses yielded a NETosis-related lncRNA signature that was subjected to probing for its suitability in prognosis employing survival and nomogram analyses. Results: The NETosis-related lncRNA signature inclusive of five lncRNAs facilitated patients to be segregated as high-risk and low-risk groups with the former documenting a poor prognosis. Regression unearthed that the risk score was an independent factor for prognosis. The receiver operating characteristic (ROC) or receiver operating characteristic curve analysis documented a one-year area under time-dependent ROC curve (AUC) value of 0.711 that is corroborative of the accuracy of this signature. Additional probing documented an evident enriching of immune-linked pathways in the low-risk patients, while the high-risk patients documented an immunologically "cold" profile as per the infiltration of immune cells. We verified lncRNA expression from our NETosis-related lncRNA signature in vitro, which reflects the reliability of our model to a certain extent. Moreover, we also verified the function of the lncRNA. We found that LINC00426 contributes to the innate immune cGAS-STING signaling pathway, which explain to some extent the role of our prognostic model in predicting "hot" and "cold" tumors. Conclusions: The plausible prognostic relevance of the NETosis-related lncRNA signature (with five lncRNAs) emerges that is suggestive of its promise in targeting HNSCC.
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Trampas Extracelulares , Neoplasias de Cabeza y Cuello , ARN Largo no Codificante , Carcinoma de Células Escamosas de Cabeza y Cuello , Neoplasias de Cabeza y Cuello/genética , Humanos , Nucleotidiltransferasas , Pronóstico , ARN Largo no Codificante/genética , Reproducibilidad de los Resultados , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Microambiente Tumoral/genéticaRESUMEN
The accumulation of lipid peroxides is recognized as a determinant of the occurrence of ferroptosis. However, the sensors and amplifying process of lipid peroxidation linked to ferroptosis remain obscure. Here we identify PKCßII as a critical contributor of ferroptosis through independent genome-wide CRISPR-Cas9 and kinase inhibitor library screening. Our results show that PKCßII senses the initial lipid peroxides and amplifies lipid peroxidation linked to ferroptosis through phosphorylation and activation of ACSL4. Lipidomics analysis shows that activated ACSL4 catalyses polyunsaturated fatty acid-containing lipid biosynthesis and promotes the accumulation of lipid peroxidation products, leading to ferroptosis. Attenuation of the PKCßII-ACSL4 pathway effectively blocks ferroptosis in vitro and impairs ferroptosis-associated cancer immunotherapy in vivo. Our results identify PKCßII as a sensor of lipid peroxidation, and the lipid peroxidation-PKCßII-ACSL4 positive-feedback axis may provide potential targets for ferroptosis-associated disease treatment.
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Coenzima A Ligasas/metabolismo , Ferroptosis/fisiología , Peroxidación de Lípido/fisiología , Proteína Quinasa C beta/metabolismo , Animales , Sistemas CRISPR-Cas/genética , Línea Celular Tumoral , Técnicas de Inactivación de Genes , Humanos , Inmunoterapia/métodos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Neoplasias/terapia , Fosforilación , Proteína Quinasa C beta/genéticaRESUMEN
Chronic obstructive pulmonary disease (COPD), primarily attributed to cigarette smoke (CS), is characterized by multiple pathophysiological changes, including oxidative stress and inflammation. Stromal interaction molecule 1 (STIM1) is a Ca2+ sensor that regulates Ca2+ entry in different types of cells. The present study aimed to explore the relationship between CS-induced oxidative stress and inflammation, as well as the functional role of STIM1 thereinto. Our results showed that the reactive oxygen species (ROS)/STIM1/Ca2+ axis played a critical role in CS-induced secretion of interleukin (IL)-8 in human alveolar macrophages. Specifically, smokers with COPD (SC) showed higher levels of ROS in the lung tissues compared with healthy non-smokers (HN). STIM1 was upregulated in the lung tissues of COPD patients. The expression of STIM1 was positively associated with ROS levels and negatively correlated with pulmonary function. The expression of STIM1 was also increased in the bronchoalveolar lavage fluid (BALF) macrophages of COPD patients and PMA-differentiated THP-1 macrophages stimulated by cigarette smoke extract (CSE). Additionally, CSE-induced upregulation of STIM1 in PMA-differentiated THP-1 macrophages was inhibited by pretreatment with N-acetylcysteine (NAC), a ROS scavenger. Transfection with small interfering RNA (siRNA) targeting STIM1 and pretreatment with NAC alleviated CSE-induced increase in intracellular Ca2+ levels and IL-8 expression. Furthermore, pretreatment with SKF-96365 and 2-APB, the inhibitors of Ca2+ influx, suppressed CSE-induced secretion of IL-8. In conclusion, our study demonstrates that CSE-induced ROS production may increase the expression of STIM1 in macrophages, which further promotes the release of IL-8 by regulating Ca2+ entry. These data suggest that STIM1 may play a crucial role in CSE-induced ROS production and inflammation, and participate in the pathogenesis of COPD.
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BACKGROUND: Albumin-to-alkaline phosphatase ratio (AAPR) has been reported as a novel prognostic predictor for numerous solid tumors. We aimed to assess the prognostic role of preoperative AAPR in surgically resectable esophageal squamous cell carcinoma (ESCC) by a propensity score matching (PSM) analysis with predictive nomograms. METHODS: Our study was conducted in a single-center prospective database between June 2009 and December 2012. Kaplan-Meier analysis was used to distinguish the difference in survival outcomes between patients stratified by an AAPR threshold. Multivariable Cox proportional hazards regression model was finally generated to specify independent prognostic markers for the entire and PSM cohorts. RESULTS: A total of 497 patients with ESCC were included in this study. An AAPR of 0.50 was determined as the optimal cutoff point for prognostic outcome stratification. Patients with AAPR<0.50 had significantly worse overall survival (OS), and progression-free survival (PFS) compared to those with AAPR≥0.50 (Log-rank P<0.001). This significant difference remained stable in the PSM analysis. Multivariable analyses based on the entire and PSM cohorts consistently showed that AAPR<0.50 might be one of the most predominant prognostic factors resulting in unfavorable OS and PFS of ESCC patients undergoing esophagectomy (P<0.001). The nomograms consisting of AAPR and other independent prognostic factors further demonstrated a plausible predictive accuracy of postoperative OS and PFS. CONCLUSION: AAPR can be considered as a simple, convenient and noninvasive biomarker with a significant prognostic effect in surgically resected ESCC.
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Pulmonary artery hypertension (PAH) is a chronic and deadly disease, for which effective medical treatments are lacking. Here, we investigated whether 2R,3R-dihydromyricetin (DHM) could prevent monocrotaline (MCT)-induced PAH in rats. The MCT-injected rats were treated with normal saline or DHM (100mg/kg body weight/d) for 4 weeks, followed by measurements of right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), pulmonary arterial remodeling (PAR), and expression levels of IL-6, TNF-α, and IL-10. In vitro, we assessed the role of DHM on IL-6-induced migration of primary human pulmonary arterial smooth muscle cells (HPASMCs). We found that DHM treatment attenuated changes in RVSP, RVHI, and PAR in MCT-injected PAH rats. The observed increase of IL-6 levels in PAH rats was inhibited by DHM treatment. In vitro, DHM pretreatment reduced IL-6-induced HPASMC migration. Furthermore, MCT- and IL-6-mediated increases in MMP9 and P-STAT3 (tyr705) PY-STAT3 levels were suppressed by DHM treatment in vivo and in vitro. These results suggest that DHM could prevent MCT-induced rat PAH and IL-6-induced HPASMC migration through a mechanism involving inhibiting of the STAT3/MMP9 axis.