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Integrating genomics and histology for cancer prognosis demonstrates promise. Here, we develop a multi-classifier system integrating a lncRNA-based classifier, a deep learning whole-slide-image-based classifier, and a clinicopathological classifier to accurately predict post-surgery localized (stage I-III) papillary renal cell carcinoma (pRCC) recurrence. The multi-classifier system demonstrates significantly higher predictive accuracy for recurrence-free survival (RFS) compared to the three single classifiers alone in the training set and in both validation sets (C-index 0.831-0.858 vs. 0.642-0.777, p < 0.05). The RFS in our multi-classifier-defined high-risk stage I/II and grade 1/2 groups is significantly worse than in the low-risk stage III and grade 3/4 groups (p < 0.05). Our multi-classifier system is a practical and reliable predictor for recurrence of localized pRCC after surgery that can be used with the current staging system to more accurately predict disease course and inform strategies for individualized adjuvant therapy.
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Carcinoma de Células Renales , Neoplasias Renales , Recurrencia Local de Neoplasia , Humanos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Neoplasias Renales/genética , Neoplasias Renales/patología , Neoplasias Renales/cirugía , Masculino , Femenino , Recurrencia Local de Neoplasia/genética , Persona de Mediana Edad , Anciano , Pronóstico , Genómica/métodos , Adulto , Estadificación de Neoplasias , Aprendizaje Profundo , Supervivencia sin EnfermedadRESUMEN
The urban thermal environment is an important indicator for evaluating the ecological environment of a city. It directly affects the health of residents and the sustainable development of the urban economy. However, there is currently a lack of analysis on the impact pathways of the thermal environment considering both natural and human factors. Based on the MODIS MYD11A2 land surface temperature data, meteorological data, and human activity data of Xi'an metropolitan area in 2020, ArcGIS spatial geostatistical analysis was used to study the temporal and spatial distribution pattern of the thermal environment in different seasons, and redundancy analysis was utilized to select the main factors affecting the thermal environment. Then, structural equation modeling was used to quantify the direct and indirect effects of the dominant factors on the urban thermal environment. The results showed that:â The surface temperature in the Xi'an urban area showed a spatial pattern of higher temperatures in the north and lower temperatures in the south, with a decrease in temperature from the city center to the surrounding areas. The most severe heat environment pollution occurred in the summer. â¡ The redundancy analysis (RDA) results indicated that the main factors that affected the thermal environment were air temperature, impermeable surfaces, vegetation, and precipitation. ⢠The results of the structural equation modeling (SEM) indicated that meteorological, surface, and anthropogenic factors affected the urban thermal environment mainly through direct pathways, which were much more important than all indirect pathways. Factors such as temperature, impervious surfaces, and point of interest density had a significant positive effect on the thermal environment (0.10 and 0.33). On the other hand, factors such as water bodies, precipitation, and vegetation had a significant negative effect on the thermal environment (-0.29 and -0.25). Human activities had a greater direct impact on nocturnal surface temperatures than surface and meteorological factors. Increasing economic efficiency is beneficial for mitigating the urban heat island effect. The results of the study can provide a reference for studying local climate change in urban heat islands and for the construction of green and ecologically livable urban environments.
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AIMS: This investigation aims to elucidate the mechanism underlying sorafenib-induced ferroptosis in hepatocellular carcinoma (HCC). METHODS: The role of dual specificity phosphatase 4 (DUSP4) in sorafenib-treated HCC was investigated using comprehensive assessments both in vitro and in vivo, including Western blotting, qRT-PCR, cell viability assay, lipid reactive oxygen species (ROS) assay, immunohistochemistry, and xenograft tumor mouse model. Additionally, label-free quantitative proteomics was employed to identify potential proteins associated with DUSP4. RESULTS: Our study revealed that suppression of DUSP4 expression heightens the susceptibility of HCC cells to ferroptosis inducers, specifically sorafenib and erastin, in both in vitro and in vivo settings. Furthermore, we identified DUSP4-mediated regulation of key ferroptosis-related markers, such as ferritin light chain (FTL) and ferritin heavy chain 1 (FTH1). Notably, label-free quantitative proteomics unveiled the phosphorylation of threonine residue T148 on YTH Domain Containing 1 (YTHDC1) by DUSP4. Further investigations unraveled that YTHDC1, functioning as an mRNA nuclear export regulator, is a direct target of DUSP4, orchestrating the subcellular localization of FTL and FTH1 mRNAs. Significantly, our study highlights a strong correlation between elevated DUSP4 expression and sorafenib resistance in HCC. CONCLUSIONS: Our findings introduce DUSP4 as a negative regulator of sorafenib-induced ferroptosis. This discovery opens new avenues for the development of ferroptosis-based therapeutic strategies tailored for HCC treatment.
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Carcinoma Hepatocelular , Fosfatasas de Especificidad Dual , Ferroptosis , Neoplasias Hepáticas , Animales , Humanos , Ratones , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Ferroptosis/genética , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Monoéster Fosfórico Hidrolasas/uso terapéutico , Sorafenib/farmacología , Sorafenib/uso terapéutico , Fosfatasas de Especificidad Dual/genética , Fosfatasas de Especificidad Dual/metabolismo , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/genética , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/metabolismoRESUMEN
BACKGROUND: N6-methyladenosine (m6A) related long noncoding RNAs (lncRNAs) may have prognostic value in bladder cancer for their key role in tumorigenesis and innate immunity. METHODS: Bladder cancer transcriptome data and the corresponding clinical data were acquired from the Cancer Genome Atlas (TCGA) database. The m6A-immune-related lncRNAs were identified using univariate Cox regression analysis and Pearson correlation analysis. A risk model was established using least absolute shrinkage and selection operator (LASSO) Cox regression analyses, and analyzed using nomogram, time-dependent receiver operating characteristics (ROC) and Kaplan-Meier survival analysis. The differences in infiltration scores, clinical features, and sensitivity to Talazoparib of various immune cells between low- and high-risk groups were investigated. RESULTS: Totally 618 m6A-immune-related lncRNAs and 490 immune-related lncRNAs were identified from TCGA, and 47 lncRNAs of their intersection demonstrated prognostic values. A risk model with 11 lncRNAs was established by Lasso Cox regression, and can predict the prognosis of bladder cancer patients as demonstrated by time-dependent ROC and Kaplan-Meier analysis. Significant correlations were determined between risk score and tumor malignancy or immune cell infiltration. Meanwhile, significant differences were observed in tumor mutation burden and stemness-score between the low-risk group and high-risk group. Moreover, high-risk group patients were more responsive to Talazoparib. CONCLUSIONS: An m6A-immune-related lncRNA risk model was established in this study, which can be applied to predict prognosis, immune landscape and chemotherapeutic response in bladder cancer.
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ARN Largo no Codificante , Neoplasias de la Vejiga Urinaria , Humanos , Pronóstico , ARN Largo no Codificante/genética , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Regulación Neoplásica de la Expresión Génica , Biomarcadores de Tumor/genéticaRESUMEN
Background: Tuberculosis (TB) always runs in the forefront of the global burden when it comes to infectious diseases. Tuberculosis, which can lead to impairment of quality of life, financial hardship, discrimination, marginalization, and social barriers, is a major public health problem. The assessment of TB burden and trend can provide crucial information for policy decision and planning, and help countries in the world to achieve the goal of sustainable development of ending the epidemic of TB in 2030. Methods: All data are from the Global Burden of Disease 2019 (GBD 2019) database, which analyzed the burden trend of age-standardized incidence, DALYs, and deaths rate in TB and HIV/AIDS-infected TB over the past 30 years. Also, GBD 2019 not only analyzed the burden distribution of TB in 204 countries and main regions of the world but also analyzed the relationship between the burden of global TB and the socio-demographic Index (SDI). Results: The age-standardized incidence, age-standardized disability-adjusted life years (DALYs), and age-standardized deaths rate for HIV-negative TB were 10,671.45 (9,395.60-12,194.10), 59,042.45 (53,684.78-64,641.53), and 1,463.62 (1,339.24-1,602.71) (95% CI, per 100,000 person-years) in 2019, respectively. Age-standardized incidence, age-standardized DALYs, and age-standardized deaths rate of HIV/AIDS-XDR-TB (95% CI, per 1,000 person-years) were 2.10 (1.51-2.90), 64.23 (28.64-117.74), and 1.01 (0.42-1.86), respectively. We found that TB is inversely proportional to SDI, the age-standardized incidence, DALYs, and deaths rate low burden countries were in high SDI areas, while high burden countries were in low SDI areas. The global TB showed a slow decline trend, but the age-standardized incidence of HIV-positive TB was increasing, and mainly distributed in sub-Saharan Africa. Conclusion: Age-standardized incidence, age-standardized DALYs, and age-standardized deaths rate of TB is related to SDI, and the burden of low SDI countries is lighter than that of high SDI countries. Without effective measures, it will be difficult for countries around the world to achieve the goal of ending the TB epidemic by 2030. Effective control of the spread of TB requires concerted efforts from all countries in the world, especially in the countries with low SDI, which need to improve the diagnosis and preventive measures of TB and improve the control of HIV/AIDS-TB.
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Circular RNAs (circRNAs) play critical roles in clear cell renal cell carcinoma (ccRCC). However, their involvement in sunitinib resistance remains largely unknown. Herein, we identified a novel circRNA, named circME1, which contributes to sunitinib resistance development in ccRCC. CircME1 also promoted proliferation, migration, and invasion of ccRCC cells. Further mechanism analysis showed that circME1 interacted with U1 snRNP at the promoter of its parental gene ME1, thereby upregulating the expression of ME1, enhancing aerobic glycolysis of ccRCC, and promoting its malignant phenotype. Furthermore, ME1 specific inhibitor could effectively repress the oncogenic functions of circME1. Taken together, our study demonstrates that the circME1/ME1 pathway is involved in ccRCC progression and sunitinib resistance development, which may be exploited for anticancer therapy.
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Carcinoma de Células Renales , Neoplasias Renales , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Glucólisis/genética , Humanos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , ARN Circular , Sunitinib/farmacologíaRESUMEN
The simultaneous quantitative investigation of aerosol ground observation data and particle concentration data is important for a better understanding of the vertical distribution characteristics of air pollution and formulating reasonable air pollution control measures in Chang'an, Xi'an. CE-318 measurements from October 2018 to April 2021 were systematically analyzed to reveal the seasonal and yearly variations in atmospheric aerosols in Chang'an. Then, the relationship between AOD and particle concentration in different seasons and different pollution degrees was explored. The obtained results were as follows:â the seasonal variation in AOD in Chang'an was determined, whereby autumn (1.02)>winter (1.00)>summer (0.63)>spring (0.47). Distinct monthly and inter-annual differences in AOD were observed, showing that the annual average of AOD in 2019 was higher than that in 2020. â¡ Obvious seasonal and monthly differences in aerosol main control modes were observed; the dominant mode of aerosols gradually changed from coarse mode to fine mode from spring to winter. The seasonal variation in the main control mode of aerosols in 2019 was similar to that in the whole observation period. The seasonal aerosol Angstrom wavelength index (Angstrom) was evenly distributed in 2020, and aerosol particles existed in coarse mode form. Generally speaking, the aerosol type in Chang'an was mostly mixed aerosol throughout the whole observation period. ⢠Significant seasonal variations in the relationship between AOD and Angstrom was shown, in which the air pollution in spring was dominated by coarse mode aerosol particles. The local pollution in summer was caused by coarse and fine mode aerosol particles, and the fine mode particles were dominant when the pollution was obvious. The characteristic distribution of Angstrom in autumn and winter was similar; in case of local pollution, the coarse mode aerosol particles were dominant, and in case of obvious pollution, the fine mode aerosol particles were dominant. ⣠The monthly concentration variation trend of PM2.5 and PM10 in Chang'an consistent with the maximum and minimum values appeared in January and summer, respectively. Seasonal variation in the concentration of PM2.5 and PM10 was apparent, with the highest values in winter. ⤠A positive correlation between AOD and particulate matter concentration in different seasons and pollution levels was obtained during the observation periods, but the correlation coefficient differed. The specific characteristics were as follows:the correlation between AOD and PM2.5 concentration was greater than that with PM10 concentration; the correlation between AOD and particle concentration in autumn and winter was greater than that in spring and summer; and the correlation between AOD and particulate matter concentration was greater in polluted weather. Particle concentration was the most important determinant of AOD change, followed by relative humidity, which was the meteorological factor with the highest interpretation rate of AOD change in Chang'an. This indicates that a higher correlation between AOD and particle concentration would benefit from a reasonable humidity correction of AOD.
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Contaminación del Aire , Monitoreo del Ambiente , Aerosoles/análisis , Contaminación del Aire/análisis , Monitoreo del Ambiente/métodos , Material Particulado/análisis , FotometríaRESUMEN
Immunotherapy with checkpoint inhibitors, such as PD-1/PD-L1 blockage, is becoming standard of practice for an increasing number of cancer types. However, the response rate is only 10%-40%. Thus, identifying biomarkers that could accurately predict the ICI-therapy response is critically important. We downloaded somatic mutation data for 46,697 patients and tumor-infiltrating immune cells levels data for 11070 patients, then combined TP53 and BRAF mutation status into a biomarker model and found that the predict ability of TP53/BRAF mutation model is more powerful than some past models. Commonly, patients with high-TMB status have better response to ICI therapy than patients with low-TMB status. However, the genotype of TP53MUTBRAFWT in high-TMB status cohort have poorer response to ICI therapy than the genotype of BRAFMUTTP53WT in low-TMB status (Median, 18 months vs 47 month). Thus, TP53/BRAF mutation model can add predictive value to TMB in identifying patients who benefited from ICI treatment, which can enable more informed treatment decisions.
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Inhibidores de Puntos de Control Inmunológico , Neoplasias , Proteínas Proto-Oncogénicas B-raf , Proteína p53 Supresora de Tumor , Biomarcadores de Tumor/genética , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia , Mutación , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Sunitinib resistance is a major challenge in systemic therapy for renal cell carcinoma (RCC). The role of circular RNAs (circRNAs) in regulating sunitinib resistance of RCC is largely unknown. We established sunitinib-resistant RCC cell lines in vivo. Through RNA-sequencing, we identified circSNX6, whose expression is upregulated in sunitinib-resistant cells compared with their parental cells. High circSNX6 expression was correlated with sunitinib resistance and worse oncologic outcomes in a cohort of 81 RCC patients. In vitro and in vivo experiments confirmed that circSNX6 could promote sunitinib resistance in RCC. circSNX6 acts as a molecular "sponge" to relieve the suppressive effect of microRNA (miR)-1184 on its target gene, glycerophosphocholine phosphodiesterase 1 (GPCPD1), which increases intracellular lysophosphatidic acid (LPA) levels and, ultimately, promotes sunitinib resistance in RCC cells. Our findings demonstrated that the circSNX6/miR-1184/GPCPD1 axis had a critical role in regulation of intracellular LPA levels and sunitinib resistance in RCC; they also provide a novel prognostic indicator and promising therapeutic targets.
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Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Lisofosfolípidos/fisiología , MicroARNs/fisiología , Fosfolipasas/fisiología , ARN Circular/fisiología , Sunitinib/farmacología , Adulto , Anciano , Animales , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/mortalidad , Línea Celular Tumoral , Resistencia a Antineoplásicos , Femenino , Humanos , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Neoplasias Renales/mortalidad , Masculino , Ratones , Ratones Endogámicos BALB C , Persona de Mediana EdadRESUMEN
Low levels of ITLN1 have been correlated with obesity-related colorectal carcinogenesis, however, the specific functions and underlying mechanisms remain unclear. Thus, we sought to explore the inhibitory role of ITLN1 in the tumor-permissive microenvironment that exists during the first occurrence and subsequent development of colorectal carcinoma (CRC). Results indicated that ITLN1 was frequently lost in CRC tissues and ITLN1 to be an independent prognostic predictor of CRC. Orthotopic and subcutaneous tumor xenograft approaches were then used to further confirm the protective role of ITLN1 during tumor progression. Increased ITLN1 expression in CRC cells significantly inhibited local pre-existing vessels sprouting, EPC recruitment and the infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs) into tumor tissues without affecting the behavior of CRC cells in vitro. Comparatively, ITLN1-derived MDSCs had a lower suppressive effect on T cell proliferation, NOS2 expression, and ROS production. In addition, ITLN1 overexpression markedly suppressed bone marrow (BM)-derived hematopoietic progenitor cells (HPC) differentiation into MDSCs as well as NOS2 activity on MDSCs. Using H-2b+YFP + chimerism through bone marrow transplantation, increased ITLN1 in HCT116 significantly reduced the BM-derived EPCs and MDSCs in vivo mobilization. Mechanistically, results indicated ITLN1 inhibited tumor-derived IL-17D and CXCL2 (MIP2) through the KEAP1/Nrf2/ROS/IL-17D and p65 NF-ĸB/CXCL2 signaling cascades dependent on PI3K/AKT/GSK3ß. This effect was reversed by the PI3K selective inhibitor LY294002. Collectively, ITLN1 synergistically suppressed IL-17D and CXCL2-mediated tumor vascularization, bone marrow derived EPC recruitment, as well as MDSCs generation and trafficking. Thus, ITLN1 potentially serves as a critical prognostic and therapeutic target for CRC.
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Neoplasias Colorrectales/genética , Citocinas/metabolismo , Proteínas Ligadas a GPI/metabolismo , Lectinas/metabolismo , Células Supresoras de Origen Mieloide/metabolismo , Animales , Neoplasias Colorrectales/patología , Humanos , Ratones , Neovascularización PatológicaRESUMEN
Long noncoding RNAs (lncRNAs) have been reported to exert important roles in tumors, including clear cell renal cell carcinoma (ccRCC). PVT1 is an important oncogenic lncRNA which has critical effects on onset and development of various cancers, however, the underlying mechanism of PVT1 functioning in ccRCC remains largely unknown. VHL deficiency-induced HIF2α accumulation is one of the major factors for ccRCC. Here, we identified the potential molecular mechanism of PVT1 in promoting ccRCC development by stabilizing HIF2α. PVT1 was significantly upregulated in ccRCC tissues and high PVT1 expression was associated with poor prognosis of ccRCC patients. Both gain-of-function and loss-of function experiments revealed that PVT1 enhanced ccRCC cells proliferation, migration, and invasion and induced tumor angiogenesis in vitro and in vivo. Mechanistically, PVT1 interacted with HIF2α protein and enhanced its stability by protecting it from ubiquitination-dependent degradation, thereby exerting its biological significance. Meanwhile, HIF2α bound to the enhancer of PVT1 to transactivate its expression. Furthermore, HIF2α specific inhibitor could repress PVT1 expression and its oncogenic functions. Therefore, our study demonstrates that the PVT1/ HIF2α positive feedback loop involves in tumorigenesis and progression of ccRCC, which may be exploited for anticancer therapy.
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Carcinoma de Células Renales , ARN Largo no Codificante , Carcinogénesis , Humanos , Neoplasias Renales , Ubiquitinación , Regulación hacia ArribaRESUMEN
Background and Aims: Aberrant transcriptional programs are highly regulated processes that play important roles in the development and progression of hepatocellular carcinoma (HCC). Emerging evidence suggests that super-enhancers (SEs) often drive critical oncogene expression. However, SE-associated genes in HCC pathogenesis are still poorly understood. Methods: We performed integrative ChIP-seq and Hi-C analyses of HCC cells and identified ajuba LIM protein (AJUBA) as a SE-associated gene. We evaluated AJUBA expression in HCC using immunohistochemistry, immunoblotting, and qRT-PCR. ChIP and luciferase reporter assays were performed to demonstrate that transcription factor 4 (TCF4) bound to AJUBA-associated SEs. We then assessed the role of AJUBA in HCC using both in vitro and in vivo assays. Epithelial-mesenchymal transition (EMT) was examined using immunofluorescence and immunoblotting assays. Furthermore, we used immunoprecipitation and BiFC assays to explore the underlying mechanisms. Results: We identified AJUBA as a SE-associated oncogene in HCC regulated by TCF4. High AJUBA expression was related to an aggressive phenotype and unfavorable outcome in HCC patients. AJUBA knockdown significantly reduced cell migration and invasion capacities both in vitro and in vivo. Furthermore, AJUBA overexpression in HCC recruited tumor necrosis factor associated factor 6 (TRAF6), enhancing the phosphorylation of Akt and increasing Akt activity toward GSK-3ß, thus promoting EMT. Conclusions: Our results provide functional and mechanistic links between the SE-associated gene AJUBA and tumor EMT in aggressive HCC.
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Carcinoma Hepatocelular/genética , Transición Epitelial-Mesenquimal/genética , Proteínas con Dominio LIM/genética , Neoplasias Hepáticas/genética , Factor de Transcripción 4/genética , Animales , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Movimiento Celular/genética , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Células Hep G2 , Humanos , Neoplasias Hepáticas/patología , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Oncogenes/genética , Factor 6 Asociado a Receptor de TNF/genéticaRESUMEN
BACKGROUND: Circular RNAs (circRNAs) have been reported to have critical regulatory roles in tumor biology. However, their contribution to melanoma remains largely unknown. METHODS: CircRNAs derived from oncogene CD151 were detected and verified by analyzing a large number of melanoma samples through quantitative real-time polymerase chain reaction (qRT-PCR). Melanoma cells were stably transfected with lentiviruses using circ_0020710 interference or overexpression plasmid, and then CCK-8, colony formation, wound healing, transwell invasion assays, and mouse xenograft models were employed to assess the potential role of circ_0020710. RNA immunoprecipitation, luciferase reporter assay and fluorescence in situ hybridization were used to evaluate the underlying mechanism of circ_0020710. RESULTS: Our findings indicated that circ_0020710 was generally overexpressed in melanoma tissues, and high level of circ_0020710 was positively correlated with malignant phenotype and poor prognosis of melanoma patients. Elevated circ_0020710 promoted melanoma cell proliferation, migration and invasion in vitro as well as tumor growth in vivo. Mechanistically, we found that high level of circ_0020710 could upregulate the CXCL12 expression via sponging miR-370-3p. CXCL12 downregulation could reverse the malignant behavior of melanoma cells conferred by circ_0020710 over expression. Moreover, we also found that elevated circ_0020710 was correlated with cytotoxic lymphocyte exhaustion, and a combination of AMD3100 (the CXCL12/CXCR4 axis inhibitor) and anti-PD-1 significantly attenuated tumor growth. CONCLUSIONS: Elevated circ_0020710 drives tumor progression via the miR-370-3p/CXCL12 axis, and circ_0020710 is a potential target for melanoma treatment.
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Biomarcadores de Tumor/metabolismo , Quimiocina CXCL12/metabolismo , Regulación Neoplásica de la Expresión Génica , Melanoma/patología , MicroARNs/genética , ARN Circular/genética , Tetraspanina 24/genética , Animales , Apoptosis , Biomarcadores de Tumor/genética , Estudios de Casos y Controles , Movimiento Celular , Proliferación Celular , Quimiocina CXCL12/genética , Progresión de la Enfermedad , Femenino , Humanos , Evasión Inmune , Masculino , Melanoma/genética , Melanoma/inmunología , Melanoma/metabolismo , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Invasividad Neoplásica , Pronóstico , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Metastasis causes the vast majority of colorectal carcinoma (CRC)-related deaths. However, little is known about the specific traits and underlying mechanisms of metastasis-initiating cells in primary CRC. And whether or not circular RNAs (circRNAs) take part in this particular event remain not adequately stated yet. METHODS: A screening method based on Transwell assay was first applied to build CRC subgroups with different metastatic potential. High throughput RNA sequencing was used to find out novel metastatic drivers in CRC metastasis-initiating step. A series of in vitro and in vivo assays were further applied to elucidate the functions and underlying molecular mechanisms of circRNAs in CRC metastasis. RESULTS: A circRNA consisting of exon 8-11 of LONP2, termed as circLONP2, was upregulated in metastasis-initiating CRC subgroups. Aberrant higher expression of circLONP2 was observed in primary CRC tissues with established metastasis, and along the invasive margin in metastatic site. High expression of circLONP2 predicted unfavorable overall survival. Functional studies revealed that circLONP2 could enhance the invasiveness of CRC cells in vitro, and targeting circLONP2 through anti-sense oligonucleotide (ASO) dramatically reduced the penetrance of metastasis to foreign organs in vivo. Mechanically, circLONP2 directly interacted with and promoted the processing of primary microRNA-17 (pri-miR-17), through recruiting DiGeorge syndrome critical region gene 8 (DGCR8) and Drosha complex in DDX1-dependent manner. Meanwhile, upregulated mature miR-17-5p could be assembled into exosomes and internalized by neighboring cells to enhance their aggressiveness. CONCLUSIONS: Our data indicate that circLONP2 acts as key metastasis-initiating molecule during CRC progression through modulating the intracellular maturation and intercellular transfer of miR-17, resulting in dissemination of metastasis-initiating ability in primary site and acceleration of metastasis formation in foreign organs. circLONP2 could serve as an effective prognostic predictor and/or novel anti-metastasis therapeutic target in CRC treatment.
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Neoplasias Colorrectales/patología , ARN Helicasas DEAD-box/metabolismo , Exosomas/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/secundario , MicroARNs/genética , ARN Circular/genética , Proteasas ATP-Dependientes/genética , Animales , Apoptosis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Proliferación Celular , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , ARN Helicasas DEAD-box/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Ratones , Ratones Desnudos , Invasividad Neoplásica , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: In our previous study, kindlin-2 promoted skin wound healing and decreased the permeability of neovascularization during angiogenesis. Herein, we explored the biological function and underlying mechanism of kindlin-2 in cutaneous melanoma. METHODS AND RESULTS: Through a series of in vitro assays, we found that high levels of kindlin-2 promoted migration and invasion of melanoma cells without influencing cell proliferation. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analyses showed that upregulated kindlin-2 promoted the cellular epithelial-mesenchymal transition (EMT). Importantly, we found that melanoma cells overexpressing kindlin-2 promoted angiogenesis and VEGFA secretion in vitro and facilitated tumour growth and lung metastasis in vivo. To unveil the underlying mechanism, we conducted Next-generation sequencing (NGS) and differential expression analyses. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that overlapping differentially expressed genes (DEGs) were primarily enriched in the TGF-ß, mTOR and VEGF signalling pathways. Then, we confirmed that the mTOR/VEGFA pathway was activated during the process of kindlin-2-induced melanoma progression and angiogenesis. Moreover, we demonstrated that kindlin-2 was significantly overexpressed in clinical melanoma samples and that a high level of kindlin-2 predicted a poor prognosis. CONCLUSIONS: Taken together, these findings showed that kindlin-2 promotes angiogenesis and tumour progression via the mTOR/VEGFA pathway.
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Melanoma/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Neovascularización Patológica/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Línea Celular , Regulación de la Expresión Génica , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones Desnudos , Neoplasias Experimentales , Serina-Treonina Quinasas TOR/genética , Regulación hacia Arriba , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
Kinesin family member C1 (KIFC1) is implicated in the clustering of multiple centrosomes to maintain tumor survival and is thought to be an oncogene in several kinds of cancers. In our experiments, we first performed bioinformatics analysis to investigate the expression levels of KIFC1 in bladder cancer (BC) specimens and normal bladder epitheliums and then, using our samples, verified findings by quantitative real-time PCR and western blotting assays. All data showed that KIFC1 was significantly upregulated in BC specimens at both the mRNA and protein levels. Immunohistochemical studies in a cohort of 152 paraffin-embedded BC tissues displayed that upregulated expression of KIFC1 clearly correlated with pT status (P = .014) and recurrent status (P = .002). Kaplan-Meier survival analysis and log-rank test indicated that patients with BC with high KIFC1 expression had both shorter cancer-specific survival (P < .001) and recurrence-free survival time (P < .001) than those with low KIFC1 expression. Furthermore, ectopic downregulation of KIFC1 weakened BC cell proliferation and migration both in vitro and in vivo, whereas upregulation of KIFC1 enhanced this in vitro. Overexpression of KIFC1 phosphorylated GSK3ß and promoted Snail through activating AKT (protein kinase B0) to induce proliferation and epithelial-mesenchymal transition (EMT) and, therefore, substantially promoted BC migration and metastasis. Our study revealed an oncogenic role for KIFC1 to promote BC cell proliferation and EMT via Akt/GSK3ß signaling; KIFC1 might be a promising prognostic biomarker as well as a therapeutic target for BC.
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Biomarcadores de Tumor/metabolismo , Transición Epitelial-Mesenquimal , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Cinesinas/metabolismo , Recurrencia Local de Neoplasia/diagnóstico , Neoplasias de la Vejiga Urinaria/patología , Animales , Línea Celular Tumoral , Proliferación Celular , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Fosforilación , Pronóstico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factores de Transcripción de la Familia Snail/metabolismo , Regulación hacia Arriba , Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/mortalidad , Urotelio/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Aim: To study the expression of EIF5A2 in urinary tract urothelial carcinoma and its clinicopathological features and prognosis. Methods: EIF5A2 expression was detected via immunohistochemistry in 101 patients. Results: Kaplan-Meier analysis showed that the EIF5A2 low expression group had significantly longer overall survival (OS; p < 0.001) and progression-free survival (PFS; p < 0.001) than the EIF5A2 high expression group. The high expression of EIF5A2 significantly predict poor OS and PFS in the subset patients (p < 0.05). EIF5A2 was an independent prognostic factor for OS and PFS (p = 0.003 and p = 0.001). The established nomogram model and its calibration curve predicted the probability of survival accurately. Conclusion: EIF5A2 is a potential molecular marker of poor prognosis in urinary tract urothelial carcinoma.
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Carcinoma de Células Transicionales/patología , Neoplasias Renales/patología , Factores de Iniciación de Péptidos/metabolismo , Proteínas de Unión al ARN/metabolismo , Neoplasias Ureterales/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Carcinoma de Células Transicionales/mortalidad , Carcinoma de Células Transicionales/cirugía , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Neoplasias Renales/mortalidad , Neoplasias Renales/cirugía , Pelvis Renal/patología , Pelvis Renal/cirugía , Masculino , Persona de Mediana Edad , Nefroureterectomía , Pronóstico , Supervivencia sin Progresión , Uréter/patología , Uréter/cirugía , Neoplasias Ureterales/mortalidad , Neoplasias Ureterales/cirugía , Factor 5A Eucariótico de Iniciación de TraducciónRESUMEN
Eukaryotic translation initiation factor (EIF) 5A2 exerts important functions that regulate the development and progression of cancers. The present study aimed to investigate the expression of EIF5A2 in prostate cancer (PCa) and its association with biological and prognostic significance. EIF5A2 mRNA and protein levels were analyzed in three paired samples of freshly resected PCa and adjacent non-tumor tissues. Immunohistochemical staining was used to detect the expression of EIF5A2 protein levels in 72 paraffin-embedded PCa tumor specimens. Subsequently, the association between EIF5A2 protein expression and clinicopathological parameters was assessed. Semi-quantitative reverse transcription-polymerase chain reaction and western blot analyses showed both EIF5A2 mRNA and protein levels were elevated in PCa compared with adjacent non-tumor tissues. Elevated EIF5A2 protein levels were observed in 73.6% (53/72) of the clinical PCa tissues using immunohistochemical staining. EIF5A2 expression was significantly associated with tumor stage (P=0.011) and biochemical recurrence status (P=0.032). Additionally, high levels of EIF5A2 predicted worse progression-free survival (P=0.007). Multivariate Cox regression analysis indicated that high expression of EIF5A2 was an independent prognostic factor for poor progression-free survival (hazard ratios, 0.366; 95% confidence interval, 0.349-0.460; P=0.021). The present study demonstrated that EIF5A2 is overexpressed in prostate cancer and may be a potential predictor and therapeutic target in PCa patients.