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Clear cell renal cell carcinoma (ccRCC) demonstrates enhanced glycolysis, critically contributing to tumor development. Programmed death-ligand 1 (PD-L1) aids tumor cells in evading T-cell-mediated immune surveillance. Yet, the specific mechanism by which glycolysis influences PD-L1 expression in ccRCC is not fully understood. Our research identified that the glycolysis-related gene (GRG) HK3 has a unique correlation with PD-L1 expression. HK3 has been identified as a key regulator of O-GlcNAcylation in ccRCC. O-GlcNAcylation exists on the serine 900 (Ser900) site of EP300 and can enhance its stability and oncogenic activity by preventing ubiquitination. Stably expressed EP300 works together with TFAP2A as a co-transcription factor to promote PD-L1 transcription and as an acetyltransferase to stabilize PD-L1 protein. Furthermore, ccRCC exhibits interactive dynamics with tumor-associated macrophages (TAMs). The uridine 5'-diphospho-N-acetylglucosamine (UDP-GlcNAc), which serves as a critical substrate for the O-GlcNAcylation process, facilitates TAMs polarization. In ccRCC cells, HK3 expression is influenced by IL-10 secreted by M2 TAMs. Our study elucidates that HK3-mediated O-GlcNAcylation of EP300 is involved in tumor immune evasion. This finding suggests potential strategies to enhance the efficacy of immune checkpoint blockade therapy.
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Antígeno B7-H1 , Carcinoma de Células Renales , Proteína p300 Asociada a E1A , Hexoquinasa , Neoplasias Renales , Humanos , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/genética , Proteína p300 Asociada a E1A/metabolismo , Antígeno B7-H1/metabolismo , Hexoquinasa/metabolismo , Hexoquinasa/genética , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Neoplasias Renales/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Animales , Evasión Inmune , Macrófagos Asociados a Tumores/metabolismo , Glucólisis , RatonesRESUMEN
Clear cell renal cell carcinoma (ccRCC) presents a unique profile characterized by high levels of angiogenesis and robust vascularization. Understanding the underlying mechanisms driving this heterogeneity is essential for developing effective therapeutic strategies. This study revealed that ubiquitin B (UBB) is downregulated in ccRCC, which adversely affects the survival of ccRCC patients. UBB exerts regulatory control over vascular endothelial growth factor A (VEGFA) by directly interacting with specificity protein 1 (SP1), consequently exerting significant influence on angiogenic processes. Subsequently, we validated that DNA methyltransferase 3 alpha (DNMT3A) is located in the promoter of UBB to epigenetically inhibit UBB transcription. Additionally, we found that an unharmonious UBB/VEGFA ratio mediates pazopanib resistance in ccRCC. These findings underscore the critical involvement of UBB in antiangiogenic therapy and unveil a novel therapeutic strategy for ccRCC.
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Carcinoma de Células Renales , Neoplasias Renales , Neovascularización Patológica , Ubiquitina , Animales , Femenino , Humanos , Masculino , Ratones , Angiogénesis , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Línea Celular Tumoral , ADN Metiltransferasa 3A/metabolismo , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica , Indazoles/farmacología , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Neovascularización Patológica/genética , Neovascularización Patológica/patología , Regiones Promotoras Genéticas , Pirimidinas/farmacología , Factor de Transcripción Sp1/metabolismo , Factor de Transcripción Sp1/genética , Sulfonamidas/farmacología , Ubiquitina/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
Background: Clear cell renal cell carcinoma (ccRCC) stands as the prevailing variant kidney cancer in humans. Unfortunately, patients with disseminated RCC at diagnosis often have a diminished prognosis. Rapid tumor growth necessitates efficient blood supply for oxygen and nutrients, involving the circulation of blood from vessels to tumor tissues, facilitating tumor cell entry into the extracellular matrix. Vasculogenic mimicry (VM) significantly contributes to tumor growth and metastasis. Within this investigation, we identified vasculogenic mimicry-related genes (VMRGs) by analyzing data from 607 cases of kidney renal clear cell carcinoma (KIRC) in The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/). These findings offer insights into ccRCC progression and metastasis. Method: We identified VMRGs-related subtypes using consistent clustering methods. The signature of the VMRGs was created using univariate Cox regression and LASSO Cox regression analyses. To evaluate differences in immune cell infiltration, we employed ssGSEA. Afterwards, we created an innovative risk assessment model, known as the VM index, along with a nomogram to forecast the prognosis of ccRCC. Additionally, we verified the expression of an important gene related to VM, peroxiredoxin 2 (PRDX2), in tissue samples. Furthermore, we assessed the sensitivity to drugs in various groups by utilizing the pRRophetic R package. Results: Significant predictors of survival rates in both high- and low-risk groups of KIRC patients were identified as VMRGs. The independent prognostic factors for RCC were confirmed by both univariate and multivariate Cox regression analyses, validating VMRG risk signatures. Differences were observed in drug sensitivity, immune checkpoint expression, and responses to immune therapy between patients classified into high- and low-VMRG-risk groups. Our nomograms consistently demonstrated precise predictive capabilities. Finally, we experimentally verified PRDX2 expression levels and their impact on prognosis. Conclusion: The signature predicts patient prognosis and therapy response, laying the groundwork for future clinical strategies in treating ccRCC patients.
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BACKGROUND: Early studies indicated that the androgen receptor (AR) could promote renal cell carcinoma (RCC) development and metastasis, but its linkage to RCC progression under hypoxia, remains unclear. RESULTS: Here we found AR expression in RCC cells decreased in response to hypoxia, which might then lead to increase the cancer stem cells (CSC) phenotype through the lncTCFL5-2-modulated YBX1/SOX2 signals. The consequences of such hypoxia-modulated AR/lncTCFL5-2/YBX1/SOX2 signals ablity to alter the CSC phenotype might render RCC cells more resistant to targeted therapy with Sunitinib. Mechanism dissection revealed that AR might alter the lncTCFL5-2/YBX1/SOX2 signaling through transcriptional suppression of the lncTCFL5-2 expression via the AR-response-elements (AREs) on the lncTCFL5-2 promoter. The lncTCFL5-2 interacts with YBX1 to increase its stability, which in turn increases SOX2 expression at a transcriptional level via the YBX1-response-elements (YBX1Es) on the SOX2 promoter. The in vivo mouse model with orthotopic xenografts of RCC cells also validates the in vitro data, and a human RCC sample survey demonstrated the clinical significance of the AR/lncTCFL5-2/YBX1/SOX2 signaling axis for the RCC prognosis, likely as a result of regulating CSC phenotypes. CONCLUSIONS: Together, these findings suggest that hypoxia may increase the RCC CSC phenotype via altering the AR/lncTCFL5-2/YBX1/SOX2 signaling axis and a potential therapy to target this newly identified signal perhaps may help improve the targeted therapy with Sunitinib to better suppress RCC progression.
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Most advanced prostate cancer (PCa) patients initially respond well to androgen deprivation therapy, but almost all eventually develop castration-resistant prostate cancer (CRPC). Early studies indicated the bipolar androgen therapy via a cycling of high dose and low dose of androgen to suppress PCa growth might be effective in a select patient population. The detailed mechanisms, however, remain unclear. Here we found the capacity of natural killer (NK) cells to suppress the CRPC cells could be suppressed by a high dose of dihydrotestosterone (DHT). Mechanism dissection indicates that transactivated AR can increase circularRNA-FKBP5 (circFKBP5) expression, which could sponge/inhibit miR-513a-5p that suppresses the PD-L1 expression via direct binding to its 3'UTR to negatively impact immune surveillance from NK cells. Preclinical data from in vitro cell lines and an in vivo mouse model indicate that targeting PD-L1 with sh-RNA or anti-PD-L1 antibody can enhance the high dose DHT effect to better suppress CRPC cell growth. These findings may help us to develop novel therapies via combination of high dose androgen with PD-1/PD-L1 checkpoint inhibitors to better suppress CRPC progression.
Asunto(s)
MicroARNs , Neoplasias de la Próstata Resistentes a la Castración , Antagonistas de Andrógenos/farmacología , Andrógenos/metabolismo , Andrógenos/farmacología , Animales , Línea Celular Tumoral , Dihidrotestosterona/farmacología , Humanos , Células Asesinas Naturales/metabolismo , Masculino , Ratones , MicroARNs/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Receptores Androgénicos/genéticaRESUMEN
Although androgen receptor (AR) can influence bladder cancer (BCa) initiation and progression, its impact on tumor immune escape remains unclear. Here, we found that targeting AR could enhance natural killer (NK) cell tumor-killing efficacy by decreasing PD-L1 expression. Both antiandrogen treatment and AR knockdown effectively reduced membrane PD-LI expression to facilitate NK cell-mediated BCa cell killing by downregulating circ_0001005. Mechanistically, AR upregulated circRNA circ_0001005 expression via the RNA-editing gene ADAR2. circ_0001005 competitively sponged the miRNA miR-200a-3p to promote PD-L1 expression. A preclinical BCa xenograft mouse model further confirmed this newly identified signaling using the small molecule circ_0001005-shRNA to improve NK cell killing of BCa tumor cells. Collectively, these results suggest that targeting the newly identified ADAR2/circ_0001005/miR-200a-3p/PD-L1 pathway to impact antitumor immunity may suppress progression and boost immunotherapeutic efficacy in BCa.
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MicroARNs , Receptores Androgénicos , Neoplasias de la Vejiga Urinaria , Animales , Humanos , Ratones , Adenosina Desaminasa/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Muerte Celular , Línea Celular Tumoral , Proliferación Celular , Células Asesinas Naturales , MicroARNs/genética , Receptores Androgénicos/genética , Proteínas de Unión al ARN/genética , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/terapia , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
BACKGROUND: Radiation therapy (RT) with androgen deprivation therapy (ADT) is an effective therapy to suppress the locally advanced prostate cancer (PCa). However, we unexpectedly found that RT could also induce the androgen receptor splice variant 7 (ARv7) expression to decrease the radiosensitivity. METHODS: The study was designed to target ARv7 expression with Quercetin or ARv7-shRNA that leads to enhancing and increasing the radiation sensitivity to better suppress the PCa that involved the modulation of the circNHS/miR-512-5p/XRCC5 signaling. RESULTS: Mechanism studies revealed that RT-induced ARv7 may function via altering the circNHS/miR-512-5p/XRCC5 signaling to decrease the radiosensitivity. Results from preclinical studies using multiple in vitro cell lines and in vivo mouse models concluded that combining RT with the small molecule of Quercetin to target full-length AR and ARv7 could lead to better efficacy to suppress PCa progression. CONCLUSION: Together, these results suggest that ARv7 may play key roles to alter the PCa radiosensitivity, and targeting this newly identified ARv7 mediated circNHS/miR-512-5p/XRCC5 signaling with Quercetin may help physicians to develop a novel RT to better suppress the progression of PCa.
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MicroARNs , Neoplasias de la Próstata , Antagonistas de Andrógenos , Animales , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Humanos , Autoantígeno Ku/genética , Autoantígeno Ku/metabolismo , Masculino , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/radioterapia , Quercetina/farmacología , Tolerancia a Radiación , Receptores Androgénicos/metabolismoRESUMEN
Background: Aberrant promoter methylation and its resultant aberrant gene expression are important epigenetic mechanisms that promote the development of breast cancer (BC). However, the prognostic value of this type of methylation-driven gene in BC is unknown. Methods: To identify DNA methylation-driven long non-coding RNAs (lncRNAs), a comprehensive analysis of RNA-sequencing and DNA methylation data of 1,200 clinical samples was performed. Differentially expressed lncRNAs (DELs) and survival-related lncRNAs in BC were identified using the R package. The function of the lncRNA was evaluated using Kaplan-Meier and receiver operating characteristic (ROC) curve analyses. The expression of the key lncRNA in tissues and cells was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Biological functions of the key lncRNA were analyzed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. The Connectivity Map (CMap) was used to search for small-molecule targeted drugs for the key lncRNA. The functions of the key lncRNA in BC progression were investigated using cell proliferation and cell cycle assays. Results: A total of 14 methylation-driven lncRNAs, 526 DELs, and 93 survival-associated lncRNAs were identified. The above data were intersected, and a unique lncRNA, LINC00092, was obtained. LINC00092 was hypermethylated and hypoexpressed in both BC tissues and cell lines. LINC00092 was found to be a diagnostic marker for BC, with its low expression being associated with poor prognosis (P=0.013). LINC00092 overexpression inhibited the proliferation and cell cycle of BC cells in vitro. Nimesulide and sulpiride were screened out as potential targeted therapeutic drugs for LINC00092 in BC, and sulpiride was observed to partially reverse the proliferative effect of (small interfer) si-LINC00092 on BC cells. Conclusions: LINC00092 is a methylation-driven lncRNA in BC and could be a potential therapeutic target for this disease.
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Motivation: Kidney renal clear cell carcinoma, which is a common type and accounts for 70-80% of renal cell carcinoma, can easily lead to metastasis and even death. A reliable signature for diagnosis of this cancer is in need. Hence, we seek to select miRNAs for identifying kidney renal clear cell carcinoma. Method: A feature selection strategy is used and improved to identify microRNAs for diagnosis of kidney renal clear cell carcinoma. Samples representing kidney renal clear cell carcinoma and normal tissues are split into training and testing groups. Accumulated scores representing the variable importance of each miRNA are derived from an iteration of resampling, training, and scoring. Those miRNAs with higher scores are selected based on the Gaussian mixture model. The sample split is repeated ten times to get more central miRNAs. Results: A total of 611 samples are downloaded from TCGA, each of which contains 1,343 miRNAs. The improved feature selection method is implemented, and five miRNAs are identified as a biomarker for diagnosis of kidney renal clear cell carcinoma. GSE151419 and GSE151423 are selected as the independent testing sets. Experimental results indicate the effectiveness of the selected signature. Both data-driven measurements and knowledge-driven evidence are given to show the effectiveness of our selection results.
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Previous studies have investigated whether tumor-associated macrophages (TAMs) play tumorigenic and immunosuppressive roles to encourage cancer development, but the role of TAMs in regulating vasculogenic mimicry (VM) in clear-cell renal cell carcinoma (ccRCC) cells has not been completely clarified. We conducted immunostaining of the tumor-associated macrophage biomarkers CD68/CD163 and double staining for PAS/CD31 in ccRCC human specimens to find that higher TAM infiltration was positively correlated with VM formation. Then we demonstrated that TAM-derived exosomes downregulate TIMP2 expression in RCC cells to promote VM and invasion by shuttling miR-193a-5p. Mechanistic analysis indicated that HIF-1α upregulation in macrophages could transcriptionally increase miR-193a-5p expression. Exosome-shuttled miR-193a-5p then targeted the 3' untranslated region (UTR) of TIMP2 mRNA to suppress its translation. A preclinical study using an in vivo orthotopic xenograft model of ccRCC in mice substantiated that TAM-derived exosomes enhance VM and enable tumor progression, which confirmed our in vitro data. Suppressing TAM-derived exosomal miR-193a-5p successfully inhibited tumor progression and metastasis. Overall, miR-193a-5p from TAM-derived exosomes downregulates the TIMP2 gene to facilitate the development of RCC, which provides a novel perspective for developing therapeutic strategies for RCC.
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Carcinoma de Células Renales , Exosomas , Neoplasias Renales , MicroARNs , Animales , Carcinoma de Células Renales/metabolismo , Línea Celular Tumoral , Proliferación Celular , Exosomas/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Renales/metabolismo , Masculino , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Inhibidor Tisular de Metaloproteinasa-2/genética , Inhibidor Tisular de Metaloproteinasa-2/metabolismo , Macrófagos Asociados a TumoresRESUMEN
Androgen deprivation therapy (ADT) is a gold standard treatment for advanced PCa. However, most patients eventually develop the castration-resistant prostate cancer (CRPC) that progresses rapidly despite ongoing systemic androgen deprivation. While early studies indicated that high physiological doses of androgens might suppress rather than promote PCa cell growth in some selective CRPC patients, the exact mechanism of this opposite effect remains unclear. Here we found that Enzalutamide-resistant (EnzR) CRPC cells can be suppressed by the high-dose-androgen (dihydrotestosterone, DHT). Mechanism dissection suggested that a high-dose-DHT can suppress the circular RNA-BCL2 (circRNA-BCL2) expression via transcriptional regulation of its host gene BCL2. The suppressed circRNA-BCL2 can then alter the expression of miRNA-198 to modulate the AMBRA1 expression via direct binding to the 3'UTR of AMBRA1 mRNA. The consequences of high-dose-DHT suppressed circRNA-BCL2/miRNA-198/AMBRA1 signaling likely result in induction of the autophagic cell death to suppress the EnzR CRPC cell growth. Preclinical studies using in vivo xenograft mouse models also demonstrated that AMBRA1-shRNA to suppress the autophagic cell death can weaken the effect of high-dose-DHT on EnzR CRPC tumors. Together, these in vitro and in vivo data provide new insights for understanding the mechanisms underlying high-dose-DHT suppression of the EnzR CRPC cell growth, supporting a potential therapy using high-dose-androgens to suppress CRPC progression in the future.
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Androgen-deprivation therapy (ADT) via targeting androgens/androgen receptor (AR) signals may suppress cell proliferation in both prostate cancer (PCa) and bladder cancer (BCa), yet its impact on the cell invasion of these two urological cancers remains unclear. Here we found targeting androgens/AR with either the recently developed antiandrogen Enzalutamide (Enz) or AR-shRNAs led to increase PCa cell invasion, yet decrease BCa cell invasion. Mechanistic dissection revealed that suppressing androgens/AR signals could result in differential alterations of the selective circular RNAs (circRNAs) as a result of differential endogenous AR transcription. A negative autoregulation in PCa, yet a positive autoregulation in BCa, as a result of differential binding of AR to different androgen-response elements (AREs) and a discriminating histone H3K4 methylation, likely contributes to this outcome between these two urological tumors. Further mechanistic studies indicated that AR-encoded circRNA-ARC1 might sponge/alter the availability of the miRNAs miR-125b-2-3p and/or miR-4736, to impact the metastasis-related PPARγ/MMP-9 signals to alter the PCa vs. BCa cell invasion. The preclinical study using the in vivo mouse model confirms in vitro cell lines data, showing that Enz treatment could increase PCa metastasis, which can be suppressed after suppressing circRNA-ARC1 with sh-circRNA-ARC1. Together, these in vitro/in vivo results demonstrate that antiandrogen therapy with Enz via targeting AR may lead to either increase PCa cell invasion or decrease BCa cell invasion. Targeting these newly identified AR/circRNA-ARC1/miR-125b-2-3p and/or miR-4736/PPARγ/MMP-9 signals may help in the development of new therapies to better suppress the Enz-altered PCa vs. BCa metastasis.
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Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , ARN Circular/genética , Receptores Androgénicos/metabolismo , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/genética , Antagonistas de Andrógenos/uso terapéutico , Animales , Benzamidas/farmacología , Línea Celular Tumoral , Proliferación Celular , Humanos , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Desnudos , MicroARNs/metabolismo , Invasividad Neoplásica , Nitrilos/farmacología , PPAR gamma/metabolismo , Feniltiohidantoína/farmacología , Neoplasias de la Próstata/patología , Receptores Androgénicos/genética , Transducción de Señal , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
The formation and physicochemical properties of kidney stones (KSs) are closely associated with diet. In view of the differences in ethnicity and dietary composition between Chinese and Western populations, the present study aimed to investigate the association between intestinal dysbacteriosis and KSs in China. The current study examined the differences in intestinal microbes between the KS disease (KSD) and the healthy control (HLT) groups, and statistically significant differences based on 16s rRNA gene amplicons were identified using a Student's ttest or oneway ANOVA. In addition, the calcium oxalate KS (COKS), uric acid KS (UAKS) and carbonate apatite KS(CCKS) groups were compared with a nonparametric statistical test. Determination of bacterial abundance was performed via the analysis of 16s rRNA marker gene sequences using nextgeneration sequencing. Firmicutes (F) and Bacteroides (B) levels were significantly higher in the KSD group compared with the HLT group (B/F=0.67 vs. 0.08; P<0.001), as were the overall levels of B (6.19fold higher compared with the HLT group; 22.2 vs. 3.6%; P<0.001). The Prevotella9 abundance levels in the KSD group were 4.65fold higher compared with those in the HLT group (8.8 vs. 1.9%; P<0.001). The levels of Blautia and Lachnoclostridium were significantly decreased in the KSD group (13.3 vs. 6.0%; and 5.0 vs. 7.9%; both P<0.05). Moreover, Prevotella9 levels were higher in noncalciferous KSs (UAKS) compared with calciferous KSs (COKS and CCKS). Therefore, the findings of the present study indicated a key association between specific KS components and intestinal flora, providing a theoretical basis for new treatment methods for KSs. Moreover, differences and interactions between these bacteria could initially predict specific types of urolithiasis.
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Disbiosis/genética , Microbioma Gastrointestinal/genética , Intestinos/microbiología , Cálculos Renales/genética , Adulto , Anciano , Anciano de 80 o más Años , China/epidemiología , Dieta , Disbiosis/complicaciones , Disbiosis/microbiología , Disbiosis/patología , Femenino , Humanos , Intestinos/patología , Cálculos Renales/etiología , Cálculos Renales/microbiología , Cálculos Renales/patología , Masculino , Persona de Mediana Edad , ARN Ribosómico 16S/genéticaRESUMEN
While the androgen receptor (AR) may influence the progression of clear cell renal cell carcinoma (ccRCC), its role to impact vasculogenic mimicry (VM) to alter the ccRCC progression and metastasis remains obscure. Here, we demonstrated that elevated AR expression was positively correlated with tumor-originated vasculogenesis in ccRCC patients. Consistently, in vitro research revealed AR promoted VM formation in ccRCC cell lines via modulating lncRNA-TANAR/TWIST1 signals. Mechanism dissection showed that AR could increase lncRNA-TANAR (TANAR) expression through binding to the androgen response elements (AREs) located in its promoter region. Moreover, we found that TANAR could impede nonsense-mediated mRNA decay (NMD) of TWIST1 mRNA by direct interaction with TWIST1 5'UTR. A preclinical study using in vivo mouse model with orthotopic xenografts of ccRCC cells further confirmed the in vitro data. Together, these results illustrated that AR-mediated TANAR signals might play a crucial role in ccRCC VM formation and metastasis, and targeting this newly identified AR/TANAR/TWIST1 signaling may help in the development of a novel anti-angiogenesis therapy to better suppress the ccRCC progression.
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Carcinoma de Células Renales/genética , Neovascularización Patológica/genética , Proteínas Nucleares/genética , ARN Largo no Codificante/genética , Receptores Androgénicos/genética , Proteína 1 Relacionada con Twist/genética , Animales , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Movimiento Celular/genética , Codón sin Sentido/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Ratones , Neovascularización Patológica/patología , Degradación de ARNm Mediada por Codón sin Sentido/genética , Transducción de Señal/genéticaRESUMEN
Most patients with advanced prostate cancer (PCa) initially respond well to androgen deprivation therapy (ADT) with antiandrogens, but most of them eventually become resistant to ADT. Here, we found that the antiandrogen Enzalutamide-resistant (EnzR) PCa cells can be suppressed by hyper-physiological doses of the androgen DHT. Mechanism dissection indicates that while androgens/androgen receptor (AR) can decrease BCL-2 expression to induce cell death, yet they can also simultaneously increase anti-apoptosis BCL-XL protein expression via decreasing its potential E3 ubiquitin ligase, PARK2, through transcriptionally increasing the miR-493-3p expression to target PARK2. Thus, targeting the high dose DHT/AR/miR-493-3p/PARK2/BCL-XL signaling with BCL-XL-shRNA can increase high-dose-DHT effect to better suppress EnzR cell growth via increasing the autophagic cell death. A preclinical study using in vivo mouse model also validated that suppressing BCL-XL led to enhance high dose DHT effect to induce PCa cell death. The success of human clinical trials in the future may help us to develop a novel therapy using high dose androgens to better suppress CRPC progression.
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Muerte Celular Autofágica/fisiología , Benzamidas/uso terapéutico , Nitrilos/uso terapéutico , Feniltiohidantoína/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Benzamidas/farmacología , Humanos , Masculino , Ratones , Ratones Desnudos , Nitrilos/farmacología , Feniltiohidantoína/farmacologíaRESUMEN
BACKGROUND: Early studies indicated that ASC-J9®, an androgen receptor (AR) degradation enhancer, could suppress the prostate cancer (PCa) progression. Here we found ASC-J9® could also suppress the PCa progression via an AR-independent mechanism, which might involve modulating the tumor suppressor ATF3 expression. METHODS: The lentiviral system was used to modify gene expression in C4-2, CWR22Rv1 and PC-3 cells. Western blot and Immunohistochemistry were used to detect protein expression. MTT and Transwell assays were used to test the proliferation and invasion ability. RESULTS: ASC-J9® can suppress PCa cell proliferation and invasion in both PCa C4-2 and CWR22Rv1 cells via altering the ATF3 expression. Further mechanistic studies reveal that ASC-J9® can increase the ATF3 expression via decreasing Glutamate-cysteine ligase catalytic (GCLC) subunit expression, which can then lead to decrease the PTK2 expression. Human clinical studies further linked the ATF3 expression to the PCa progression. Preclinical studies using in vivo mouse model also proved ASC-J9® could suppress AR-independent PCa cell invasion, which could be reversed after suppressing ATF3. CONCLUSIONS: ASC-J9® can function via altering ATF3/PTK2 signaling to suppress the PCa progression in an AR-independent manner.
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Factor de Transcripción Activador 3/metabolismo , Curcumina/análogos & derivados , Quinasa 1 de Adhesión Focal/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Curcumina/farmacología , Humanos , Masculino , Ratones , Ratones Desnudos , Invasividad Neoplásica , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Drug delivery systems with magnetization facilitate the accumulation of drug at the target site. This study aimed to explore the mechanism by which docosahexaenoic acid (DHA)-modified porous metal-organic framework (MOF) UIO-66-NH2 loads chemotherapeutic drug 5-fluorouracil (5-FU) and reduces the chemotherapy resistance of breast cancer (BC) cells. METHODS: UIO-66-NH2 was synthesized and DHA with carboxyl end was used to modify the surface of UIO-66-NH2. 5-FU was incorporated to UIO-66-NH2 or DHA-UIO-66-NH2 by a post-synthesis method. The loading and release of 5-FU by @DHA-UIO-66-NH2 was investigated with ultraviolet (UV) spectroscopy. RT-qPCR was conducted to detect the expression of let-7a in cells. The uptake of DHA-UIO-66-NH2 by MCF-7 BC cells was observed by confocal laser scanning microscope (CLSM). Cell counting kit-8 (CCK-8), flow cytometry, and live/dead cell staining were applied to investigate the effects of 5-FU@DHA-UIO-66-NH2 on BC cells, and a BC mouse model was established to explore its effects on tumorigenesis. HE staining and routine blood index analysis were applied for determination of the biological safety of 5-FU@DHA-UIO-66-NH2. RESULTS: 5-FU@DHA-UIO-66-NH2 was successfully constructed and characterized. The loading amount of DHA-UIO-NH2 for 5-FU reached 30.31%. DHA-UIO-66-NH2 was effectively taken up by MCF-7 cells. Further, 5-FU@DHA-UIO-66-NH2 exhibited stronger inhibitory effects on MCF-7 cell viability in vitro as well as tumorigenesis in vivo than 5-FU and 5-FU@UIO-66-NH2. DHA up-regulated let-7a to reduce the resistance of MCF-7 cells to 5-FU. Moreover, the biosafety of 5-FU@DHA-UIO-66-NH2 was identified. CONCLUSIONS: 5-FU@DHA-UIO-66-NH2 increased the level of let-7a in BC cells, repressed cell viability and augmented apoptosis, and thus reduced the chemotherapy resistance of BC cells.
RESUMEN
The FDA-approved anti-androgen Enzalutamide (Enz) has been used successfully as the last line therapy to extend castration-resistant prostate cancer (CRPC) patients' survival by an extra 4.8 months. However, CRPC patients eventually develop Enz-resistance that may involve the induction of the androgen receptor (AR) splicing variant ARv7. Here we found that Cisplatin (Cis) or Carboplatin, currently used in chemotherapy/radiation therapy to suppress tumor progression, could restore the Enz sensitivity in multiple Enz-resistant (EnzR) CRPC cells via directly degrading/suppressing the ARv7. Combining Cis or Carboplatin with Enz therapy can also delay the development of Enz-resistance in CRPC C4-2 cells. Mechanism dissection found that Cis or Carboplatin might decrease the ARv7 expression via multiple mechanisms including targeting the lncRNA-Malat1/SF2 RNA splicing complex and increasing ARv7 degradation via altering ubiquitination. Preclinical studies using in vivo mouse model with implanted EnzR1-C4-2 cells also demonstrated that Cis plus Enz therapy resulted in better suppression of EnzR CRPC progression than Enz treatment alone. These results not only unveil the previously unrecognized Cis mechanism to degrade ARv7 via targeting the Malat1/SF2 complex and ubiquitination signals, it may also provide a novel and ready therapy to further suppress the EnzR CRPC progression in the near future.