ABSTRACT
Benign prostatic hyperplasia (BPH), characterized by the non-malignant enlargement of the prostate, exhibits a pronounced association with inflammation resulting from androgen receptor (AR) deficiency. Ferroptosis, a cell death mechanism triggered by iron-dependent lipid peroxidation and closely linked to inflammation, has yet to be fully understood in the context of BPH. Using RNA sequencing, we observed a significant elevation of taurine-upregulated gene 1 (TUG1) long noncoding RNA (lncRNA) in BPH tissues compared to normal prostate tissue. High levels of TUG1 exhibited a discernible correlation with both prostate volume and the extent of inflammatory infiltration in BPH patients. The suppression of TUG1 not only led to a reduction in prostate size but also ameliorated AR-deficiency-induced prostatic hyperplasia. Mechanistically, a decrease in AR in prostate luminal cells prompted macrophage aggregation and the release of IL-1ß, subsequently fostering the transcription of TUG1 via MYC. Induced TUG1, through competitive binding with miR-188-3p, facilitated the expression of GPX4, thereby diminishing intracellular ROS levels and impeding ferroptosis in prostate luminal cells. Notably, the ferroptosis inducer JKE-1674 alleviated inflammation-induced prostatic hyperplasia in vivo. Together, these findings suggest that AR deficiency crucially inhibits ferroptosis, promoting BPH via the TUG1/miR-188-3p/GPX4 signaling axis, and making ferroptosis induction a promising therapeutic strategy for BPH patients with AR deficiency.
Subject(s)
Ferroptosis , MicroRNAs , Phospholipid Hydroperoxide Glutathione Peroxidase , Prostatic Hyperplasia , RNA, Long Noncoding , Receptors, Androgen , Signal Transduction , Male , Ferroptosis/genetics , Prostatic Hyperplasia/metabolism , Prostatic Hyperplasia/genetics , Prostatic Hyperplasia/pathology , Receptors, Androgen/metabolism , Receptors, Androgen/genetics , Humans , MicroRNAs/genetics , Animals , RNA, Long Noncoding/genetics , Mice , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/genetics , Disease SusceptibilityABSTRACT
BACKGROUND: The introduction of multiparameter MRI and novel biomarkers has greatly improved the prediction of clinically significant prostate cancer (csPCa). However, decision-making regarding prostate biopsy and prebiopsy examinations is still difficult. We aimed to establish a quick and economic tool to improve the detection of csPCa based on routinely performed clinical examinations through an automated machine learning platform (AutoML). METHODS: This study included a multicenter retrospective cohort and two prospective cohorts with 4747 cases from 9 hospitals across China. The multimodal data, including demographics, clinical characteristics, laboratory tests, and ultrasound reports, of consecutive participants were retrieved using extract-transform-load tools. AutoML was applied to explore potential data processing patterns and the most suitable algorithm to build the Prostate Cancer Artificial Intelligence Diagnostic System (PCAIDS). The diagnostic performance was determined by the receiver operating characteristic curve (ROC) for discriminating csPCa from insignificant prostate cancer (PCa) and benign disease. The clinical utility was evaluated by decision curve analysis (DCA) and waterfall plots. RESULTS: The random forest algorithm was applied in the feature selection, and the AutoML algorithm was applied for model establishment. The area under the curve (AUC) value in identifying csPCa was 0.853 in the training cohort, 0.820 in the validation cohort, 0.807 in the Changhai prospective cohort, and 0.850 in the Zhongda prospective cohort. DCA showed that the PCAIDS was superior to PSA or fPSA/tPSA for diagnosing csPCa with a higher net benefit for all threshold probabilities in all cohorts. Setting a fixed sensitivity of 95%, a total of 32.2%, 17.6%, and 26.3% of unnecessary biopsies could be avoided with less than 5% of csPCa missed in the validation cohort, Changhai and Zhongda prospective cohorts, respectively. CONCLUSIONS: The PCAIDS was an effective tool to inform decision-making regarding the need for prostate biopsy and prebiopsy examinations such as mpMRI. Further prospective and international studies are warranted to validate the findings of this study. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100048428. Registered on 06 July 2021.
Subject(s)
Artificial Intelligence , Prostatic Neoplasms , Male , Humans , Retrospective Studies , Algorithms , Machine LearningABSTRACT
BACKGROUND: Melittin is a small molecule polypeptide extracted from the abdominal cavity of bees, which is used to treat inflammatory diseases and relieve pain. However, the antitumor effect of melittin and its mechanisms remain unclear, especially in castration-resistant prostate cancer (CRPC). METHODS: Through CCK-8 assay, colony formation assay, wound healing assay and Transwell migration assay, we explored the effect of melittin on CRPC cell lines. In addition, with microarray analysis, gene ontology analysis and kyoto encyclopedia of genes and genomes analysis, this study identified key genes and signaling pathways that influence the growth of PC-3 cells. Meanwhile, the effect of melittin on CRPC was also verified through subcutaneous tumor formation experiments. Finally, we also tested the relevant indicators of human prostate cancer (PCa) specimens through immunohistochemistry and Hï¼E stating. RESULTS: Here, melittin was verified to inhibit the cell proliferation and migration of CPRC. Moreover, RNA-sequence analysis demonstrated that Interleukin-17 (IL-17) signaling pathway gene Lipocalin-2 (LCN2) was downregulated by melittin treatment in CRPC. Further investigation revealed that overexpression of LCN2 was able to rescue tumor suppression and cisplatin sensitivity which melittin mediated. Interestingly, the expression of LCN2 is highly related to metastasis in PCa. CONCLUSIONS: In brief, our study indicates that LCN2 plays an oncogenic role in CRPC and melittin may be selected as an attractive candidate for CRPC therapy.
Subject(s)
Cisplatin , Prostatic Neoplasms, Castration-Resistant , Male , Humans , Animals , Lipocalin-2/genetics , Lipocalin-2/metabolism , Lipocalin-2/pharmacology , Cisplatin/pharmacology , Cisplatin/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/metabolism , Interleukin-17/metabolism , Interleukin-17/pharmacology , Melitten/pharmacology , Melitten/metabolism , Cell Line, Tumor , Signal Transduction , Cell Proliferation , Cell MovementABSTRACT
Exosomes are small extracellular vesicles that can be utilized as noninvasive biomarkers for diagnosis and treatment of cancer and other diseases. This study reports on a strategy involving a hybridized chain reaction-amplified chain coupled with an alkaline phosphatase-induced Ag-shell nanostructure for the ultrasensitive and rapid surface-enhanced Raman scattering immunoassay of exosomes. Exosomes from prostate cancer were captured using prostate-specific membrane antigen aptamer-modified magnetic beads; then, the hybridized chain reaction-amplified chain was released, incorporating a large number of functional moieties with signal amplification effects. Moreover, the steps of traditional immunoassay were simplified using magnetic materials, and the rapid, sensitive, and accurate detection of exosomes was achieved. Results could be obtained within 40 min with a detection limit of 19 particles/µL. Furthermore, the sera of human prostate cancer patients could be easily distinguished from those of healthy controls, highlighting the potential use of exosome analysis in clinical diagnostics.
Subject(s)
Exosomes , Nanostructures , Prostatic Neoplasms , Male , Humans , Alkaline Phosphatase/analysis , Exosomes/chemistry , Spectrum Analysis, Raman , Prostatic Neoplasms/diagnosis , Immunoassay/methodsABSTRACT
Although several therapeutic options have been shown to improve survival of most patients with prostate cancer, progression to castration-refractory state continues to present challenges in clinics and scientific research. As a highly heterogeneous disease entity, the mechanisms of castration-resistant prostate cancer (CRPC) are complicated and arise from multiple factors. Among them, noncoding RNAs (ncRNAs), the untranslated part of the human transcriptome, are closely related to almost all biological regulation, including tumor metabolisms, epigenetic modifications and immune escape, which has encouraged scientists to investigate their role in CRPC. In clinical practice, ncRNAs, especially miRNAs and lncRNAs, may function as potential biomarkers for diagnosis and prognosis of CRPC. Therefore, understanding the molecular biology of CRPC will help boost a shift in the treatment of CRPC patients. In this review, we summarize the recent findings of miRNAs and lncRNAs, discuss their potential functional mechanisms and highlight their clinical application prospects in CRPC.
Subject(s)
MicroRNAs , Prostatic Neoplasms, Castration-Resistant , RNA, Long Noncoding , Male , Humans , Prostatic Neoplasms, Castration-Resistant/pathology , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , RNA, Untranslated/genetics , MicroRNAs/genetics , Biomarkers , Receptors, Androgen/metabolism , Gene Expression Regulation, NeoplasticABSTRACT
BACKGROUND: To summarize our clinical experience of cryoablation in renal cell carcinoma (RCC) of Chinese population and to evaluate the long-term outcomes of laparoendoscopic single-site (LESS) cryoablation (LCA) as well as percutaneous CT-guided cryoablation (PCA) for biopsy-proven T1a and T1b RCC. METHODS: This was a multi-center, retrospective study investigating T1 stage RCC patients from 2011 to 2021. The patients were treated by LCA or PCA according to individual situation. Overall survival (OS), cancer-related survival (CSS), and progression-free survival (PFS) were evaluated for oncological outcomes, and kidney function, complications, and hospital stay were used to estimate technical outcomes. RESULTS: A total of 163 consecutive patients were included. Among them, 59 cases were treated by LCA and PCA was performed in 104 cases. All operations were processed successfully. Mean diameter of the mass was (2.9±1.4) cm; median blood volume was 45ml (10~200 ml). The mean operation time was 84.0 ± 24.5 min. The median postoperative hospital stay was 3 days (1~6 days). Compared with LCA, procedure time of PCA was shortened, the volume of bleeding was reduced, and the hospital stay was decreased. The overall adverse events rate was 9.8% (16/163). The mean preoperative and postoperative eGFR of LCA were 77.6±15.3 ml/min and 75.6±17.4 ml/min, respectively. Analogously, the values of PCA were 78.7±12.9 ml/min and 76.7±14.3 ml/min. Mean follow-up time was 64.2 ± 30.2 months (range, 7-127 months). Local recurrence was observed in 13 patients (8.0%), 4 (6.8%) cases of LCA and 9 (8.7%) cases of PCA. PFS at 5 and 10 years were 95.5% and 69.2% for LCA and 96.7% and 62.8% for PCA. In total, 26 patients (16.0%) (11 patients from LCA and 15 from PCA) died throughout the follow-up period. OS at 5 and 10 years were 93.8% and 31.4% for LCA, and 97.4% and 52.7% for PCA. Six patients (3.7%) (3 cases from LCA and 3 from PCA) died of metastatic RCC. CCS for LCA were 98.0% and 82.8% at 5 and 10 years, while the data were 100% and 86.4% for PCA. CONCLUSION: LCA and PCA for T1 stage RCC provides satisfactory long-term oncological and renal function preservation outcomes, with acceptable complication rates.
Subject(s)
Carcinoma, Renal Cell , Cryosurgery , Kidney Neoplasms , Laparoscopy , Biopsy , Carcinoma, Renal Cell/surgery , Cryosurgery/adverse effects , Cryosurgery/methods , Humans , Kidney Neoplasms/pathology , Laparoscopy/adverse effects , Retrospective StudiesABSTRACT
Prostate cancer is still the main male health problem in the world. The role of metabolism in the occurrence and development of prostate cancer is becoming more and more obvious, but it is not clear. Here we firstly identified a metabolism-related gene-based subgroup in prostate cancer. We used metabolism-related genes to divide prostate cancer patients from The Cancer Genome Atlas into different clinical benefit populations, which was verified in the International Cancer Genome Consortium. After that, we analyzed the metabolic and immunological mechanisms of clinical beneficiaries from the aspects of functional analysis of differentially expressed genes, gene set variation analysis, tumor purity, tumor microenvironment, copy number variations, single-nucleotide polymorphism, and tumor-specific neoantigens. We identified 56 significant genes for non-negative matrix factorization after survival-related univariate regression analysis and identified three subgroups. Patients in subgroup 2 had better overall survival, disease-free interval, progression-free interval, and disease-specific survival. Functional analysis indicated that differentially expressed genes in subgroup 2 were enriched in the xenobiotic metabolic process and regulation of cell development. Moreover, the metabolism and tumor purity of subgroup 2 were higher than those of subgroup 1 and subgroup 3, whereas the composition of immune cells of subgroup 2 was lower than that of subgroup 1 and subgroup 3. The expression of major immune genes, such as CCL2, CD274, CD276, CD4, CTLA4, CXCR4, IL1A, IL6, LAG3, TGFB1, TNFRSF4, TNFRSF9, and PDCD1LG2, in subgroup 2 was almost significantly lower than that in subgroup 1 and subgroup 3, which is consistent with the results of tumor purity analysis. Finally, we identified that subgroup 2 had lower copy number variations, single-nucleotide polymorphism, and neoantigen mutation. Our systematic study established a metabolism-related gene-based subgroup to predict outcomes of prostate cancer patients, which may contribute to individual prevention and treatment.
ABSTRACT
Background: 5-Methylcytidine (m5C) methylation is an emerging epigenetic modification in recent years, which is associated with the development and progression of various cancers. However, the prognostic value of m5C regulatory genes and the correlation between m5C methylation and the tumor microenvironment (TME) in prostate cancer remain unknown. Methods: In the current study, the genetic and transcriptional alterations and prognostic value of m5C regulatory genes were investigated in The Cancer Genome Atlas and Gene Expression Omnibus datasets. Then, an m5C prognostic model was established by LASSO Cox regression analysis. Gene set variation analyses (GSVA), gene set enrichment analysis (GSEA), clinical relevance, and TME analyses were conducted to explain the biological functions and quantify the TME scores between high-risk and low-risk subgroups. m5C regulatory gene clusters and m5C immune subtypes were identified using consensus unsupervised clustering analysis. The Cell-type Identification By Estimating Relative Subsets of RNA Transcripts algorithm was used to calculate the contents of immune cells. Results: TET3 was upregulated at transcriptional levels in PCa compared with normal tissues, and a high TET3 expression was associated with poor prognosis. An m5C prognostic model consisting of 3 genes (NSUN2, TET3, and YBX1) was developed and a nomogram was constructed for improving the clinical applicability of the model. Functional analysis revealed the enrichment of pathways and the biological processes associated with RNA regulation and immune function. Significant differences were also found in the expression levels of m5C regulatory genes, TME scores, and immune cell infiltration levels between different risk subgroups. We identified two distinct m5C gene clusters and found their correlation with patient prognosis and immune cell infiltration characteristics. Naive B cells, CD8+ T cells, M1 macrophages and M2 macrophages were obtained and 2 m5C immune subtypes were identified. CTLA4, NSUN6, TET1, and TET3 were differentially expressed between immune subtypes. The expression of CTLA4 was found to be correlated with the degree of immune cell infiltration. Conclusions: Our comprehensive analysis of m5C regulatory genes in PCa demonstrated their potential roles in the prognosis, clinical features, and TME. These findings may improve our understanding of m5C regulatory genes in the tumor biology of PCa.
Subject(s)
Cytidine/analogs & derivatives , Prostatic Neoplasms , Cytidine/genetics , Cytidine/metabolism , Genes, Regulator , Humans , Male , Methylation , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , RNA/genetics , RNA/metabolism , Tumor Microenvironment/geneticsABSTRACT
Ovarian tumor (OTU) subfamily deubiquitinases are involved in various cellular processes, such as inflammation, ferroptosis and tumorigenesis; however, their pathological roles in prostate cancer (PCa) remain largely unexplored. In this study, we observed that several OTU members displayed genomic amplification in PCa, among which ovarian tumor deubiquitinase 6A (OTUD6A) amplified in the top around 15-20%. Further clinical investigation showed that the OTUD6A protein was highly expressed in prostate tumors, and increased OTUD6A expression correlated with a higher biochemical recurrence risk after prostatectomy. Biologically, wild-type but not a catalytically inactive mutant form of OTUD6A was required for PCa cell progression. In vivo experiments demonstrated that OTUD6A oligonucleotides markedly suppressed prostate tumorigenesis in PtenPC-/- mice and patient-derived xenograft (PDX) models. Mechanistically, the SWI/SNF ATPase subunit Brg1 and the nuclear receptor AR (androgen receptor) were identified as essential substrates for OTUD6A in PCa cells by a mass spectrometry (MS) screening approach. Furthermore, OTUD6A stabilized these two proteins by erasing the K27-linked polyubiquitination of Brg1 and K11-linked polyubiquitination of AR. OTUD6A amplification exhibited strong mutual exclusivity with mutations in the tumor suppressors FBXW7 and SPOP. Collectively, our results indicate the therapeutic potential of targeting OTUD6A as a deubiquitinase of Brg1 and AR for PCa treatment.
Subject(s)
DNA Helicases , Nuclear Proteins , Ovarian Neoplasms , Prostatic Neoplasms , Receptors, Androgen , Transcription Factors , Animals , Cell Transformation, Neoplastic , DNA Helicases/metabolism , Deubiquitinating Enzymes/metabolism , Female , Heterografts , Humans , Male , Mice , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Ovarian Neoplasms/pathology , Prostate/pathology , Prostatic Neoplasms/pathology , Receptors, Androgen/metabolism , Repressor Proteins/metabolism , Transcription Factors/metabolism , UbiquitinationABSTRACT
Conventional microfluidics with a solid mixer for exosome detection is constrained by the low binding efficiency of the solid-liquid boundary effects and reduced sensitivity of individual markers. Here, we report a 3D-SiO2 porous chip that combines nanoscale porous characteristics and multiple exosome specific markers to greatly improve the sensitivity for biosensing. The lower limit of detection was 220 particles/µL exosomes in PBS. We applied the 3D-SiO2 porous chip for prostate cancer (PCa) staging in mice and early detection of clinical PCa patients. The developed method could significantly differentiate the different stages of PCa in mice and improve the early detection rate in clinical patients. Expression of multiple specific markers in clinical serum samples identified disease fingerprints, alongside histological results, which supports the potential application of exosomes as a noninvasive surrogate biopsy for PCa.
Subject(s)
Exosomes , Nanostructures , Prostatic Neoplasms , Animals , Exosomes/metabolism , Humans , Male , Mice , Microfluidics/methods , Prostatic Neoplasms/diagnosis , Prostatic Neoplasms/metabolism , Silicon Dioxide/metabolismABSTRACT
Given that there is lack of effective therapies for castration-resistant prostate cancer (CRPC), the combination of photothermal (PTT), photodynamic (PDT), and chemical therapy (CT) has emerged as a prominent strategy. Tumor-targeted delivery and controlled release of antitumor drug are key-elements of any combined therapy. Considering these important elements, we designed and constructed tumor microenvironment (TME)-activated nanoprobes (PGP/CaCO3@IR820/DTX-HA). The CaCO3 shell could efficiently entrap the photosensitizer IR820 and the chemotherapeutic docetaxel (DTX) on the surface of pentagonal gold prisms (PGPs) to prevent elimination from the circulation, and it could act as a TME-trigger to achieve TME-responsive drug release. After modification with hyaluronic acid, PGP/CaCO3@IR820/DTX-HA was capable of synergistic TME-triggered PTT/PDT/CT and tumor-targeted delivery. Our in vitro and in vivo studies demonstrate that PGP/CaCO3@IR820/DTX-HA could achieve synergistic antitumor effects following near-infrared (NIR)-light irradiation. In addition, using the NIR fluorescence signal from IR820 and the photoacoustic (PA) signal from PGPs, i.e., through multimodal fluorescence/photoacoustic imaging, we could monitor the in vivo distribution and excretion of PGP/CaCO3@IR820/DTX-HA. Therefore, it can be concluded that PGP/CaCO3@IR820/DTX-HA shows promising clinical translational potential as a treatment for CRPC. STATEMENT OF SIGNIFICANCE: Utilizing pentagonal gold prisms (PGPs), we constructed a multifunctional nanoplatform (PGP/CaCO3@IR820/DTX-HA) for effectively delivering agents into the tumor microenvironment (TME) for the diagnosis and therapy of castration-resistant prostate cancer (CRPC). The synthetic nanoplatform can satisfy TME-activated synergistic photothermal therapy (PTT)/photodynamic therapy (PDT)/chemical therapy (CT) and NIR fluorescence imaging/photoacoustic (PA) imaging. Hyaluronic acid (HA) on the surface of nanoplatform allowed the specific tumor-targeting capacity and biocompatibility. In conclusion, PGP/CaCO3@IR820/DTX-HA could be a promising integrated nanoplatform for CRPC diagnosis and treatment.
Subject(s)
Nanoparticles , Photochemotherapy , Prostatic Neoplasms, Castration-Resistant , Cell Line, Tumor , Docetaxel , Gold/pharmacology , Humans , Hyaluronic Acid , Hydrogen-Ion Concentration , Male , Multimodal Imaging , Nanoparticles/therapeutic use , Photochemotherapy/methods , Prostatic Neoplasms, Castration-Resistant/diagnostic imaging , Prostatic Neoplasms, Castration-Resistant/drug therapy , Tumor MicroenvironmentABSTRACT
Over the last decade, more than 10 independent SNPs have been discovered to be associated with the risk of renal cell carcinoma among different populations. However, the biological functions of them remain poorly understood. In this study, we performed eQTL analysis, ChIP-PCR, luciferase reporter assay, and Cox regression analysis to identify the functional role and underlying mechanism of rs67311347 in RCC. The ENCORI database, which contains the lncRNA-miRNA-mRNA interactions, was used to explore the possible target miRNA of ENTPD3-AS1. The results showed that the G > A mutation of rs67311347 created a binding motif of ZNF8 and subsequently upregulated ENTPD3-AS1 expression by acting as an enhancer. The TCGA-KIRC and our cohorts both confirmed the downregulation of ENTPD3-AS1 in RCC tissues and demonstrated that increased ENTPD3-AS1 expression was associated with good OS and PFS. Furthermore, ENTPD3-AS1 interacted with miR-155-5p and activated the expression of HIF-1α, which was an important tumor suppressor gene in the development of RCC. The functional experiments revealed that overexpression of ENTPD3-AS1 inhibited cell proliferation in RCC cell lines and the effect could be rescued by knocking down HIF-1α. Our findings reveal that SNP-mediated lncRNA-ENTPD3-AS1 upregulation suppresses renal cell carcinoma via miR-155/HIF-1α signaling.
Subject(s)
Carcinoma, Renal Cell/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Kidney Neoplasms/metabolism , Kruppel-Like Transcription Factors/genetics , MicroRNAs/metabolism , Polymorphism, Single Nucleotide , RNA, Long Noncoding/metabolism , Binding Sites , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Cell Line, Tumor , Cell Proliferation , Databases, Genetic , Gene Expression Regulation, Neoplastic , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Kruppel-Like Transcription Factors/metabolism , MicroRNAs/genetics , Protein Binding , RNA, Long Noncoding/genetics , Signal Transduction , Up-RegulationABSTRACT
Our previously study shown that Lysophosphatidylcholine Acyltransferase1 (LPCAT1) is overexpressed in castration resistant prostate cancer (CRPC) relative to primary prostate cancer (PCa), and androgen controls its expression via the Wnt signaling pathway. While highly expressed in CRPC, the role of LPCAT1 remains unclear. In vitro cell experiments referred to cell transfection, mutagenesis, proliferation, migration, invasion, cell cycle progression and apoptosis, Western blotting, Pulse-chase RNA labeling. BALB/c nude mice were used for in vivo experiments. We found that LPCAT1 overexpression enhanced the proliferation, migration, and invasion of CRPC cells both in vitro and in vivo. Silencing of LPCAT1 reduced the proliferation and the invasive capabilities of CRPC cells. Providing exogenous PAF to LPCAT1 knockdown cells increased their invasive capabilities; however platelet activating factor acetylhydrolase (PAF-AH) and the PAFR antagonist ABT-491 both reversed this phenotype; proliferation of CRPC cells was not affected in either model. LPCAT1 was found to mediate CRPC growth via nuclear re-localization and Histone H4 palmitoylation in an androgen-dependent fashion, increasing mRNA synthesis rates. We also found that LPCAT1 overexpression led to CRPC cell resistance to treatment with paclitaxel. LPCAT1 overexpression in CRPC cells drives tumor progression via increased mRNA synthesis and PAF production. Our results highlight LPCAT1 as a viable therapeutic target in the context of CRPC.
Subject(s)
1-Acylglycerophosphocholine O-Acyltransferase/genetics , Platelet Activating Factor/metabolism , Prostatic Neoplasms, Castration-Resistant/pathology , Up-Regulation , Animals , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Disease Progression , Drug Resistance, Neoplasm , Gene Expression Regulation, Neoplastic/drug effects , Humans , Imidazoles/pharmacology , Indoles/pharmacology , Male , Mice , PC-3 Cells , Paclitaxel/pharmacology , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/metabolism , Up-Regulation/drug effectsABSTRACT
Tumor-derived exosomes, which contain RNA, DNA, and proteins, are a potentially rich non-invasive source of biomarkers. However, no efficient isolation or detection methods are yet available. Here, we developed a microfluidic Raman biochip designed to isolate and analyze exosomes in situ. Anti-CD63 magnetic nanoparticles were used to enrich exosomes through mixing channels of a staggered triangular pillar array. EpCAM-functionalized Raman-active polymeric nanomaterials (Raman beads) allow rapid analysis of exosome samples within 1 h, with a quantitative signal at 2230 cm-1. The limit of detection of this biochip approaches 1.6 × 102 particles per mL with 20 µL samples. The newly developed biochip assay was successfully applied in the determination of exosomes from clinical serum samples. Thus, this novel device may have potential as a clinical exosome analysis tool for prostate cancer.
Subject(s)
Exosomes , Nanostructures , Prostatic Neoplasms , Humans , Male , Microarray Analysis , Microfluidics , Prostatic Neoplasms/diagnosisABSTRACT
BACKGROUND: Long non-coding RNAs (lncRNAs) can affect tumorigenesis. Data from The Cancer Genome Atlas (TCAG) suggest that LINC02783 is highly expressed in renal cell carcinoma (RCC) and is expected to be a potential biological target. We conducted this study to verify this. PATIENTS AND METHODS: We conducted this study to verify the opinion that "LINC02783 is highly expressed in renal cell carcinoma (RCC) and is expected to be a potential biological target". We employed quantitative real-time polymerase chain reaction (qRT-PCR) to test LINC02783 expression in RCC tissues, CKK-8 assay and transwell assay to assess the viability and invasion of RCC cells, Western blot to quantify Sox-4 expression, dual-luciferase reporter (DLR) assay and RNA immunoprecipitation (RIP) assay to analyze the interaction between LINC02783 and miR-20b, in vivo experiments to test tumor formation. RESULTS: We detected high LINC02783 expression in RCC patients. Patients with higher LINC02783 levels had a markedly poorer prognosis. In vitro and in vivo, the down-regulation of LINC02783 suppressed the viability and invasion of RCC cells. The DLR assay results revealed that LINC02783 enhanced Sox-4 expression by regulating miR-20b. LINC02783 can act as a sponge for miR-20b to inhibit Sox-4 expression. CONCLUSION: LINC02783 is highly expressed in RCC patients and indicates a poor prognosis. LINC02783 can affect the occurrence and progression of RCC through the miR-20b/Sox-4 axis, making it a promising target for the treatment of RCC.
ABSTRACT
The serum MALDI-TOF MS spectrum includes signals for serum proteins and peptides between 1000 and 12,000 Da in size, presenting a fingerprint-like pattern. However, whole serum MALDI-TOF MS signals are complex and prejudiced for data analysis. Pre-treatment with specific nanomaterials can simplify the mass spectrum while retaining the characteristics of the fingerprint pattern. In the present study, we used hydrophilic interaction chromatography nanoparticles (HICNPs) to enrich proteins and peptides in serum from a large number prostate cancer samples and controls. After pre-treatment with HICNPs, the serum MALDI-TOF MS signals for samples were simpler, with more analysable fingerprint-like patterns. Principal component analysis and partial least squares discriminant analysis of the samples demonstrated a significant difference in the MALDI-TOF signals between prostate cancer and controls, with an analytical accuracy of 77%, approaching that of methods based on prostate-specific antigen. Due to the low cost and high flux, MALDI-TOF MS fingerprinting can be used in large-scale evaluation of various cancers, including prostate cancer.
Subject(s)
Blood Proteins , Nanoparticles , Prostatic Neoplasms , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Blood Proteins/analysis , Humans , Male , Peptides/analysis , Prostatic Neoplasms/diagnosisABSTRACT
Numerous studies have demonstrated that cancer-related matrix metalloproteinase-9 (MMP-9) is an ideal biomarker for cancer diagnosis. However, most MMP-9 detection methods are expensive and time-consuming, and more convenient and specific MMP-9 detection methods are needed both clinically and in research. In the present study, peptide-linked polymer dots were assembled onto a graphene oxide surface to construct a graphene oxide-peptide-polymer dot (GO-Pep-Pdot) nanocomplex for sensitive, rapid, and accurate detection of MMP-9. In the absence of MMP-9, the nanocomplex was in an "off" state, whereas in the presence of MMP-9, the nanocomplex was turned "on", resulting in the emission of a fluorescence signal that is linearly correlated with the MMP-9 concentration. The limit of detection of the nanocomplex was 3.75 ng mL-1, lower than most methods. This method was successfully verified by detecting MMP-9 in clinical serum samples of prostate cancer. The results suggest that this protease nanocomplex is generic and can be adopted to respond to other proteases by selecting specific peptides with suitable cleavage sites in clinics.
Subject(s)
Biosensing Techniques/methods , Fluorescent Dyes/chemistry , Graphite/chemistry , Matrix Metalloproteinase 9/analysis , Nanostructures/chemistry , Polymers/chemistry , Fluorescence Resonance Energy Transfer , Humans , Limit of Detection , Matrix Metalloproteinase 9/bloodABSTRACT
Exosome-derived miRNAs are regarded as biomarkers for the diagnosis and prognosis of many human cancers. However, its function in clear cell renal cell carcinoma (ccRCC) remains unclear. In this study, differentially expressed miRNAs from urinal exosomes were identified using next-generation sequencing (NGS) and verified using urine samples of ccRCC patients and healthy donors. Then, the exosomes were analysed in early-stage ccRCC patients, healthy individuals and patients suffering from other urinary system cancers. Thereafter, the target gene of the miRNA was detected. Its biological function was investigated in vitro and in vivo. The results showed that miR-30c-5p could be amplified in a stable manner. Its expression pattern was significantly different only between ccRCC patients and healthy control individuals, but not compared with that of other urinary system cancers, which indicated its specificity for ccRCC. Additionally, the overexpression of miR-30c-5p inhibited ccRCC progression in vitro and in vivo. Heat-shock protein 5 (HSPA5) was found to be a direct target gene of miR-30c-5p. The depletion of HSPA5 caused by miR-30c-5p inhibition reversed the promoting effect of ccRCC growth. In conclusion, urinary exosomal miR-30c-5p acts as a potential diagnostic biomarker of early-stage ccRCC and may be able to modulate the expression of HSPA5, which is correlated with the progression of ccRCC.
Subject(s)
Biomarkers, Tumor/urine , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/urine , Exosomes/genetics , Heat-Shock Proteins/genetics , Kidney Neoplasms/genetics , Kidney Neoplasms/urine , MicroRNAs/urine , Adult , Aged , Animals , Base Sequence , Biomarkers, Tumor/genetics , Carcinoma, Renal Cell/pathology , Cell Line, Tumor , Disease Progression , Endoplasmic Reticulum Chaperone BiP , Female , Gene Expression Regulation, Neoplastic , Heat-Shock Proteins/metabolism , Humans , Kidney Neoplasms/pathology , Male , Mice, Inbred BALB C , Mice, Nude , MicroRNAs/genetics , Middle Aged , Young AdultABSTRACT
Background: Unilateral renal tumor cryoablation and contralateral radical nephrectomy of bilateral renal tumors were performed by transumbilical three-dimensional (3D) multichannel laparoendoscopic single-site (LESS) surgery, in an attempt to verify the feasibility and safety of the procedure, sum up the operational experience, and evaluate the surgical outcome. Case Presentation: This was a 47-year-old female patient with a body mass index of 27.34 kg/m2 without backache, low back pain, hematuria, urinary urgency, frequent urination, dysuria, and other symptoms. Contrast-enhanced CT scan of the kidney on admission showed four masses in the left kidney and two masses in the right kidney. Preoperative serum creatinine (SCr) was 87 µmol/L. Operation was performed under general anesthesia by first laying the patient in a left lateral position. A 2-cm longitudinal transumbilical skin incision was made to expose the right kidney for complete dissection of the two tumors. First, puncture biopsy was performed, and then two freeze-thaw cryoablation cycles for the two tumors were performed. At last, the patient was laid in a right lateral position for radical nephrectomy of the left kidney. The operative duration, cryoablation time, and estimated blood loss were 200 minutes, 40 minutes, and 100 mL, respectively. Postoperative pathological examination revealed clear-cell renal cell carcinoma. The right glomerular filtration rate tested was 42.36 mL/minute and SCr was 131 µmol/L at day 5 after surgery. There was no evidence of contrast enhancement at the cryoablative region as shown by renal contrasted CT scan performed 4 days after surgery and renal contrasted MRI scan performed 6 weeks after surgery, indicating that there was no tumor remnant or recurrence. Conclusion: Our preliminary experience shows that the treatment of bilateral renal tumors with unilateral renal tumor cryoablation and contralateral radical nephrectomy by transumbilical 3D LESS is safe, feasible, and effective. It may prove to be a viable option for patients with significant comorbidities and an insensitive treatment intention.