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INTRODUCTION: Angiogenesis plays a significant role in the development of tumor progression and inflammatory diseases. The role of IL-28A in angiogenesis and its precise regulatory mechanisms remain rarely elucidated. OBJECTIVES: We report the novel regulatory role of IL-28A in physiological angiogenesis. The study aimed to elucidate the regulatory mechanisms involved in IL-28A-mediated angiogenesis and identify key genes associated with IL-28A-induced angiogenic responses. METHODS: To know the effect of IL-28A on angiogenesis, HUVECs were applied to perform proliferation, migration, invasion, tube formation, immunoblot, and EMSA. Gene expression changes in HUVECs following IL-28A treatment were analyzed by NGS. The functional role of HSP70-1 and IL-10Rß in IL-28A-induced angiogenic responses was evaluated using PCR and siRNA knockdown. Animal studies were conducted by aortic ring ex vivo assays, Matrigel plug in vivo assays, and immunochemistry using HSP70-1 knockout and transgenic mice models. The efficacy of IL-28A in angiogenesis was confirmed in a hind-limb ischemia model. RESULTS: Autocrine/paracrine actions in HUVECs regulated IL-28A protein expression. Exogenous IL-28A increased the proliferation of HUVECs via eNOS/AKT and ERK1/2 signaling. IL-28A treatment promoted migration, invasion, and capillary tube formation of HUVECs through induction of the AP-1/NF-κB/MMP-2 network, which was associated with eNOS/AKT and ERK1/2 signaling. The efficacy of IL-28A-induced angiogenic potential was confirmed by aortic ring and Matrigel plug assay. HSP70-1 was identified as an IL-28A-mediated angiogenic effector gene using bioinformatics. Knockdown of HSP70-1 abolished angiogenic responses and eNOS/AKT signaling in IL-28A-treated HUVECs. IL-28A-induced microvessel sprouting formation was testified in HSP70-1-deficient and HSP70-1 transgenic mice. Flow recovery in hind-limb ischemia mice was accelerated by IL-28A injection. Finally, ablation of the IL-10Rß gene impeded the angiogenic responses and eNOS/AKT signaling stimulated by IL-28A in HUVECs. CONCLUSION: HSP70-1 drives the progression of angiogenesis by the IL-28A/IL-10Rß axis via eNOS/AKT signaling and the AP-1/NF-κB/MMP-2 network.
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Bisphenol A (BPA), an exogenous endocrine-disrupting chemical, is widely used to produce polycarbonate plastics. The widely used BPA has been detected in human urine samples, raising public anxiety about the detrimental effects of BPA on the bladder. In this study, we explored regulatory mechanisms for the adverse effects of BPA in human bladder BdFC and T24 cells. BPA induced extrinsic and intrinsic apoptosis and G2/M cell cycle arrest caused by the ATM-CHK1/CHK2-CDC25c-CDC2 signaling, which ultimately inhibited the growth of human bladder cells. We also found that BPA decreased the binding activity of AP-1 and NF-κB transcription factors in human bladder cells, which inhibited migration and invasion through matrix metallopeptidase-2 and -9 inactivation. Phosphorylation of MAPKs was implicated with BPA-mediated detrimental effects in human bladder cells. Collectively, our results provide a novel explanation for the underlying molecular mechanisms that BPA induces cytotoxicity in human bladder cells.
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Compostos Benzidrílicos , Fenóis , Fatores de Transcrição , Bexiga Urinária , Humanos , Fosforilação , Apoptose , Pontos de Checagem da Fase G2 do Ciclo Celular , Linhagem Celular Tumoral , Ciclo CelularRESUMO
PURPOSE: T1 high grade (T1HG) bladder cancer (BC) is a type of non-muscle invasive BC (NMIBC) that is recognized as an aggressive subtype with a heightened propensity for progression. Current risk stratification methods for NMIBC rely on clinicopathological indicators; however, these approaches do not adequately capture the aggressive nature of T1HG BC. Thus, new, more accurate biomarkers for T1HG risk stratification are needed. Here, we enrolled three different patient cohorts and investigated expression of collagen type VI alpha 1 (COL6A1), a key component of the extracellular matrix, at different stages and grades of BC, with a specific focus on T1HG BC. MATERIALS AND METHODS: Samples from 298 BC patients were subjected to RNA sequencing and real-time polymerase chain reaction. RESULTS: We found that T1HG BC and muscle invasive BC (MIBC) exhibited comparable expression of COL6A1, which was significantly higher than that by other NMIBC subtypes. In particular, T1HG patients who later progressed to MIBC had considerably higher expression of COL6A1 than Ta, T1 low grade patients, and patients that did not progress, highlighting the aggressive nature and higher risk of progression associated with T1HG BC. Moreover, Cox and Kaplan-Meier survival analyses revealed a significant association between elevated expression of COL6A1 and poor progression-free survival of T1HG BC patients (multivariate Cox hazard ratio, 16.812; 95% confidence interval, 3.283-86.095; p=0.001 and p=0.0002 [log-rank test]). CONCLUSIONS: These findings suggest that COL6A1 may be a promising biomarker for risk stratification of T1HG BC, offering valuable insight into disease prognosis and guidance of personalized treatment decisions.
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Neoplasias não Músculo Invasivas da Bexiga , Neoplasias da Bexiga Urinária , Humanos , Prognóstico , Bexiga Urinária , Neoplasias da Bexiga Urinária/genética , Medição de RiscoAssuntos
Neoplasias não Músculo Invasivas da Bexiga , Neoplasias da Bexiga Urinária , Humanos , Prognóstico , Vacina BCG/uso terapêutico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/tratamento farmacológico , Progressão da Doença , Administração Intravesical , Adjuvantes Imunológicos/uso terapêutico , Recidiva Local de Neoplasia , Invasividade NeoplásicaRESUMO
BACKGROUND: Prostate cancer is the second most common cause of cancer death worldwide in men. The development of novel and highly efficient therapeutic strategies is strongly recommended to treat prostate cancer. Cyperaceae are an ecologically and economically important family of plants with several pharmacological effects. However, the biological efficacy of Cyperus exaltatus var. iwasakii (CE) is unknown. PURPOSE: This study aimed to investigate the antitumor effect of the ethanol extract of CE against prostate cancer. METHODS: In vitro antitumor efficacy of CE was explored by the MTT assay, cell counting assay, FACS analysis, immunoblot, wound-healing migration, invasion assay, zymographic assay, and EMSA in prostate cancer cells, DU145 and LNCaP. For in vivo experiments, xenograft mice were injected with LNCaP cells. Histology (H&E and Ki-67) and biochemical enzyme assay were then performed. The toxicity test was evaluated by an acute toxicity assay. The phytochemical constituents of CE were identified by spectrometric and chromatographic analyses. RESULTS: CE exerted a significant antiproliferative effect against prostate cancer cells. CE-induced antiproliferative cells were associated with cell cycle arrest at G0/G1 (cyclin D1/CDK4, cyclin E/CDK2, p21Waf1) in DU145 cells, but G2/M (ATR, CHK1, Cdc2, Cdc25c, p21Waf1, and p53) in LNCaP cells. CE stimulated the phosphorylation of ERK1/2, p38 MAPK, and AKT in DU145 cells, but only p38 MAPK phosphorylation was increased in LNCaP cells. CE treatment suppressed migration and invasion in the two types of prostate cancer cells by inhibiting MMP-9 activity through the regulation of transcription factors, such as AP-1 and NF-κB. In vivo experiments showed a reduction in tumor weight and size following oral CE administration. Histochemistry confirmed that CE inhibited tumor growth in the mouse LNCaP xenograft model. The administration of CE had no adverse effects on body weight, behavioral patterns, blood biochemistry, and histopathology findings of vital organs in mice. Finally, a total of 13 phytochemical constituents were identified and quantified in CE. The most abundant secondary metabolites in CE were astragalin, tricin, and p-coumaric acid. CONCLUSION: Our results demonstrated the antitumor efficacy of CE against prostate cancer. These findings suggest that CE might be a potential candidate for prostate cancer prevention or treatment.
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Cyperus , Neoplasias da Próstata , Masculino , Humanos , Animais , Camundongos , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sistema de Sinalização das MAP Quinases , Etanol/farmacologia , Metaloproteinase 9 da Matriz/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Linhagem Celular Tumoral , Ciclo Celular , Neoplasias da Próstata/tratamento farmacológico , Proliferação de Células , ApoptoseRESUMO
Previous studies have associated bisphenol A (BPA) with malignant tumor formation, infertility, and atherosclerosis in vitro and in vivo. However, the precise mechanisms through which BPA affects the cardiovascular system under normal conditions remain unclear. Therefore, this study investigated the biological mechanisms through which BPA affects the responses of aortic vascular smooth muscle cells (VSMCs). BPA treatment inhibited the proliferative activity of VSMCs and induced G2/M-phase cell cycle arrest via stimulation of the ATM-CHK2-Cdc25C-p21WAF1-Cdc2 cascade in VSMCs. Furthermore, BPA treatment upregulated the phosphorylation of mitogen-activated protein kinase (MAPK) pathways such as ERK, JNK, and p38 MAPK in VSMCs. However, the phosphorylation level of AKT was down-regulated by BPA treatment. Additionally, the phosphorylation of ERK, JNK, and p38 MAPK was suppressed when the cells were treated with their respective inhibitors (U0126, SP600125, and SB203580). BPA suppressed MMP-9 activity by reducing the binding activity of AP-1, Sp-1, and NF-κB, thus inhibiting the invasive and migratory ability of VSMCs. These data demonstrate that BPA interferes with the proliferation, migration, and invasion capacities of VSMCs. Therefore, our findings suggest that overexposure to BPA can lead to cardiovascular damage due to dysregulated VSMC responses.
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Músculo Liso Vascular , Proteínas Quinases p38 Ativadas por Mitógeno , Proliferação de Células , Células Cultivadas , Fosforilação , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Miócitos de Músculo Liso/metabolismo , Movimento CelularRESUMO
To evaluate the utility of different risk assessments in non-muscle-invasive bladder cancer (NMIBC) patients, a total of 178 NMIBC patients from Chungbuk National University Hospital (CBNUH) were enrolled, and the predictive value of the molecular signature-based subtype predictor (MSP888) and risk calculators based on clinicopathological factors (EORTC, CUETO and 2021 EAU risk scores) was compared. Of the 178 patients, 49 were newly analyzed by the RNA-sequencing, and their MSP888 subtype was evaluated. The ability of the EORTC, MSP888 and two molecular subtyping systems of bladder cancer (Lund and UROMOL subtypes) to predict progression of 460 NMIBC patients from the UROMOL project was assessed. Cox regression analyses showed that the MSP888 was an independent predictor of NMIBC progression in the CBNUH cohort (p = 0.043). Particularly in patients without an intravesical BCG immunotherapy, MSP888 significantly linked with risk of disease recurrence and progression (both p < 0.05). However, the EORTC, CUETO and 2021 EAU risk scores showed disappointing results with respect to estimating the NMIBC prognosis. In the UROMOL cohort, the MSP888, Lund and UROMOL subtypes demonstrated a similar capacity to predict NMIBC progression (all p < 0.05). Conclusively, the MSP888 is favorable for stratifying patients to facilitate optimal treatment.
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Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Invasividade Neoplásica , Progressão da Doença , Fatores de RiscoRESUMO
Formalin-fixed paraffin-embedded (FFPE) tissue is the most common source of archived material for genomic medicine. However, FFPE tissue is suboptimal for high-throughput analyses, such as RNA sequencing, because the quality of nucleic acids in FFPE tissues is low. We compared RNA-seq with the nCounter system to evaluate use of FFPE tissue for genomic medicine. Twelve fresh frozen bladder cancer samples were analyzed by both RNA sequencing and nCounter, and matched FFPE samples, by nCounter. Gene-expression values obtained by these two platforms were compared by calculating Pearson correlation coefficients for each sample (across the set of matched genes) and for each matched gene (across the set of samples). For each sample, gene-expression levels measured by RNA sequencing highly correlated with those measured by nCounter (all Pearson's R > 0.8, P < 0.0001), as seen by hierarchical clustering. RNA sequencing results for fresh frozen tissues positively correlated with nCounter results for FFPE tissues (R ranged from 0.675 to 0.873, all P < 0.0001). Correlation and hierarchical-clustering analyses of nCounter data from the two specimens demonstrated a strong positive correlation between each group (R ranged from 0.779 to 0.977, all P < 0.0001). Our findings suggest that the nCounter system is useful for assaying archived-FFPE samples and that the gene-expression signatures obtained from FFPE samples represent those from fresh frozen tissues.
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RNA , Neoplasias da Bexiga Urinária , Humanos , Inclusão em Parafina/métodos , RNA/genética , Neoplasias da Bexiga Urinária/genética , Perfilação da Expressão Gênica , Transcriptoma , FormaldeídoRESUMO
Biochemical recurrence (BCR) is common after radical prostatectomy, but effective treatment options for men with BCR after curative treatment remain controversial. Although prostate-specific antigen is widely used as a surrogate marker for prostate cancer survival, it cannot fully differentiate between prostate-cancer-specific survival and overall survival. Thus, it is challenging for physicians to determine the timing of treatment to halt or slow the clinical progression of disease in patients with BCR while avoiding overtreatment for patients whose disease may not progress beyond BCR. Adjuvant therapy for radical prostatectomy or radiotherapy in intermediate- or high-risk localized prostate cancer has a benefit in terms of disease progression and survival but is not recommended in low-risk prostate cancer because of the significant adverse effects related to radiotherapy and androgen-deprivation therapy (ADT). Salvage radiotherapy (SRT) is also recommended for patients with BCR after radical prostatectomy. Several options for management of BCR after radical prostatectomy include SRT to the prostatic bed and/or pelvis, continuous or intermittent ADT, or observation. Patients' comorbidity, preferences, and cancer-related factors must be considered when deciding the best management strategy. Modern imaging technology such as positron emission tomography imaging of prostate-specific membrane antigen-positive regions enables earlier detection of disease progression, thus enhancing decision making for future disease management.
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Próstata , Neoplasias da Próstata , Masculino , Humanos , Antagonistas de Androgênios/uso terapêutico , Neoplasias da Próstata/cirurgia , Neoplasias da Próstata/radioterapia , Recidiva Local de Neoplasia/cirurgia , Prostatectomia/efeitos adversos , Prostatectomia/métodos , Antígeno Prostático Específico , Terapia de Salvação/métodos , Progressão da Doença , Estudos RetrospectivosRESUMO
Bladder cancer is a common global cancer with a high percentage of metastases and high mortality rate. Thus, it is necessary to identify new biomarkers that can be helpful in diagnosis. Pyruvate dehydrogenase kinase 4 (PDK4) belongs to the PDK family and plays an important role in glucose utilization in living organisms. In the present study, we evaluated the role of PDK4 in bladder cancer and its related protein changes. First, we observed elevated PDK4 expression in high-grade bladder cancers. To screen for changes in PDK4-related proteins in bladder cancer, we performed a comparative proteomic analysis using PDK4 knockdown cells. In bladder cancer cell lines, PDK4 silencing resulted in a lower rate of cell migration and invasion. In addition, a PDK4 knockdown xenograft model showed reduced bladder cancer growth in nude mice. Based on our results, PDK4 plays a critical role in the metastasis and growth of bladder cancer cells through changes in ERK, SRC, and JNK.
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Inibidores de Proteínas Quinases , Neoplasias da Bexiga Urinária , Animais , Humanos , Camundongos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Nus , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteômica , Piruvato Desidrogenase Quinase de Transferência de Acetil , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinases da Família src/efeitos dos fármacos , Quinases da Família src/metabolismoRESUMO
The edible Rosa hybrida (RH) petal is utilized in functional foods and cosmetics. Although the biological function of RH petal extract is known, mechanism of action studies involving tumor-associated angiogenesis have not yet been reported. Herein, we investigated the regulatory effect of the ethanol extract of RH petal (EERH) on tumor growth and tumor angiogenesis against bladder cancer. EERH treatment inhibited the bladder carcinoma T24 cell and 5637 cell proliferation because of G1-phase cell cycle arrest by inducing p21WAF1 expression and reducing cyclins/CDKs level. EERH regulated signaling pathways differently in both cells. EERH-stimulated suppression of T24 and 5637 cell migration and invasion was associated with the decline in transcription factor-mediated MMP-9 expression. EERH oral administration to xenograft mice reduced tumor growth. Furthermore, no obvious toxicity was observed in acute toxicity test. Decreased CD31 levels in EERH-treated tumor tissues led to examine the angiogenic response. EERH alleviated VEGF-stimulated tube formation and proliferation by downregulating the VEGFR2/eNOS/AKT/ERK1/2 cascade in HUVECs. EERH impeded migration and invasion of VEGF-induced HUVECs, which is attributed to the repressed MMP-2 expression. Suppression of neo-microvessel sprouting, induced by VEGF, was verified by treatment with EERH using the ex vivo aortic ring assay. Finally, kaempferol was identified as the main active compound of EERH. The present study demonstrated that EERH may aid the development of antitumor agents against bladder cancer.
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Rosa , Neoplasias da Bexiga Urinária , Inibidores da Angiogênese/farmacologia , Animais , Movimento Celular , Proliferação de Células , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Camundongos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Rosa/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND/OBJECTIVES: Zanthoxylum schinifolium is traditionally used as a spice for cooking in East Asian countries. This study was undertaken to evaluate the anti-proliferative potential of ethanol extracts of Z. schinifolium leaves (EEZS) against human bladder cancer T24 cells. MATERIALS/METHODS: Subsequent to measuring the cytotoxicity of EEZS, the anti-cancer activity was measured by assessing apoptosis induction, reactive oxygen species (ROS) generation, and mitochondrial membrane potential (MMP). In addition, we determined the underlying mechanism of EEZS-induced apoptosis through various assays, including Western blot analysis. RESULTS: EEZS treatment concentration-dependently inhibited T24 cell survival, which is associated with apoptosis induction. Exposure to EEZS induced the expression of Fas and Fas-ligand, activated caspases, and subsequently resulted to cleavage of poly (ADP-ribose) polymerase. EEZS also enhanced the expression of cytochrome c in the cytoplasm by suppressing MMP, following increase in the ratio of Bax:Bcl-2 expression and truncation of Bid. However, EEZS-mediated growth inhibition and apoptosis were significantly diminished by a pan-caspase inhibitor. Moreover, EEZS inhibited activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway, and the apoptosis-inducing potential of EEZS was promoted in the presence of PI3K/Akt inhibitor. In addition, EEZS enhanced the production of ROS, whereas N-acetyl cysteine (NAC), a ROS scavenger, markedly suppressed growth inhibition and inactivation of the PI3K/Akt signaling pathway induced by EEZS. Furthermore, NAC significantly attenuated the EEZS-induced apoptosis and reduction of cell viability. CONCLUSIONS: Taken together, our results indicate that exposure to EEZS exhibits anti-cancer activity in T24 bladder cancer cells through ROS-dependent induction of apoptosis and inactivation of the PI3K/Akt signaling pathway.
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Krill oil (KO) obtained from Euphausia superba is nutrient-rich and has a positive effect on human health. Here, we explored the efficacy of KO in inhibiting tumor progression and tumor vascularization. KO (100-300 µg/mL) repressed the proliferation of bladder tumor cell lines MBT-2 and T24. Treatment of cells with KO raised cell-cycle arrest at G0/G1-phase via modulation of positive regulators and negative regulators in bladder cancer cells. KO treatment regulated phosphorylation of proteins involved in PI3K/AKT and MAPK signaling pathways, including ERK, JNK, and p38 MAPK. Additionally, KO hampered the invasion and migration of both cell lines via reduction of MMP-9 expression levels by disrupting transcriptional binding of Sp-1, AP-1, and NF-κB motifs. Moreover, in animal studies, KO (150-300 mg/kg) significantly decreased tumor growth in xenograft mice bearing T24 tumor cells. No significant toxic effects were observed in acute toxicity tests, including biological analysis and H&E staining. The reduced level of CD31 expression in KO-treated tumor tissues prompted us to investigate the effect of KO on tumor angiogenesis. KO (5-40 µg/mL) treatment impeded VEGF-induced capillary tube formation and proliferation by inhibiting VEGFR2-modulated eNOS/AKT/ERK1/2 signaling axis in HUVECs. Treatment of HUVECs with KO inhibited VEGF-stimulated migration and invasion by reducing MMP-2 expression level. VEGF-driven sprouting capacity of neo-microvessels was suppressed in the presence of KO (20-40 µg/mL), as determined via an ex vivo aortic ring assay. Our results indicated that KO can regulate both tumor growth and tumor-associated angiogenesis via a novel mechanism. Thus, KO may be a promising antitumor candidate, potentially useful to prevent or treat bladder cancer.
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Euphausiacea , Neoplasias da Bexiga Urinária , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Animais , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Neovascularização Patológica/tratamento farmacológico , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Purpose: Approximately 7% of patients with newly diagnosed prostate cancer (PCa) in the US will have have metastatic disease. The dogma that there is no role for surgery in this population has been questioned recently. Here we report long-term outcomes of a phase 1 clinical trial on cytoreductive radical prostatectomy. Materials and methods: This is a multicenter phase 1 trial. The major inclusion criterion was biopsy proven N1M0 or NxM1a/b PCa. Primary end point was the Clavien-Dindo-based major complication rate. Secondary outcomes were biochemical progression and overall survival. RNA-seq correlative study was conducted in nine select cases as a pilot study. Results: Final accrual was 32 patients of which 25 and 7 were cNxM1 and cN1M0, respectively. With the median follow-up of 46 months (interquartile range 31.7 - 52.7 months), 25 out of the 32 patients (75%) were alive at the time of last contact. There were three disparate groups based on the oncologic outcome: favorable, intermediate, and poor. In seven men with favorable response, androgen deprivation therapy was switched to intermittent approach and five remain free of any evidence of disease after more than two years off all systemic therapy with the normalization of serum testosterone. Of these five patients, three had M1 disease. Long-term use of one pad or less per day was 80%. RNA-seq analysis revealed an enriched downregulation of tumor necrosis factor (TNF)-α signature in the favorable group. Conclusion: Overall long-term oncologic outcome of cytoreductive radical prostatectomy was significantly higher than historical results. Importantly, the combination of surgery with systemic therapy may result in a long durable response in a minority of men who present with metastatic PCa.
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Numerous biomarkers and risk tables can be used to predict recurrence or progression of patients with primary or recurrent non-muscle invasive bladder cancer (NMIBC) receiving Bacillus Calmette-Guerin (BCG). However, few are suitable for BCG-unresponsive disease (i.e., recurrence or progression after BCG treatment). Therefore, identification of a novel marker that allows accurate prediction of prognosis, particularly risk of recurrence, is critically important in clinical practice. In the current study, gene ontology and gene set enrichment analyses of microarray datasets (GSE13507, nâ¯=â¯47) revealed that differentially expressed genes in recurred NMIBC patients after BCG treatment were associated with virus and ribosomal pathways. Among the core-enrichment genes, the expression of RPL9, a putative tumor suppressor, was lower in recurred NMIBC patients after BCG therapy than in patients without recurrence (P = 0.033) from the E-MTAT-4321 European cohort (nâ¯=â¯84). Data from The Cancer Genome Atlas (nâ¯=â¯406) showed that bladder cancer patients with higher RPL9 expression had a longer overall survival probability than patients with lower RPL9 expression (P = 0.011). Moreover, we used the latest digital PCR platform to examine 59 NMIBC patients and identified downregulation of RPL9 in patients with recurrence after BCG therapy (P = 0.031). The Kaplan-Meier survival estimator showed that NMIBC patients with higher expression of RPL9 had longer recurrence-free survival (log-rank test, P = 0.015). Therefore, we conclude that RPL9 expression is a prospective predictor of recurrence after BCG therapy in NMIBC patients.
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Neoplasias da Bexiga Urinária , Adjuvantes Imunológicos/uso terapêutico , Administração Intravesical , Vacina BCG/uso terapêutico , Feminino , Humanos , Masculino , Invasividade Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologiaRESUMO
PURPOSE: Tumor microRNAs (miRNAs) are released to biofluids directly or indirectly. Although urinary miRNAs are promising non-invasive biomarkers for the diagnosis of prostate cancer (PCa), their clinical application is challenging for technical reasons. We examined the efficacy of urinary hsv2-miR-H9 to hsa-miR-3659 ratio as a non-invasive diagnostic biomarker of PCa. MATERIALS AND METHODS: The expression of urinary miRNAs was quantified by real-time PCR in 116 samples from 53 patients with benign prostatic hyperplasia (BPH) and 63 patients with PCa. The miRNA expression ratio was calculated using an upregulated miRNA (hsv2-miR-H9) as the numerator and a downregulated miRNA (hsa-miR-3659) as the denominator. RESULTS: The urinary miR-H9 to miR-3659 ratio was significantly higher in PCa than in BPH controls (p<0.001). The diagnostic accuracy of the urinary miRNA expression ratio was comparable with that of prostate-specific antigen (PSA) (receiver operating characteristic [ROC] curve comparison, p=0.287). The area under the curve for urinary miRNA expression ratio was 0.862 and that for PSA was 0.642 in the "PSA gray zone" (3-10 ng/mL) (ROC curve comparison, p=0.034). The use of the urinary miRNA expression ratio would have prevented 70.6% of unnecessary prostate biopsies; however, 28.6% of PCa cases could be missed in patients within the PSA gray zone. CONCLUSIONS: The expression ratio of urinary miR-H9 to miR-3659 could be a relevant non-invasive biomarker for PCa diagnosis, particularly for patients within the PSA gray zone.
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MicroRNAs , Hiperplasia Prostática , Neoplasias da Próstata , Biomarcadores , Humanos , Hiperplasia , Masculino , Próstata , Antígeno Prostático Específico , Hiperplasia Prostática/diagnóstico , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genéticaRESUMO
BACKGROUND: Prostate-specific antigen (PSA) is a marker of prostate cancer (PCa), although its efficacy as a diagnostic marker remains controversial. A high false-positive rate leads to repeat biopsy in approximately 70% of patients, which may not be necessary. Epigenetic biomarkers of field cancerization have been investigated widely as promising tools for the diagnosis of patients with suspected tumors. In the current study, we examined the diagnostic value of two microRNA (miRNA) candidates, hsv1-miR-H18 and hsv2-miR-H9, using formalin-fixed paraffin-embedded (FFPE) tissues from patients with PCa or benign prostate hyperplasia (BPH) (as controls) to determine the usefulness of these markers for detecting the presence of cancer. METHODS: Expression of hsv1-miR-H18 and hsv2-miR-H9 in 201 FFPE tissues, including 52 primary tumors, 73 surrounding noncancerous tissues, and 90 BPH nontumor controls was examined by real-time PCR. RESULTS: Expression of hsv1-miR-H18 and hsv2-miR-H9 was significantly higher in primary tumors from PCa patients than in BPH controls (P < 0.0001). In patients within the PSA gray zone, the two viral miRNAs could distinguish PCa from controls with appropriate sensitivity and specificity. Expression of the two miRNAs did not differ between primary tumors and noncancerous surrounding tissues. CONCLUSIONS: The viral miRNAs hsv1-miR-H18 and hsv2-miR-H9 may be associated with field cancerization of PCa and could be promising supplemental biomarkers to the PSA assay to decrease the rate of unnecessary biopsy, particularly in patients within the PSA gray zone.
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Molecular markers detected in urine may improve our understanding of the evolution of bladder cancer (BCa) and its micro- and macroenvironment. Detection of such markers will identify disease earlier, allow stratification of patients according to risk, and improve prognostication and prediction of outcomes, thereby facilitating targeted therapy. However, current guidelines have yet to embrace such markers for routine management of BCa, and most research studies have focused on urine-based tumor markers. In this review, we summarize known urinary biomarkers for BCa and highlight newly identified molecules. We then discuss the challenges that must be overcome to incorporate these markers into clinical care.