The splicing factor SF3B1 confers ferroptosis resistance and promotes lung adenocarcinoma progression via upregulation of SLC7A11.

This study aimed to investigate the expression of SF3B1 in non-small cell lung cancer, and its clinical significance, biological function, and molecular mechanisms. SF3B1 mRNA and protein levels were elevated in both lung squamous cell carcinoma and lung adenocarcinoma (LUAD) tissues based on TCGA data and immunohistochemistry. Notably, high SF3B1 expression in LUAD was significantly associated with increased lymph node metastasis. Functional experiments involving SF3B1 knockdown and overexpression demonstrated that SF3B1 facilitated the proliferation, invasion, and migration of LUAD cells. Additionally, the SF3B1 inhibitor pladienolide-B attenuated the aggressive behavior of LUAD cells both in vitro and in vivo. RNA sequencing analysis indicated that differentially expressed genes in the SF3B1 knockdown and SF3B1 inhibitor groups were enriched in ferroptosis-related pathways compared to their respective control groups. The antiferroptotic role of SF3B1 in LUAD cells was validated by detecting glutathione depletion, lipid peroxidation, and observing morphological changes using transmission electron microscopy. This process was confirmed to be independent of apoptosis and autophagy, as evidenced by the effects of the ferroptosis inducer erastin, the apoptosis inhibitor Z-VAD-FMK, and the autophagy inhibitor 3-methyladenine. Rescue experiments indicated that the antiferroptotic role of SF3B1 in LUAD is partially mediated by upregulating the expression of SLC7A11.

LINC01082 Inhibits Non-Small Cell Lung Cancer by Targeting the miR-543/TNRC6A Axis.

Non-small cell lung cancer (NSCLC) accounts for over 80% of lung cancer cases and have poor clinical outcomes. Increasing number of lncRNAs are reported to be implicated in the carcinogenesis of NSCLC. Previous lncRNA-seq results showed that LINC01082 was under-expressed in several cancer types. In the current study, we focused on the role of LINC01082 in NSCLC development. An online bioinformatics tool was utilized to assess the expression profile of LINC01082, miR-543, and TNRC6A in NSCLC samples. RT-qPCR analysis was performed for evaluating LINC01082, TNRC6A and miR-543 expression in cells (NSCLC cells vs. normal lung cells). Impact of LINC01082 upregulation on cell proliferation in vitro was investigated by MTT and EdU experiments. Transwell assay was applied to analyze the migration and invasion of NSCLC cells. The cell apoptosis after plasmid transfection was detected by flow cytometry. The interactions among LINC01082, miR-543 and TNRC6A were measured by RNA pulldown and luciferase reporter assays. We showed that LINC01082 levels were downregulated in NSCLC samples and NSCLC cells. Overexpression of LINC01082 inhibited NSCLC cell proliferation, migration and invasion and strengthened cell apoptosis. LINC01082 directly bound to miR-543, and miR-543 targeted TNRC6A. TNRC6A was downregulated and miR-543 was overexpressed in NSCLC cells. miR-543 inhibition suppressed malignant cellular behaviors. TNRC6A knockdown reversed the effects of LINC01082 on the malignant character of NSCLC cells. In conclusion, LINC01082 exerts an antioncogenic role in NSCLC via interaction with miR-543 to regulate TNRC6A expression.

Conditional survival of trimodal therapy for nonmetastatic muscle-invasive bladder cancer: A SEER database analysis.

OBJECTIVE: Conventional survival analysis plays a limited role in patients who have survived a period after initial treatment. The present study analyzed how conditional survival (CS) predicted survival rate over time for nonmetastatic muscle-invasive bladder cancer (MIBC) patients after trimodal treatment. METHOD: This retrospective study from the SEER database included consecutive patients with nonmetastatic MIBC who received trimodal therapy (TMT) between January 2010 and December 2017. Kaplan-Meier analysis was used to estimate overall survival (OS) and cancer-specific survival (CSS). CS was defined as the rate of surviving y years after already surviving for x years. Multivariate Cox regression analysis was used to identify prognostic factors. RESULT: A total of 1110 nonmetastatic MIBC patients treated with TMT were included. Given a 1-, 2-, 3-, and 4-year after TMT, the rate of surviving to 5-year, respectively, improved by +5.0 (20.0%), +17.0 (32.0%), +30.0 (45.0%), and +52.8 (67.8%) from those calculated at baseline (15.0%). The 2-year CS rate of patients who had survived 1-, 2-, or 3-year after TMT improved, respectively, compared to 3-, 4-, or 5-year actual survival. Multivariate Cox regression analysis demonstrated that adverse variables (T stage, age) of OS and CSS lost their prognostic significance over time. DISCUSSION AND CONCLUSION: Conditional survival rate of surviving to 5-year after TMT kept a relatively stable level over time. In addition, those adverse variables were not always the prognostic factors over time. Only age was always the significant prognostic factor for conditional OS from baseline to 5-year survival. Our results provided real-time survival information and prognosis estimates to adjust follow-up plans for nonmetastatic MIBC patients after TMT.

A Prognostic Model of Bladder Cancer Based on Metabolism-Related Long Non-Coding RNAs.

Background: Some studies have revealed a close relationship between metabolism-related genes and the prognosis of bladder cancer. However, the relationship between metabolism-related long non-coding RNAs (lncRNA) regulating the expression of genetic material and bladder cancer is still blank. From this, we developed and validated a prognostic model based on metabolism-associated lncRNA to analyze the prognosis of bladder cancer. Methods: Gene expression, lncRNA sequencing data, and related clinical information were extracted from The Cancer Genome Atlas (TCGA). And we downloaded metabolism-related gene sets from the human metabolism database. Differential expression analysis is used to screen differentially expressed metabolism-related genes and lncRNAs between tumors and paracancer tissues. We then obtained metabolism-related lncRNAs associated with prognosis by correlational analyses, univariate Cox analysis, and logistic least absolute shrinkage and selection operator (LASSO) regression. A risk scoring model is constructed based on the regression coefficient corresponding to lncRNA calculated by multivariate Cox analysis. According to the median risk score, patients were divided into a high-risk group and a low-risk group. Then, we developed and evaluated a nomogram including risk scores and Clinical baseline data to predict the prognosis. Furthermore, we performed gene-set enrichment analysis (GSEA) to explore the role of these metabolism-related lncRNAs in the prognosis of bladder cancer. Results: By analyzing the extracted data, our research screened out 12 metabolism-related lncRNAs. There are significant differences in survival between high and low-risk groups divided by the median risk scoring model, and the low-risk group has a more favorable prognosis than the high-risk group. Univariate and multivariate Cox regression analysis showed that the risk score was closely related to the prognosis of bladder cancer. Then we established a nomogram based on multivariate analysis. After evaluation, the modified model has good predictive efficiency and clinical application value. Furthermore, the GSEA showed that these lncRNAs affected bladder cancer prognosis through multiple links. Conclusions: A predictive model was established and validated based on 12 metabolism-related lncRNAs and clinical information, and we found these lncRNA affected bladder cancer prognosis through multiple links.

Circular RNA circSHPRH inhibits the malignant behaviors of bladder cancer by regulating the miR-942/BARX2 pathway.

Bladder cancer (BCa) is one of the most common tumors of the genitourinary system. However, the detailed molecular mechanism of BCa progression is still unclear. Recently, an increasing number of studies have demonstrated that circular RNAs (circRNAs) play a critical role in the tumorigenesis and progression of BCa. In this article, we showed that circSHPRH expression was obviously decreased in BCa tissues, compared with adjacent normal tissues. Moreover, a low circSHPRH level was positively correlated with a high grade, a high pathological stage, lymphatic metastasis and an unfavorable prognosis for BCa patients. Cell function studies indicated that silencing circSHPRH dramatically increased the proliferation, migration and invasion of BCa cells. Animal experiments revealed that circSHPRH overexpression repressed tumor growth. Mechanistic studies demonstrated that circSHPRH could combine with miR-942 and serve as a sponge of miR-942, which targets BARX2 in BCa cells. Rescue experiments showed that suppression of miR-942 or BARX2 overexpression could significantly abrogate the promoting effects of circSHPRH silencing on BCa cell proliferation and invasion. Furthermore, circSHPRH overexpression partly eliminated the suppressive effects of miR-942 on BARX2 expression. In addition, circSHPRH knockdown promoted activation of the Wnt/ß-catenin signaling pathway by regulating BARX2. Taken together, our findings indicate that circSHPRH serves as a sponge of miR-942 to inhibit BCa progression by upregulating BARX2 expression, thereby inhibiting the Wnt/ß-catenin signaling pathway.

Selection of Optimal Candidates for Cytoreductive Nephrectomy in Patients with Metastatic Clear Cell Renal Cell Carcinoma: A Predictive Model Based on SEER Database.

BACKGROUND: Currently, the progress of targeted drugs in the treatment of metastatic clear cell renal cell carcinoma (mccRCC) is limited. Cytoreductive nephrectomy (CN), as an alternative treatment, can improve the prognosis of patients with metastatic renal cell carcinoma to some extent. However, it is unclear which patients would benefit from this tumor reduction operation. As a consequence, we developed a predictive model to identify patients who may well benefit from CN in terms of survival. METHODS: We identified patients with metastatic clear cell renal cell carcinoma retrospectively from the Surveillance, Epidemiology, and End Results (SEER) database (2010-2015) and classified them into surgery and non-surgery groups. Propensity score matching (PSM) was performed to balance the baseline characteristics. Patients who survived longer than the median overall survival (OS) of no-surgery group were defined as surgical-benefit patients. Then, we developed a predictive model based on preoperative characteristics using multivariable Logistic regression. Calibration curves and the area under the receiver operating characteristic (AUC) were used to evaluate the efficiency of the predictive model. The clinical value of the nomogram was assessed utilizing decision curve analysis (DCA). RESULTS: Our study collected 5544 patients from the SEER database, with 2352(42.4%) receiving cytoreductive surgery. Overall survival (OS) was longer in the CN group than in the non-surgery group after 1:1 propensity scoring matching (median OS: 19 months vs 7 months; hazard ratio (HR) =0.4106, P< 0.001). In the matched surgery group, 65.7% (367) patients survived more than 7 months after the operation and they were considered to benefit from CN. The predictive model performed well on both the training group (AUC=73.4%) and the validation group (AUC=71.9%) and the calibration curves indicated a high degree of consistency. The decision curve analysis curve demonstrated the clinical utility. We classified surgical patients into the beneficial group and non-beneficial group by using the predictive model, then discovered a substantial difference in OS between the two groups. CONCLUSIONS: We developed a nomogram to select ideal mccRCC patients who might benefit from cytoreductive nephrectomy. Clinicians could make a more precise treatment strategy for mccRCC patients.

A nomogram to predict stricture-free survival in patients with ureteral stricture after balloon dilation.

BACKGROUND: Balloon dilation is a commonly used minimally invasive endourological treatment of ureteral stricture, but the postoperative recurrence rate is relatively high. And factors contributing to recurrence after treatment are poorly understood. Herein, we sought to develop a novel clinical nomogram to predict ureteral stricture-free survival in patients suffering from ureter stricture and performed balloon dilation. METHODS: The nomogram was established based on a retrospective analysis of 321 patients who received endoscopic balloon dilation alone for ureter strictures from January 2016 to January 2020 in Sun Yat-sen Memorial Hospital using the Cox regression model. Perioperative clinical data and disease outcomes were analyzed. The primary endpoint was the onset of ureteral re-stricture after ureter balloon dilation. Discrimination of the nomogram was assessed by the concordance index (C-index) and the calibration curve. The results were internally validated using bootstrap resampling. RESULTS: Overall, 321 patients with a median follow-up of 590 days were enrolled in the study, among which 97 patients (30.2%) developed recurrence of ureteral stricture during follow-up. Five variables remained significant predictors of ureteral re-stricture after multivariable analyses: stricture nature (P < 0.001), urinary nitrite (P = 0.041), CKD (P = 0.005), stent retention time (P < 0.001), and balloon size (P = 0.029). The calibration craves for the probability of 1-, 3-, and 5-years stricture-free survival (SFS) presented satisfied with the consistency of nomogram prediction and actual observation. The C-index of the model was 0.74 (95% CI 0.70-0.79). CONCLUSIONS: Our study developed the first nomogram to effectively predict stricture-free survival in patients suffering from ureter stricture after balloon dilation. It is helpful to identify the optimal patients with ureter stricture for balloon dilation and improve treatment outcomes. However, further external validation of the nomogram is warranted.

In-Fiber Polymer Microdisk Resonator and Its Sensing Applications of Temperature and Humidity.

We proposed and realized an all-in-fiber polymer microdisk whispering-gallery mode (WGM) resonator, which is composed of a nanoscale polymer waveguide in conjunction with a polymer microdisk. The resonator is manufactured by femtosecond laser-induced two-photon polymerization inside a single-mode optical fiber, and its transmission spectrum has been investigated theoretically and experimentally. The WGM resonance was excited successfully, exhibiting a high Q factor of 2.3 × 103 at a resonant wavelength of 1416.6 nm. The temperature and humidity responses of the resonator were tested as examples of possible application. Temperature sensitivity of -96 pm/°C when the temperature increased from 25 to 60 °C and humidity sensitivity of 54 pm/%RH when the relative humidity increased from 30 to 90% were obtained. The proposed in-fiber microdisk resonator is highly suitable for detection of microorganisms, bacteria, and single molecules.

Targeting WD repeat domain 5 enhances chemosensitivity and inhibits proliferation and programmed death-ligand 1 expression in bladder cancer.

BACKGROUND: Chemotherapy and/or immunotherapy are first-line treatments for advanced muscle-invasive bladder cancer (BCa), but the unsatisfactory objective response rate to these treatments yields poor 5-year patient survival. Discovery of therapeutic targets essential for BCa maintenance is critical to improve therapy response in clinic. This study evaluated the role of targeting WD repeat domain 5 (WDR5) with the small molecule compound OICR-9429 and whether it could be used to treat bladder cancer. METHODS: We analysed the expression and clinical prognosis of WDR5 in a TCGA cohort. The pharmacological role of OICR-9429 was further investigated in vitro and in vivo. RNA sequencing, western blot, and chromatin immunoprecipitation (ChIP) were utilized to explored the mechanism underlying OICR-9429-induced WDR5 inhibition. RESULTS: First, we found that WDR5 expression was upregulated in BCa and was associated with histologic grade, metastasis status, histologic subtype, and molecular subtype. High WDR5 expression level was also correlated with shorter overall survival (OS) in BCa. The WDR5 inhibitor OICR-9429 reduced cell viability by decreasing H3K4me3 levels but not WDR5 levels in T24, UM-UC-3, and TCCSUP BCa cells. OICR-9429 suppressed the proliferation of BCa cells by blocking the G1/S phase transition. Next, OICR-9429 enhanced apoptosis and chemosensitivity to cisplatin in BCa cells. In addition, OICR-9429 independently inhibited the motility and metastatic behaviour of BCa cells. In vivo experiments further revealed that OICR-9429 suppressed tumour growth, enhanced chemosensitivity, and reduced the toxicity of cisplatin in BCa. Notably, WDR5 was positively correlated with programmed death-ligand 1 (PD-L1) expression, and OICR-9429 suppressed immune evasion by blocking PD-L1 induced by IFN-γ. Mechanistically, some cell cycle-, antiapoptosis-, DNA repair-, metastasis-, and immune evasion-related genes, including BIRC5, XRCC2, CCNB1, CCNE2, PLK1, AURKA, FOXM1, and PD-L1 were identified to be directly regulated by OICR-9429 in a H3K4me3-dependent manner. CONCLUSIONS: Our novel finding is that the WDR5 inhibitor, OICR-9429, suppressed proliferation, metastasis and PD-L1-based immune evasion while enhancing apoptosis and chemosensitivity to cisplatin in BCa by blocking the WDR5-MLL complex mediating H3K4me3 in target genes. Hence, our findings offer insight into a multipotential anticancer compound, OICR-9429, which enhances the antitumour effect of cisplatin or immunotherapy in BCa.

Single-Nanoparticle Coulometry Method with High Sensitivity and High Throughput to Study the Electrochemical Activity and Oscillation of Single Nanocatalysts.

To explore nanocatalysts with high electro-catalytic performance and less loading of precious metals, efforts have been made to develop electrochemical methods with high spatial resolution at the single nanoparticle level. Herein, a highly sensitive single-nanoparticle coulometry method is successfully developed to study the electrochemical activity and oscillation of single PtTe nanocatalysts. Based on microbattery reactions involving the formic acid electro-oxidation and the deposition of Ag on the single PtTe nanocatalyst surface, this method enables the transition from the undetectable sub-fA electric signal of the formic acid electro-oxidation into strong localized surface plasmon resonance scattering signal of Ag detected by dark-field microscopy. The lowest limiting current for a single nanocatalyst is found to be as low as 25.8 aA. Different trends of activity versus the formic acid concentration and types of activity of the single nanocatalyst have been discovered. Unveiled frequency-amplitude graph shows that the two electrochemical oscillation modes of low frequency with high amplitude and vice versa coexist in a single PtTe nanocatalyst, indicating the abundantly smooth surfaces and defects of nanocatalysts. This conducted study will open up the new avenue for further behavioral and mechanistic investigation of more types of nanocatalysts in the electrochemistry community.

Gastrodin attenuates lithium-pilocarpine-induced epilepsy by activating AMPK-mediated PPARα in a juvenile rat model.

Gastrodin has shown the potential as an anticonvulsant. Epilepsy is a neurological disease with significant effects in children. In the current study, the therapeutic potential of gastrodin in handling pediatric epilepsy was explored by focusing on the AMPK/PPARα pathway. Three-week-old Sprague-Dawley rats were subjected to lithium-pilocarpine method to induce epileptic symptoms and then administrated with gastrodin. The effects of gastrodin on rats were first assessed using electroencephalogram (EEG) recording, Racine classification, Morris water maze test, and histological staining. The levels of BDNF and NGF, and the activity of AMPK/PPARα were measured. Based on the results of EEG, behavior analyses, and histological staining, epileptic symptoms were significantly alleviated by gastrodin. Moreover, the administration of gastrodin also suppressed the levels of BDNF and NGF, and activated the AMPK/PPARα pathway. In conclusion, our results demonstrated that gastrodin contributed to the alleviation of pediatric epilepsy by activating AMPK/PPARα signaling transduction.

A Model for Identifying Optimal Patients for Primary Tumor Resection in Patients With Metastatic Bladder Cancer.

BACKGROUND: A survival benefit was observed in metastatic bladder cancer patients who underwent primary tumor resection, but it was still confusing which patients are suitable for the surgery. For this purpose, we developed a model to screen stage M1 patients who would benefit from primary tumor resection. METHODS: Patients with metastatic bladder cancer were screened from the Surveillance, Epidemiology, and End Results database (2004-2016) and then were divided into surgery (partial or complete cystectomy) group and non-surgery group. To balance the characteristics between them, a 1:1 propensity score matching analysis was applied. A hypothesis was proposed that the received primary tumor resection group has a more optimistic prognosis than the other group. The multivariable Cox model was used to explore the independent factors of survival time in two groups (beneficial and non-beneficial groups). Logistic regression was used to build a nomogram based on the significant predictive factors. Finally, a variety of methods are used to evaluate our model. RESULTS: A total of 7,965 patients with metastatic bladder cancer were included. And 3,314 patients met filtering standards, of which 545 (16.4%) received partial or complete cystectomy. Plots of the Kaplan-Meier and subgroup analyses confirmed our hypothesis. After propensity score matching analysis, a survival benefit was still observed that the surgery group has a longer median overall survival time (11.0 vs. 6.0 months, p < 0.001). Among the surgery cohort, 303 (65.8%) patients lived longer than 6 months (beneficial group). Differentiated characteristics included age, gender, TNM stage, histologic type, differentiation grade, and therapy, which were integrated as predictors to build a nomogram. The nomogram showed good discrimination in both training and validation cohorts (area under the receiver operating characteristic curve (AUC): 0.806 and 0.742, respectively), and the calibration curves demonstrated good consistency. Decision curve analysis showed that the nomogram was clinically useful. Compared with TNM staging, our model shows a better predictive value in identifying optimal patients for primary tumor resection. CONCLUSIONS: A practical predictive model was created and verified, which might be used to identify the optimal candidates for the partial or complete cystectomy group of the primary tumor among metastatic bladder cancer.

Fiber-interface directional coupler inscribed by femtosecond laser for refractive index measurements.

A novel fiber-interface directional waveguide coupler was inscribed on the surface of a coreless fiber by femtosecond laser, and was successfully applied to highly sensitive refractive index (RI) measurements. The primary arm was first inscribed to couple light from a lead-in single mode fiber to the fiber interface, then back to a lead-out single mode fiber. A side arm was inscribed parallel and in close proximity to the primary arm. Light propagating in the primary arm could then be efficiently coupled into the side arm when a phase-matching condition was met, which produced a dramatic spectral dip at the coupling wavelength. The proposed device achieved a sensitivity as high as ∼8249 nm/RIU over an RI range of 1.44-1.45, due to strong evanescent fields excited in fiber-interface waveguides. The proposed in-fiber directional coupler exhibits high mechanical strength, a compact configuration, and excellent RI sensitivity. As such, it has significant potential for practical applications in biochemical sensing.

High-energy mode-locked holmium-doped fiber laser operating in noise-like pulse regime.

An all-fiber mode-locked holmium-doped fiber laser operating in the noise-like pulse regime is reported. Employing a nonlinear amplifying loop mirror as the artificial saturable absorber, the laser generates pulses with energy up to 280 nJ, which is, to the best of our knowledge, the highest pulse energy ever achieved from mode-locked holmium-doped fiber lasers. We also discover a peculiar mode-locking operation mode using the laser. The peculiar mode falls into the category of a noise-like pulse, while it possesses a number of unique features (strong spikes in the optical spectrum, high temporal coherence, and chair-like pulse profile) that are not observed in previous research works regarding noise-like pulse lasers.

A novel AR translational regulator lncRNA LBCS inhibits castration resistance of prostate cancer.

BACKGROUND: Progression to a castration resistance state is the main cause of deaths in prostate cancer (PCa) patients. Androgen Receptor (AR) signaling plays the central role in progression of Castration Resistant Prostate Cancer (CRPC), therefore understanding the mechanisms of AR activation in the milieu of low androgen is critical to discover novel approach to treat CRPC. METHODS: Firstly, we explore the CRPC associated lncRNAs by transcriptome microarray. The expression and clinical features of lnc-LBCS are analyzed in three independent large-scale cohorts. The functional role and mechanism of lnc-LBCS are further investigated by gain and loss of function assays in vitro. RESULTS: The expression of Lnc-LBCS was lower in CRPC cells lines and tissues. LBCS downregulation was correlated with higher Gleason Score, T stage and poor prognosis of PCa patients. LBCS overexpression decreases, whereas LBCS knockdown increases, the traits of castration resistance in prostate cancer cells under androgen ablated or AR blocked condition. Moreover, knockdown of LBCS was sufficient to activate AR signaling in the absence of androgen by elevating the translation of AR protein. Mechanistically, LBCS interacted directly with hnRNPK to suppress AR translation efficiency by forming complex with hnRNPK and AR mRNA. CONCLUSIONS: Lnc-LBCS functions as a novel AR translational regulator that suppresses castration resistance of prostate cancer by interacting with hnRNPK. This sheds a new insight into the regulation of CRPC by lncRNA mediated AR activation and LBCS-hnRNPK-AR axis provides a promising approach to the treatment of CRPC.

Polypyrimidine tract binding protein 1 promotes lymphatic metastasis and proliferation of bladder cancer via alternative splicing of MEIS2 and PKM.

Lymph node (LN) metastasis is the leading cause of bladder cancer-related mortality. Splicing factors facilitate cancer progression by modulating oncogenic variants, but it is unclear whether and how splicing factors regulate bladder cancer LN metastasis. In this study, Polypyrimidine tract binding protein 1 (PTBP1) expression was found to relate to bladder cancer LN metastasis, and was positively correlated with LN metastasis status, tumor stage, histological grade, and poor patient prognosis. Functional assays demonstrated that PTBP1 promoted bladder cancer cell migration, invasion, and proliferation in vitro, as well as LN metastasis and tumor growth in vivo. Mechanistic investigations revealed that PTBP1 upregulated MEIS2-L variant to promote metastasis and increased expression of PKM2 variant to enhance proliferation by modulating alternative mRNA splicing. Moreover, overexpression of MEIS2-L or PKM2 could rescue the oncogenic abilities of bladder cancer cells and the expression of MMP9 or CCND1 respectively after PTBP1 knockdown. In conclusion, our data demonstrate that PTBP1 induces bladder cancer LN metastasis and proliferation through an alternative splicing mechanism. PTBP1 may serve as a novel prognostic marker and therapeutic target for LN-metastatic bladder cancer.

DANCR Promotes Metastasis and Proliferation in Bladder Cancer Cells by Enhancing IL-11-STAT3 Signaling and CCND1 Expression.

The prognosis for patients with bladder cancer (BCa) with lymph node (LN) metastasis is poor, and it is not improved by current treatments. Long noncoding RNAs (lncRNAs) are involved in the pathology of various tumors, including BCa. However, the role of Differentiation antagonizing non-protein coding RNA (DANCR) in BCa LN metastasis remains unclear. In this study, we discover that DANCR was significantly upregulated in BCa tissues and cases with LN metastasis. DANCR expression was positively correlated with LN metastasis status, tumor stage, histological grade, and poor patient prognosis. Functional assays demonstrated that DANCR promoted BCa cell migration, invasion, and proliferation in vitro and enhanced tumor LN metastasis and growth in vivo. Mechanistic investigations revealed that DANCR activated IL-11-STAT3 signaling and increased cyclin D1 and PLAU expression via guiding leucine-rich pentatricopeptide repeat containing (LRPPRC) to stabilize mRNA. Moreover, oncogenesis facilitated by DANCR was attenuated by anti-IL-11 antibody or a STAT3 inhibitor (BP-1-102). In conclusion, our findings indicate that DANCR induces BCa LN metastasis and proliferation via an LRPPRC-mediated mRNA stabilization mechanism. DANCR may serve as a multi-potency target for clinical intervention in LN-metastatic BCa.

Long Noncoding RNA LBCS Inhibits Self-Renewal and Chemoresistance of Bladder Cancer Stem Cells through Epigenetic Silencing of SOX2.

PURPOSE: Chemoresistance and tumor relapse are the leading cause of deaths in bladder cancer patients. Bladder cancer stem cells (BCSCs) have been reported to contribute to these pathologic properties. However, the molecular mechanisms underlying their self-renewal and chemoresistance remain largely unknown. In the current study, a novel lncRNA termed Low expressed in Bladder Cancer Stem cells (lnc-LBCS) has been identified and explored in BCSCs. EXPERIMENTAL DESIGN: Firstly, we establish BCSCs model and explore the BCSCs-associated lncRNAs by transcriptome microarray. The expression and clinical features of lnc-LBCS are analyzed in three independent large-scale cohorts. The functional role and mechanism of lnc-LBCS are further investigated by gain- and loss-of-function assays in vitro and in vivo. RESULTS: Lnc-LBCS is significantly downregulated in BCSCs and cancer tissues, and correlates with tumor grade, chemotherapy response, and prognosis. Moreover, lnc-LBCS markedly inhibits self-renewal, chemoresistance, and tumor initiation of BCSCs both in vitro and in vivo. Mechanistically, lnc-LBCS directly binds to heterogeneous nuclear ribonucleoprotein K (hnRNPK) and enhancer of zeste homolog 2 (EZH2), and serves as a scaffold to induce the formation of this complex to repress SRY-box 2 (SOX2) transcription via mediating histone H3 lysine 27 tri-methylation. SOX2 is essential for self-renewal and chemoresistance of BCSCs, and correlates with the clinical severity and prognosis of bladder cancer patients. CONCLUSIONS: As a novel regulator, lnc-LBCS plays an important tumor-suppressor role in BCSCs' self-renewal and chemoresistance, contributing to weak tumorigenesis and enhanced chemosensitivity. The lnc-LBCS-hnRNPK-EZH2-SOX2 regulatory axis may represent a therapeutic target for clinical intervention in chemoresistant bladder cancer.

Circular RNA circUBXN7 represses cell growth and invasion by sponging miR-1247-3p to enhance B4GALT3 expression in bladder cancer.

Circular RNAs (circRNAs) have recently been confirmed to participate in different pathological processes, including cancer progression. However, the role and precise mechanism of action of the majority of circRNAs have not been elucidated in bladder cancer (BC). Here, we identified a novel circular RNA, termed circUBXN7, which was significantly downregulated in BC tissues compared with matched nontumor tissues. Importantly, we found that decreased circUBXN7 expression was associated with pathological stage, grade and poor prognosis of BC patients. Functional experiments showed that circUBXN7 overexpression dramatically inhibited proliferation, migration and invasion in vitro and suppressed tumor growth in vivo. Mechanistically, circUBXN7 could directly bind to miR-1247-3p and reverse the oncogenic effects induced by miR-1247-3p. Furthermore, B4GALT3 was predicted and confirmed to be a target of miR-1247-3p. Rescue experiments demonstrated that circUBXN7 abrogated miR-1247-3p-mediated inhibition of B4GALT3 expression. Finally, silencing of B4GALT3 promoted proliferation and invasion of BC cells; and partially abolished the tumor suppressive effects caused by circUBXN7. Taken together, our study revealed that circUBXN7 serves as a competitive endogenous RNA of miR-1247-3p to elevate B4GALT3 expression, consequently inhibiting cell viability and invasion in BC. The circUBXN7-miR-1247-3p-B4GALT3 regulatory network may provide a new perspective for gene-based treatment strategies for BC.