Androgen-repressed lncRNA LINC01126 drives castration-resistant prostate cancer by regulating the switch between O-GlcNAcylation and phosphorylation of androgen receptor.

BACKGROUND: Prostate cancer (PCa) initially shows satisfactory response to therapies targeting the androgen receptor (AR). However, progression to a castration-resistant stage indicates poor prognosis in PCa patients. AR signalling still plays a central role in most castration-resistant prostate cancers (CRPC). Therefore, unveiling the mechanisms of AR reactivation under androgen-deprived conditions is imperative to discover novel therapeutic targets for CRPC. METHODS: Using an integrative analysis of the transcriptomics of three independent PCa cohorts and a published landscape of AR-regulated long non-coding RNA (lncRNA), lncRNA LINC01126 was selected as a candidate gene that could drive CRPC progression for further study. Quantitative reverse transcription polymerase chain reaction, in situ hybridisation (ISH) and fluorescent ISH were performed to detect LINC01126 in PCa tissues and cells. The functional role and mechanism of LINC01126 were further investigated using in vitro and in vivo gain and loss of function assays. RESULTS: LINC01126, identified as an AR-repressed lncRNA, was significantly upregulated after AR-targeted therapies. In addition, we found that LINC01126 was upregulated in CRPC and was associated with poor prognosis. We also proved that LINC01126 stabilised AR protein and enhanced AR nuclear translocation and transactivation by promoting the transition from O-GlcNAcylation at threonine 80 to phosphorylation at serine 81 (S81) within the AR protein. Mechanism analysis revealed that LINC01126 facilitates the interaction of CDK9 with AR and impedes the binding of O-linked N-acetylglucosamine (O-GlcNAc) transferase to AR. Consequently, LINC01126 expression was sufficient to activate AR signalling without androgen. LINC01126 overexpression increased, whereas LINC01126 knockdown decreased castration resistance traits in PCa cells in vitro and in vivo. Furthermore, our data showed that LINC01126-targeting antisense oligonucleotides (ASO) substantially inhibited CRPC cells in vitro. CONCLUSIONS: Our research expands the functions of AR-regulated lncRNA in sustaining androgen-independent AR activity and promoting CRPC progression and reveals that LINC01126 may be a new therapeutic target for PCa.

circWSB1 promotes tumor progression in ccRCC via circWSB1/miR-182-5p/WSB1 axis.

Clear cell renal cell carcinoma (ccRCC) is one of the most prevalent urological carcinomas with a low overall 5-year survival rate, and its prognosis remains dismal. circular RNAs (circRNAs) has been discovered to be important regulators in ccRCC. However, the specific regulatory mechanisms of circRNAs and their impact on phenotypes require further in-depth research. circRNA microarray sequencing analysis was used in this study to explore the expression pattern of circRNAs in ccRCC. circWSB1 was discovered, and we evaluated its derivation, potential diagnostic efficacy, and prognostic significance in ccRCC tissues. We discovered that circWSB1 is highly expressed in ccRCC. We identified that circWSB1 interacts with miR-182-5p and upregulates the expression of its host gene, WSB1. Through models in vivo and in vitro models, we found that circWSB1 increases WSB1 expression via the circWSB1/miR-182-5p/WSB1 axis, which promotes ccRCC cell proliferation and migration. The high expression of circWSB1 and WSB1 is correlated with poorer clinical prognosis and pathological grading. circWSB1 diminishes the inhibitory impact of miR-182-5p on WSB1 and increases WSB1 expression, thereafter promoting ccRCC development. Our findings provide a promising predictive biomarker and therapeutic target for ccRCC.

Benign Prostatic Hyperplasia-Related False-Positive of Prostate-Specific Membrane Antigen-Positron Emission Tomography in the Diagnosis of Prostate Cancer: The Achilles' Heel of Biopsy-Free Radical Prostatectomy?

PURPOSE: Radical prostatectomy is one of the primary treatments for localized clinically significant prostate cancer. Generally, its application is based on prior biopsy. PSMA (prostate-specific membrane antigen)-PET (positron emission tomography) is considered promising in biopsy-free radical prostatectomy. The expression of PSMA in benign prostatic hyperplasia tissue and corresponding positive reaction are crucial concerns for a no-biopsy strategy. Currently, no study has explored the benign prostatic hyperplasia-related false-positive of PSMA-PET in the detection of prostate cancer. Furthermore, the influence of maximum standardized uptake value and Prostate Imaging Reporting & Data System on biopsy-free radical prostatectomy is also poorly characterized. MATERIALS AND METHODS: A retrospective study was conducted on patients who received PSMA-PET because of clinical suspicion of prostate cancer and were confirmed to have benign prostatic hyperplasia or prostate cancer. The receiver operating characteristic curve was generated for maximum standardized uptake value. Results of interest were the false-positive rate of PSMA-PET and the efficacy of maximum standardized uptake value or multiparametric MRI in excluding false-positives. RESULTS: The benign prostatic hyperplasia-related false-positive rate of PSMA-PET in detecting prostate cancer was 30%. Maximum standardized uptake value could effectively exclude benign prostatic hyperplasia and Grade Group 1 patients with an area under the curve of 0.86; the optimal maximum standardized uptake value cutoff value with 100% specificity was 15, with a sensitivity of 41%. Notably, the sensitivity and specificity of stringent PET score and Prostate Imaging Reporting & Data System criteria (both ≥4) in diagnosing clinically significant prostate cancer were 49% and 100%, respectively. CONCLUSIONS: Our findings revealed benign prostatic hyperplasia-related false-positive rate of PSMA-PET and provided a preliminary reference in biopsy-free radical prostatectomy.

FOXM1-regulated ZIC2 promotes the malignant phenotype of renal clear cell carcinoma by activating UBE2C/mTOR signaling pathway.

Background: As a transcription factor, Zic family member 2 (ZIC2) has been involved in more and more studies of tumorigenesis, which has been proved by our research team to be an effective prognostic marker for Pan-cancer. However, the prognosis, tumor promoting effect and regulatory mechanism of ZIC2 in clear cell renal cell carcinoma (ccRCC) are still unknown. Methods: The potential clinical significance of ZIC2 was evaluated by bioinformatics analysis using data from TCGA, GEO, and ArrayExpress data sets. WB and IHC were used to detect ZIC2 expression in tumors and adjacent tissues. CCK-8, EdU, colony formation, cell cycle, wound healing, transwell, subcutaneous xenograft, and lung metastasis models were used to detect the biological function of ZIC2. The regulatory mechanism of ZIC2 was confirmed by data of RNA-seq, ATAC-seq, MS-PCR, Chip-PCR, and luciferase reporter experiments. Results: ZIC2 was markedly upregulated and correlated with poor clinicopathological features in ccRCC. Knockdown of ZIC2 resulted in reduced cell proliferation, invasion, migration, induction of G2/M phase arrest, and reduced tumor formation and lung metastasis in nude mice. The opposite was observed after overexpression. Mechanistically, the high expression of ZIC2 is regulated by hypomethylation and high H3K4Me3 in the promoter region, as well as positive transcriptional regulation by FOXM1. And then, ZIC2 transcriptase-positively regulates UBE2C and activates AKT/mTOR signaling pathway to promote tumor malignant progression. Conclusion: This study reveals that FOXM1-ZIC2-UBE2C-mTOR signaling axis promotes the progression of ccRCC, which can be used as a prognostic indicator and potential therapeutic target.

The evolving role of checkpoint inhibitors in the treatment of urothelial carcinoma.

The most prevalent pathological subtype of bladder and upper urinary tract malignancy is urothelial carcinoma (UC). Traditional therapies mainly include surgical resection, chemotherapy and radiotherapy. Checkpoint inhibitors, which are monoclonal antibodies developed to specifically target immune checkpoint molecules, have recently emerged as potential treatment options for UC patients, especially those targeting the programmed cell death protein 1 (PD-1) and its ligand (PD-L1). However, anti-PD-1/PD-L1 therapy does not work for a considerable number of UC patients. Current antitumour immunotherapy research hotspots include seeking biomarkers that might predict therapeutic effects and exploring novel immune checkpoint molecules crucial for the antitumour immune response. Hence, we will recapitulate the latest preclinical and clinical trials of 5 PD-1/PD-L1 inhibitors, 1 cytotoxic T-lymphocyte-associated protein 4 inhibitor and combination therapies for UC treatment, including combined immunotherapy and immunotherapy with chemotherapy or radiotherapy. We will also summarize other potential immune checkpoint molecules found in ongoing UC studies. Moreover, we will highlight the role of biomarkers linked with the oncological efficacy of anti-PD-1/PD-L1 immunotherapy and address the mechanisms of immunotherapy drug resistance in UC, with the hope of providing more systematic guidance for its application and development.

Epigenetic Regulation in Urothelial Carcinoma

Urothelial carcinoma (UC) is a common malignancy that remains a clinical challenge: Non-muscle-invasive urothelial carcinoma (NMIUC) has a high rate of recurrence and risk of progression, while muscle-invasive urothelial carcinoma (MIUC) has a high mortality. Although some new treatments, such as immunotherapies, have shown potential effects on some patients, most cases of advanced UC remain incurable. While treatments based on epigenetic mechanisms, whether combined with traditional platinum-based chemotherapy or emerging immunotherapy, show therapeutic advantages. With the advancement of sequencing and bioinformatics, the study of epigenomics, containing DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA, is increasingly linked with the occurrence and progression of UC. Since the epigenetics of UC is a constantly developing field of medicine, this review aims to summarize the latest research on epigenetic regulation of UC, generalize the mechanism of epigenetics in UC, and reveal the potential epigenetic therapies in the clinical setting, in order to provide some new clues on the discovery of new drugs based on the epigenetics.

Outcomes and prognostic factors in patients with locally advanced cervical cancer treated with concurrent chemoradiotherapy.

BACKGROUND: To investigate the prognostic factors affecting long-term survival in locally advanced cervical cancer (LACC) patients treated with concurrent chemoradiotherapy (CCRT). METHODS: We retrospectively analyzed 192 naive LACC (stage IIB-IVA) patients who underwent intensity-modulated radiotherapy (IMRT) with concurrent platinum-based chemotherapy in Xiangya Hospital from January 2014 to June 2017. The clinicopathological factors of all patients were collected. To explore the relationship between factors and prognosis, survival rates were estimated by the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards models were used to evaluate the effect of various factors on overall survival (OS) and progression-free survival (PFS). The nomogram and calibration curves were generated on the basis of survival analysis. RESULTS: The median follow-up time was 39.5 months. There-year rates of OS and PFS were 89.1% and 82.8%. LACC patients with non-squamous cell carcinoma [NSCC, including adenocarcinoma or adenosquamous carcinoma (AC/ASC)], advanced stage (IIIA-IVA), initially positive lymph node (pelvic or para-aortic lymph node, PLN/PALN), and a lower pretreatment hemoglobin (HGB) level (< 126 g/L) had lower survival rates. In univariate analysis, patients with NSCC, advanced stage, PLN or PALN metastasis had worse OS. Patients with NSCC, advanced stage, PLN or PALN metastasis, and a lower pretreatment HGB level had worse PFS. In multivariate analysis, NSCC and PALN metastasis were independent prognostic parameters of OS. NSCC, PALN metastasis and a lower pretreatment HGB level were independent prognostic parameters of PFS. CONCLUSIONS: NSCC and PALN metastasis were poor prognostic factors of OS and PFS, a lower pretreatment HGB level was an independent prognostic factor of PFS in LACC patients treated with CCRT.

Current role of prostate-specific membrane antigen-based imaging and radioligand therapy in castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) is a therapy-resistant and lethal form of prostate cancer as well as a therapeutic challenge. Prostate-specific membrane antigen (PSMA) has been proved as a promising molecular target for optimizing the theranostics for CRPC patients. When combined with PSMA radiotracers, novel molecular imaging techniques such as positron emission tomography (PET) can provide more accurate and expedient identification of metastases when compared with conventional imaging techniques. Based on the PSMA-based PET scans, the accurate visualization of local and disseminative lesions may help in metastasis-directed therapy. Moreover, the combination of 68Ga-labeled PSMA-based PET imaging and radiotherapy using PSMA radioligand therapy (RLT) becomes a novel treatment option for CRPC patients. The existing studies have demonstrated this therapeutic strategy as an effective and well-tolerated therapy among CRPC patients. PSMA-based PET imaging can accurately detect CRPC lesions and describe their molecular features with quantitative parameters, which can be used to select the best choice of treatments, monitor the response, and predict the outcome of RLT. This review discussed the current and potential role of PSMA-based imaging and RLT in the diagnosis, treatment, and prediction of prognosis of CRPC.

Identifying a Ferroptosis-Related Gene Signature for Predicting Biochemical Recurrence of Prostate Cancer.

Ferroptosis induced by lipid peroxidation is closely related to cancer biology. Prostate cancer (PCa) is not only a malignant tumor but also a lipid metabolic disease. Previous studies have identified ferroptosis as an important pathophysiological pathway in PCa development and treatment, but its role in the prognosis of PCa is less well known. In this study, we constructed a nine-ferroptosis-related gene risk model that demonstrated strong prognostic and therapeutic predictive power. The higher risk score calculated by the model was significantly associated with a higher ferroptosis potential index, higher Ki67 expression, higher immune infiltration, higher probability of biochemical recurrence, worse clinicopathological characteristics, and worse response to chemotherapy and antiandrogen therapy in PCa. The mechanisms identified by the gene set enrichment analysis suggested that this signature can accurately distinguish high- and low-risk populations, which is possibly closely related to variations in steroid hormone secretion, regulation of endocrine processes, positive regulation of humoral immune response, and androgen response. Results of this study were confirmed in two independent PCa cohorts, namely, The Cancer Genome Atlas cohort and the MSK-IMPACT Clinical Sequencing Cohort, which contributed to the body of scientific evidence for the prediction of biochemical recurrence in patients with PCa. In addition, as the main components of this signature, the effects of the AIFM2 and NFS1 genes on ferroptosis were evaluated and verified by in vivo and in vitro experiments, respectively. The above findings provided new insights and presented potential clinical applications of ferroptosis in PCa.

Evaluation and analysis of incidence and risk factors of lower extremity venous thrombosis after urologic surgeries: A prospective two-center cohort study using LASSO-logistic regression.

BACKGROUND: Deep vein thrombosis (DVT) is among the most frequent complications of surgery. This study aimed to analyse the incidence and risk factors of lower extremity venous thrombosis after urologic surgery. MATERIALS AND METHODS: This prospective two-centre study was conducted from August 2019 to January 2020. Patients who underwent urological procedures were enrolled. The primary endpoint was the detection of asymptomatic or symptomatic DVT of the lower extremity within 7 days after surgery. Univariate and least absolute shrinkage and selection operator (LASSO) logistic regression analyses were performed. RESULTS: Fifty-six of 1011 patients developed DVT. In the univariate analysis, Barthel Index ≤40, d-dimer level ≥0.5 mg/L and age ≥60 years (p < 0.001) were identified as the most significant risk factors. The LASSO logistic regression model identified nine factors: age, history of DVT, lymph node dissection, perioperative steroid use, Caprini score, Barthel Index, D-dimer level, cystectomy, and prostatectomy. CONCLUSION: Our study used the LASSO logistic regression model to provide reliable data on the risk factors for DVT after comprehensive urologic surgery. The incidence of DVT in this group was 5.54%. This might facilitate individualised anticoagulant management in patients undergoing urological procedures.

circ_100984-miR-432-3p axis regulated c-Jun/YBX-1/ß-catenin feedback loop promotes bladder cancer progression.

Bladder cancer (BC) is one of the most commonly diagnosed cancers globally. Recently, circular RNAs (circRNAs) have been revealed to participate in BC progression with diverse mechanisms. However, mechanisms of circ_100984 in BC have not been determined. Here, we found that circ_100984 and YBX-1 were high presented, while miR-432-3p was low presented in BC. Silencing of circ_100984 and YBX-1 repressed BC tumor growth, migration, and invasion in vitro and in vivo. Mechanistically, we revealed that circ_100984 served as a competing endogenous RNA that sponged miR-432-3p to indirectly regulate YBX-1 and epithelial-mesenchymal transition (EMT)-related molecules. Moreover, we confirmed that YBX-1 or c-Jun acted as a transcription regulatory factor for ß-catenin or YBX-1, respectively, in BC cells. Knockdown of YBX-1 inhibited the expression of ß-catenin and c-Jun, whereas downregulated c-Jun inversely repressed the expression of YBX-1 and ß-catenin. Our results suggested that circ_100984-miR-432-3p axis regulated c-Jun/YBX-1/ß-catenin feedback loop promotes BC progression, providing a potential therapeutic axis for BC progression.

Evaluation of transrectal ultrasound-based dosimetry for brachytherapy of prostate cancer: a single-center experience.

PURPOSE: To explore the possibility of intraoperative transrectal ultrasound (TRUS)-based dose verification in transperineal brachytherapy (BT) with iodine-125 (125I) seeds for prostate cancer. MATERIAL AND METHODS: Fifteen patients with prostate cancer were treated using BT with 125I seeds. Post-implant TRUS and computed tomography (CT) images were imported into treatment planning system (TPS) for dosimetry. Dosimetry parameters, including minimum dose received by 90% of the volume (D90), percentage of the volume receiving 100% of prescribed dose (V100), and percentage of the volume receiving 200% of prescribed dose (V200) were calculated based on TRUS and CT images, separately. The D90 value of TRUS-based dosimetry was transformed to its expected value. Comparisons of the dosimetric parameters between post-operative verification and preoperative plans were made by paired t-test. One-way ANOVA model was used to assess the differences in preoperative plans. Agreements were evaluated between the preoperative planning and post-operative actual dose parameters using Bland-Altman analysis. RESULTS: In total, 825 of 125I seeds were implanted successfully in 15 patients. In TRUS-based dosimetry, 674 seeds (81%) were identified clearly in TRUS-based images, and the expected value of D90 parameter showed no significant differences compared with the preoperative planning and CT post-operation results (p > 0.05). In CT-based dosimetry, 810 seeds (98%) were identified clearly in CT-based images, and there was good consistency of D90, V100, and V200 values (p > 0.05). Post-implant CT-based dosimetry indicated that 125I seed implantation had fulfilled the expected plan. CONCLUSIONS: Intraoperative TRUS can be used for dosimetric verification of BT for prostate cancer.

Multiple extracranial metastases from glioblastoma multiforme: a case report and literature review.

Extracranial metastasis from glioblastoma multiforme (GBM) is rare, especially multi-site metastases without intracranial recurrence. However, the metastatic mechanism of GBM remains unknown and there is currently no consensus regarding the best therapeutic regimen. We report the case of a 46-year-old man with primary GBM who developed scalp metastases and subsequent multiple pulmonary metastases. He was treated with the Stupp regimen after surgery for the intracranial tumor. However, a series of soft masses in the scalp were subsequently identified, and new nodules were found in his left eyebrow arch during chemoradiotherapy. Despite salvage chemotherapy and targeted therapy, the patient eventually died of respiratory failure with multiple pulmonary metastases. This case highlights the need for rigorous follow-up, including brain magnetic resonance imaging, in patients with GBM. The occurrence of extra-central nervous system symptoms indicates the possibility of metastasis, and the relevant examinations should be conducted promptly. Positive therapies may help to relieve symptoms and prolong survival in patients with metastatic GBM.