Long non-coding RNAs (lncRNAs) act as important regulators of tumorigenesis and development in bladder cancer. However, the underlying molecular mechanisms remain elusive. We previously identified a ...novel lncRNA signature related to immunity and progression in bladder cancer. Here we further explored the function of RP11-89, a lncRNA discovered in the previous signature. Loss- and gain-of function experiments were performed using CCK-8 assay, flow cytometry, Transwell assays, scratch tests and subcutaneous nude mouse models. High-throughput RNA sequencing was conducted to identify dysregulated genes in bladder cancer cells with RP11-89 knockdown or overexpression. Regulation of RP11-89 on miR-129-5p and PROM2 was explored through luciferase reporter assay, RIP assay and RNA pull-down assay. RP11-89 promoted cell proliferation, migration and tumorigenesis and inhibited cell cycle arrest via the miR-129-5p/PROM2 axis. We found that RP11-89 "sponges" miR-129-5p and upregulates PROM2. Elevated PROM2 in cells was associated with attenuated ferroptosis through iron export, formation of multivesicular bodies and less mitochondrial abnormalities. We demonstrated that RP11-89 is a novel tumorigenic regulator that inhibits ferroptosis via PROM2-activated iron export. RP11-89 may serve as a potential biomarker for targeted therapy in bladder cancer.
Non-invasive assays for early cancer screening are hampered by challenges in the isolation and profiling of circulating biomarkers. Here, we show that surface proteins from serum extracellular ...vesicles labelled with a panel of seven fluorescent aptamers can be profiled, via thermophoretic enrichment and linear discriminant analysis, for cancer detection and classification. In a cohort of 102 patients, including 6 cancer types at stages I-IV, the assay detected stage I cancers with 95% sensitivity (95% confidence interval (CI): 74-100%) and 100% specificity (95% CI: 80-100%), and classified the cancer type with an overall accuracy of 68% (95% CI: 59-77%). For patients who underwent prostate biopsies, the assay was superior to the analysis of prostate-specific antigen levels (area under the curve: 0.94 versus 0.68; 33 patients) for the discrimination of prostate cancer and benign prostate enlargement, and also in the assessment of biochemical cancer recurrence after radical prostatectomy. The assay is inexpensive, fast, and requires small serum volumes (<1 µl), and if validated in larger cohorts may facilitate cancer screening, classification and monitoring.
Whole-mount histopathology (WMH) has been a powerful tool to investigate the characteristics of prostate cancer. However, the latest advancement of WMH was yet under summarization. In this review, we ...offer a comprehensive exposition of current research utilizing WMH in diagnosing and treating prostate cancer (PCa), and summarize the clinical advantages of WMH and outlines potential on future prospects.
An extensive PubMed search was conducted until February 26, 2023, with the search term "prostate", "whole-mount", "large format histology", which was limited to the last 4 years. Publications included were restricted to those in English. Other papers were also cited to contribute a better understanding.
WMH exhibits an enhanced legibility for pathologists, which improved the efficacy of pathologic examination and provide educational value. It simplifies the histopathological registration with medical images, which serves as a convincing reference standard for imaging indicator investigation and medical image-based artificial intelligence (AI). Additionally, WMH provides comprehensive histopathological information for tumor volume estimation, post-treatment evaluation, and provides direct pathological data for AI readers. It also offers complete spatial context for the location estimation of both intraprostatic and extraprostatic cancerous region.
WMH provides unique benefits in several aspects of clinical diagnosis and treatment of PCa. The utilization of WMH technique facilitates the development and refinement of various clinical technologies. We believe that WMH will play an important role in future clinical applications.
Prostate cancer (PCa) is one of the most common malignancies in male. We aim to establish a novel gene signature for immune infiltration and outcome (biochemical recurrence (BCR) and overall survival ...(OS)) of patients with prostate cancer (PCa) to augment Gleason patterns for evaluating prognosis and managing patients undergoing radical prostatectomy (RP). Combined with our microarray data and the Cancer Genome Atlas Project (TCGA) database (discovery set), we identified a six-gene signature. The Gene Expression Omnibus (GEO) database served as the test set. The databases of Fudan University Shanghai Cancer Center (FUSCC) and Third Affiliated Hospital of Nantong University (TAHNU) served as an external validation set. Immunohistochemistry was used to investigate the relationship between risk groups and the immune infiltrate. We identified a six-gene signature to predict immune cell infiltration and outcome of PCa patients. The AUC values used to predict early BCR in the discovery, test, FUSCC, and TAHNU sets were 0.73, 0.76, 0.72, and 0.81, respectively. Low-risk score patients in each dataset experienced significantly longer OS (P = .01, 0.04, 0.02, respectively). The signature also predicted high regulatory T cells (Tregs) and M2-polarized macrophages infiltration in high-risk score patients with PCa. Additionally, high mutation load, related signal pathways, and sensitivity to anticancer drugs that correlated with high-risk score of cancer progression and death were also identified. The six-gene signature may improve prognostic information, serve as a prognostic tool to manage patients after RP, and advance basic studies of PCa.
As conditional survival could provide more relevant prognostic information at each follow-up time, the present study aimed to assess conditional overall survival (COS) based on two cohorts and assess ...the risks of death due to renal cell carcinoma (RCC) vs. other causes.
The Fudan University Shanghai Cancer Center (FUSCC) and Surveillance, Epidemiology, and End Results (SEER) database were used as the source of data for our analysis. COS and cancer-specific survival were evaluated using the Kaplan-Meier method.
A total of 90,927 patients (SEER cohort = 88,807, FUSCC cohort = 2,120) were enrolled. Our results suggest that hazards of other causes-related death were always higher than that of cancer-specific death in low-risk RCC patients, but lower in metastatic RCC patients. It exceeded that of cancer-specific death by 8 years in high-risk RCC patients. Only in metastatic RCC patients, the COS improved markedly with survivorship increasing. After surviving 1, 2, 3, 4, and 5 years, the 5 years COS increased by +10, +18, +23, +29, and 35% (the observed 5 years OS: 12%), respectively.
COS can better help patients with metastatic RCC rather than other RCC patients. Additionally, COS brings optimism for metastatic RCC patients with expected poorer prognosis psychologically.
The purpose of this study was to explore the composition of tumor-infiltrating immune cells (TIIC) and prognostic significance of tumor-infiltrating mast cells (TIMC) in adrenocortical carcinoma ...(ACC).
The gene expression profiles of ACC were downloaded from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GSE90713, GSE12368). The abundance of TIICs in ACC samples was calculated by CIBERSORT algorithm and immunohistochemistry was used to identify mast cells of 39 tumor samples from Fudan University Shanghai Cancer Center (FUSCC). Differentially expressed genes (DEGs) were analyzed by LIMMA package using R software. Survival analysis was analyzed by Kaplan-Meier method and Cox regression models.
The abundance of mast cells (p = .008) was positively correlated with ACC patients' outcome in TCGA cohort and was also positively correlated with both overall survival (p < .05) and progression-free survival (p < .05) in FUSCC cohort. Different TIMC infiltrations showed significant changes in signaling pathways including DNA replication, nuclear chromosome segregation, and meiotic cell cycle process of ACC. In addition, elevated expression of eight hub genes (KIF18A, CDCA8, SKA1, CEP55, BUB1, CDK1, SGOL1, SGOL2) related to the abundance of TIMC in ACC was significantly correlated with the poor prognosis of the patients.
In conclusion, higher TIMC infiltration was positively correlated with ACC patients' outcome in both TCGA and FUSCC cohort. Lower TIMC infiltration and elevated expression of hub genes (KIF18A, CDCA8, SKA1, CEP55, BUB1, CDK1, SGOL1, SGOL2) are markedly correlated with aggressive progression and poor prognosis, which might shed lights on novel targets for treatment strategies.
Aim of this study was to develop a multi-gene signature to help better predict prognosis for stage III renal cell carcinoma (RCC) patients.
Fourteen pairs of stage III tumor and normal tissues mRNA ...expression data from GSE53757 and 16 pairs mRNA expression data from TCGA clear cell RCC database were used to analyze differentially expressed genes between tumor and normal tissues. Common different expressed genes in both datasets were used for further modeling. Lasso Cox regression analysis was performed to select and build prognostic multi-gene signature in TCGA stage III kidney cancer patients (
= 122). Then, the multi-gene signature was validated in stage III renal cancer cases in Fudan University Shanghai Cancer Center (
= 77). C-index and time-dependent ROC were used to test the efficiency of this signature in predicting overall survival.
In total, 1,370 common different expressed genes were found between tumor and normal tissues in both datasets. After Lasso Cox modeling, nine mRNAs were finally identified to build a classifier. Using this classifier, we could classify stage III clear cell RCC patients into high-risk group and low-risk group. Prognosis was significantly different between these groups in discovery TCGA cohort, validation FUSCC cohort and entire set (All
< 0.001). Multivariate cox regression in entire set (
= 199) revealed that risk group classified by 9-gene signature, age of diagnosis, pN stage and ISUP grade were independent prognostic factor of overall survival in stage III kidney cancer patients.
We developed a robust multi-gene classifier that can effectively classify stage III RCC patients into groups with low and high risk of poor prognosis. This signature may help select high-risk patients who require more aggressive adjuvant target therapy or immune therapy.
Background
Prostate cancer (PCa) is a major type of cancer in man worldwide. Androgen deprivation therapy (ADT) and the next‐generation androgen receptor (AR) pathway inhibitors have acquired great ...success in treating PCa. However, patients treated with ADT or AR targeted therapy are inevitably developing into castration‐resistant prostate cancer (CRPC) or becoming drug resistance. The role of mRNA 5‐methylcytosine (m5C) modification in cancers is largely unknown. This study aimed to explore the role of the m5C methyltransferase NSUN2 in Prostate
cancer (PCa).
Methods
The expression of NSUN2 and its clinicopathological impact were evaluated in PCa cohorts. The effect of NSUN2 on the biological characteristics of PCa cells was investigated on the basis of gain‐offunction and loss‐of‐function analyses. Subcutaneous models further uncovered the role of NSUN2 in tumor growth. Epi‐transcriptome assays with RNA bisulfite sequencing (RNA‐BisSeq) analysis and in vitro enzyme reaction assays were performed to validate the targeted effect of NSUN2 on AR. AR‐binding sites in the NSUN2 promoter were investigated by ChIP and luciferase assays to uncover the interplay between NSUN2 and AR signaling. RIP‐qPCR and EMSA methods were performed to confirm that YBX1 binds to AR m5C sites.
Results
NSUN2 is highly expressed in PCa and predicts poor outcome. NSUN2 plays roles as a PCa oncogene both in vitro and in vivo. Depletion of NSUN2 results in decreased expression and activities of AR, including AR‐V7. Mechanistically, NSUN2 posttranscriptionally stabilized AR by cluster m5C modification in a m5CYBX1‐dependent manner. Strikingly, treatment with enzalutamide, an effective AR inhibitor, reduces NSUN2 expression and decreases the m5C modification level in prostate cancer cells. Finally, we found that AR transcriptionally regulates NSUN2.
Conclusion
NSUN2 stabilizes AR mRNA through cluster 5‐methylcytosine modification and activates a positive feedback loop to promote prostate cancer.
NSUN2 expression is upregulated in PCa and associated with a worse prognosis.
AR mRNA is modified by NSUN2 and is stabilized in an m5C‐YBX1‐dependent manner.
The m5C modification located in the 5′ region of AR mRNA, influenced several AR variants including AR‐V7.
NSUN2 expression is also transcriptionally regulated by AR and can respond to ADT and ARSI treatment.
Background
This study aims to establish an N6-methyladenosine (m
6
A) RNA methylation regulators-mediated methylation model and explore its role in predicting prognostic accuracy of immune contexture ...and characterizations of clear cell renal cell carcinoma (ccRCC).
Methods
The m
6
A modification subclasses (m
6
AMS) were identified by unsupervised cluster analysis and three clusters were determined by consensus clustering algorithm in a discovering cohort. Testing and real-world validation cohorts were used to identify predictive responses for immune checkpoint therapies (ICTs) of m
6
AMS.
Results
Prognostic implications landscape of m
6
A regulators in cancers and its differential expression levels in ccRCC patients were identified. Based on discovering cohort, ccRCC were automatically divided into three m
6
AMS, and cluster 3 showed significant worse survival than cluster 1/2. Importantly, it was found that the immune checkpoint molecules expression was significantly elevated in cluster 3. Besides, m
6
A score
Low
group (cluster 1&2) have significantly elevated TIDE score compared with m
6
A score
High
group (cluster 3). There was conspicuous tertiary lymphoid tissue, aggressive phenotype, elevated glycolysis, expression of PD-L1, abundance of CD8
+
T cells, CD4
+
FOXP3
+
Treg cells and TCRn immune cells infiltration in the high m
6
A score group. Interestingly, there are significantly increased patients with clinical benefit in m
6
A score
High
group in 368 patients receiving ICTs from testing IMvigor210 (n = 292) and validation FUSCC (n = 55) cohorts.
Conclusion
Our discovery highlights the relationship between tumor epigenetic heterogeneity and immune contexture. Immune-rejection cluster 3 has pro-tumorigenic immune infiltration, and shows significant clinical benefits for ccRCC patients receiving ICTs, enabling patient selection for future clinical treatment.
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