Bladder cancer (BC) is a common and serious type of cancer that ranks among the top ten most prevalent malignancies worldwide. Due to the high occurrence rate of BC, the aggressive nature of cancer cells, and their resistance to medication, managing this disease has become a growing challenge in clinical care. Long noncoding RNAs (lncRNAs) are a group of RNA transcripts that do not code for proteins and are more than 200 nucleotides in length. They play a significant role in controlling cellular pathways and molecular interactions during the onset, development and progression of different types of cancers. Recent advancements in high-throughput gene sequencing technology have led to the identification of various differentially expressed lncRNAs in BC, which indicate abnormal expression. In this review, we summarize that these lncRNAs have been found to impact several functions related to the development of BC, including proliferation, cell growth, migration, metastasis, apoptosis, epithelial-mesenchymal transition, and chemo- and radio-resistance. Additionally, lncRNAs may improve prognosis prediction for BC patients, indicating a future use for them as prognostic and diagnostic biomarkers for BC patients. This review highlights that genetic tools and anti-tumor agents, such as CRISPR/Cas systems, siRNA, shRNA, antisense oligonucleotides, and vectors, have been created for use in preclinical cancer models. This has led to a growing interest in using lncRNAs based on positive research findings. 

Molecular landscape of LncRNAs in bladder cancer: From drug resistance to novel LncRNA-based therapeutic strategies.

Identification of exosomes-related lncRNAs in clear cell renal cell carcinoma based on Bayesian spike-and-slab lasso approach

Abstract Objective We aimed to investigate the role and potential mechanisms of long non-coding RNAs (lncRNAs) in bladder cancer (BC), as well as determine their prognostic value. Methods LncRNA expression data and clinical data from BC patients were downloaded from The Cancer Genome Atlas (TCGA) database. R software was used to carry out principal component analysis (PCA), differential analysis, and prognostic analysis. Lasso regression and multivariate Cox regression analyses were performed to identify potential prognostic genes. The expression of five identified genes and their correlation with prognosis were verified using TCGA and GSE13507 datasets. In addition, quantitative real-time polymerase chain reaction (qRT-PCR) was used to confirm the expression of these five genes in cell lines (two human BC cell lines and one human bladder epithelial cell line) and tissues (84 pairs of BC tissues and the corresponding paracancerous tissues). Risk scores that had been generated from the five genes and their prognostic ability were assessed by receiver operating characteristic (ROC) and Kaplan–Meier (KM) curves. Co-expressed genes were screened by WGCNA and analyzed by GO and KEGG, while functional enrichment and immune infiltration analyses were performed using STRING ( https://cn.string-db.org/ ) and TIMER2.0 ( http://timer.cistrome.org/ ) online tools, respectively. Results CYP4F8, FAR2P1, LINC01518, LINC01764, and DTNA were identified as potential prognostic genes. We found that these five genes were differentially expressed in BC tissue, as well as in BC cell lines, and were significantly correlated with the prognosis of BC patients. KM analysis considering risk scores as independent parameters revealed differences in overall survival (OS) by subgroups. The ROC curve revealed that a combined model consisting of all five genes had good predictive ability at 1, 3, and 5 years. GO and KEGG analyses of 567 co-expressed genes revealed that these genes were significantly associated with muscle function. Conclusion LncRNAs can be good predictors of BC development and prognosis, and may act as potential tumor markers and therapeutic targets that may be beneficial in helping clinicians decide the most effective treatment strategies. 

/pdf/construction-of-an-lncrna-model-for-prognostic-prediction-of-2x17p353.pdf

Construction of an lncRNA model for prognostic prediction of bladder cancer

Roles of non-coding RNAs in the metabolism and pathogenesis of bladder cancer

N6-methyladenosine (m6A) modification has shown critical roles in regulating mRNA fate. Non-coding RNAs also have important roles in various diseases, including hepatocellular carcinoma (HCC). However, the potential influences of m6A modification on non-coding RNAs are still unclear. In this study, we identified a novel m6A-modified ATP8B1-AS1 and aimed to investigate the effects of m6A on the expression and role of ATP8B1-AS1 in HCC.qPCR was performed to measure the expression of related genes. The correlation between gene expression and prognosis was analyzed using public database. m6A modification level was measured using MeRIP and single-base elongation- and ligation-based qPCR amplification method. The roles of ATP8B1-AS1 in HCC were investigated using in vitro and in vivo functional assays. The mechanisms underlying the roles of ATP8B1-AS1 were investigated by ChIRP and ChIP assays.ATP8B1-AS1 is highly expressed in HCC tissues and cell lines. High expression of ATP8B1-AS1 is correlated with poor overall survival of HCC patients. ATP8B1-AS1 is m6A modified and the 792 site of ATP8B1-AS1 is identified as an m6A modification site. m6A modification increases the stability of ATP8B1-AS1 transcript. m6A modification level of ATP8B1-AS1 is increased in HCC tissues and cell lines, and correlated with poor overall survival of HCC patients. ATP8B1-AS1 promotes HCC cell proliferation, migration, and invasion, which were abolished by the mutation of m6A-modified 792 site. Mechanistic investigation revealed that m6A-modified ATP8B1-AS1 interacts with and recruits m6A reader YTHDC1 and histone demethylase KDM3B to MYC promoter region, leading to the reduction of H3K9me2 level at MYC promoter region and activation of MYC transcription. Functional rescue assays showed that depletion of MYC largely abolished the oncogenic roles of ATP8B1-AS1.m6A modification level of ATP8B1-AS1 is increased and correlated with poor prognosis in HCC. m6A-modified ATP8B1-AS1 exerts oncogenic roles in HCC via epigenetically activating MYC expression. 

N6-Methyladenosine-Modified ATP8B1-AS1 Exerts Oncogenic Roles in Hepatocellular Carcinoma via Epigenetically Activating MYC

Molecular subtyping of bladder cancer has revealed luminal tumors generally have a more favourable prognosis. However, some aggressive forms of variant histology, including micropapillary, are often classified luminal. In previous work, we found long non-coding RNA (lncRNA) expression profiles could identify a subgroup of luminal bladder tumors with less aggressive biology and better outcomes. In the present study, we aimed to investigate whether lncRNA expression profiles could identify high-grade T1 micropapillary bladder cancer with differential outcome. LncRNAs were quantified from RNA-seq data from a HGT1 bladder cancer cohort that was enriched for primary micropapillary cases (15/84). Unsupervised consensus clustering of variant lncRNAs identified a three-cluster solution, which was further characterised using a panel of micropapillary-associated biomarkers, molecular subtypes, gene signatures, and survival analysis. A single-sample genomic signature was trained using lasso-penalized logistic regression to classify micropapillary-like gene-expression, as characterised by lncRNA clustering. The genomic classifier (GC) was tested on luminal tumors derived from the TCGA cohort (N = 202). Patient and tumor characteristics were compared between subgroups by using X2 tests and two-sided Wilcoxon rank-sum tests. Primary endpoints were overall, progression-free and high-grade recurrence-free survival, calculated as the date of high-grade T1 disease at TURBT till date of death from any cause, progression, or recurrence, respectively. Survival rates were estimated using weighted Kaplan–Meier (KM) curves. Primary micropapillary HGT1 showed decreased FGFR3, SHH, and p53 pathway activity relative to tumors with conventional urothelial carcinoma. Many bladder cancer-associated lncRNAs were downregulated in micropapillary tumors, including UCA1, LINC00152, and MALAT1. Unsupervised consensus clustering resulted in a lncRNA cluster 1 (LC1) with worse prognosis that was enriched for primary micropapillary histology and the Luminal Unstable (LumU) molecular subtype. Interestingly, LC1 appeared to better identify aggressive HGT1 disease, compared to stratifying outcomes using primary histologic characteristics. A signature trained to identify LC1 cases showed good performance in the testing cohort, identifying seven cases with significantly worse survival (p < 0.001). Limitations include the retrospective nature of the study and the lack of a validation cohort. Using the lncRNA transcriptome we identified a subgroup of aggressive HGT1 bladder cancer that was enriched with micropapillary histology. These data suggest that lncRNAs can facilitate the identification of aggressive micropapillary-like tumors, potentially improving patient management. 

/pdf/non-muscle-invasive-micropapillary-bladder-cancer-has-a-10vng6r2.pdf

Non-muscle-invasive micropapillary bladder cancer has a distinct lncRNA profile associated with unfavorable prognosis

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Non-muscle-invasive micropapillary bladder cancer has a distinct lncRNA profile associated with unfavorable prognosis