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.

Bladder cancer (BLCA) is one of the most common urological cancer with increasing cases and deaths every year. In the present study, we aim to construct an immune‐related prognostic lncRNA signature (IRPLS) in bladder cancer (BLCA) patients and explore its immunogenomic implications in pan‐cancers. First, the immune‐related differentially expressed lncRNAs (IRDELs) were identified by ‘limma’ R package and the score of IRPLS in every patient were evaluated by Cox regression. The dysregulation of IRDELs expression between cancer and para‐cancer normal tissues was validated through RT‐qPCR. Then, we further explore the biological functions of a novel lncRNA from IRPLS, RP11‐89 in BLCA using CCK8 assay, Transwell assay and Apoptosis analysis, which indicated that RP11‐89 was able to promote cell proliferation and invasive capacity while inhibits cell apoptosis in BLCA. In addition, we performed bioinformatic methods and RIP to investigate and validate the RP11‐89/miR‐27a‐3p/PPARγ pathway in order to explore the mechanism. Next, CIBERSORT and ESTIMATE algorithm were used to evaluate abundance of tumour‐infiltrating immune cells and scores of tumour environment elements in BLCA with different level of IRPLS risk scores. Finally, multiple bioinformatic methods were performed to show us the immune landscape of these four lncRNAs for pan‐cancers. In conclusion, this study first constructed an immune‐related prognostic lncRNA signature, which consists of RP11‐89, PSORS1C3, LINC02672 and MIR100HG and might shed lights on novel targets for individualized immunotherapy for BLCA patients.

Lung adenocarcinoma (LUAD) is a highly heterogeneous tumor and the most prevalent pathological type of lung cancer. The alternative splicing (AS) of mRNA enables the generation of multiple protein products from a single gene. This is a tightly regulated process that significantly contributes to the proteome diversity in eukaryotes. Recent multi-omics studies have delineated the splicing profiles that underline LUAD tumorigenesis from initiation to metastasis. Such progress holds robust promise to facilitate the development of screening strategies and individualized therapies. Perturbed AS fosters the emergence of novel neoantigen resources and disturbances in the immune microenvironment, which allow new investigations into modulatory targets for LUAD immunotherapy. This review presents an update on the landscape of dysregulated splicing events in LUAD and the associated mechanisms and theranostic perspectives with unique insights into AS-based immunotherapy, such as Chimeric Antigen Receptor T cell therapy. These AS variants can be used in conjunction with current therapeutic modules in LUAD, allowing bench to bedside translation to combat this highly malignant cancer.