Abstract
A subset of long non-coding RNAs (lncRNAs), categorized as miRNA-host gene lncRNAs (lnc-miRHGs), is processed to produce miRNAs and involved in cancer progression. This work aimed to investigate the influences and the molecular mechanisms of lnc-miRHGs MIR497HG in bladder cancer (BCa). The miR-497 and miR-195 were derived from MIR497HG. We identified that lnc-miRHG MIR497HG and two harbored miRNAs, miR-497 and miR-195, were downregulated in BCa by analyzing The Cancer Genome Atlas and our dataset. Silencing of MIR497HG by CRISPR/Cas13d in BCa cell line 5637 promoted cell growth, migration, and invasion in vitro. Conversely, overexpression of MIR497HG suppressed cell progression in BCa cell line T24. MiR-497/miR-195 mimics rescued significantly the oncogenic roles of knockdown of MIR497HG by CRISPR/Cas13d in BCa. Mechanistically, miR-497 and miR-195 co-ordinately suppressed multiple key components in Hippo/Yap and transforming growth factor β signaling and particularly attenuated the interaction between Yap and Smad3. In addition, E2F4 was proven to be critical for silencing MIR497HG transcription in BCa cells. In short, we propose for the first time to reveal the function and mechanisms of MIR497HG in BCa. Blocking the pathological process may be a potential strategy for the treatment of BCa.
Highlights
Bladder cancer (BCa) is one of the most prevalent epithelial malignancies worldwide (Sanli et al, 2017)
Cell Counting Kit-8 (CCK-8) assays and colony formation assays showed that inhibition of MIR497HG via CRISPR/Cas13d significantly promoted cell proliferation, migration, and invasion in 5637 (Figures 2C–F)
Consistent with these findings, we confirmed that concomitant low expression of MIR497HG, miR-497, and miR-195 occurred in bladder cancer (BCa) and that miR-497 and miR-195 co-ordinately play critical antioncogenic roles in BCa cells
Summary
Bladder cancer (BCa) is one of the most prevalent epithelial malignancies worldwide (Sanli et al, 2017). MIBC is more aggressive and have a worse prognosis (Felsenstein and Theodorescu, 2018; Robertson et al, 2018). Existing therapies for MIBC have not changed mortality rates over the past years (Felsenstein and Theodorescu, 2018). Genome and transcriptome profiling studies have revealed considerable differences in the molecular and genetic features of BCa cells, such as mutations, copy number, and gene epigenetic alterations, determining tumor heterogeneity and therapeutic resistance (Guo G. et al, 2013; Robertson et al, 2018; Kamoun et al, 2020). Non-genetic or epigenetic mechanisms in BCa remain elusive
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