m6A is the most common form of mRNA modification. However, little is known about its role in clear cell renal cell carcinoma (ccRCC). This study aims to identify gene signatures and prognostic values of m6A regulators in ccRCC. In this study, a total of 528 ccRCC patients from TCGA database with sequencing and CNV data were included. Survival analysis was performed using log-rank tests and Cox regression model. The association between alteration of m6A regulators and clinicopathological characteristics was examined using chi-square test. The results showed that alteration of m6A regulators was associated with pathologic stage. Patients with any CNVs of the regulatory genes had worse OS and DFS than those with diploid genes. Moreover, deletion of m6A “writer” genes was an independent risk factor for OS, and copy number gain of “eraser” genes could magnify the effect in a synergistic way. Additionally, low expression of the writer gene METTL3 was related to activations of adipogenesis and mTOR pathways. Thus, we for the first time determined genetic alterations of m6A regulators in ccRCC and found a significant relationship between the alterations and worse clinical characteristics. The findings provide us clues to understand epigenetic modification of RNA in ccRCC.
TP53 is a classic tumor suppressor, but its role in kidney cancer remains unclear. In our study, we tried to explain the role of p53 in kidney cancer through the p53-related enhancer RNA pathway. Functional experiments were used to explore whether P53-bound enhancer regions 2 (p53BER2) has a role in the cell cycle and senescence response of TP53-wild type (WT) renal cancer cells in vitro or vivo. RNA-sequencing was used to identify the potential target of p53BER2. The results showed that the expression level of P53BER2 was downregulated in renal cancer tissues and cell lines, further dual-luciferase experiments and APR-256-reactivated experiments showed p53BER2 expresses in a p53-dependent way. Moreover, knockdown p53BER2 could reverse nutlin-3-induced cytotoxic effect in TP53-WT cell lines. Further exploration showed the downregulation of p53BER2 could reverse nutlin-3-induced G1-arrest and senescence in TP53-WT cell lines. What is more, the knockdown of p53BER2 showed resistance to nutlin-3 treatment in vivo. Additionally, we found BRCA2 could be regulated by p53BER2 in vitro and vivo; further experiment showed p53BER2 could induce cell-cycle arrest and DNA repair by mediating BRCA2. In summary, the p53-associated enhancer RNA-p53BER2 mediates the cell cycle and senescence of p53 in TP53-WT renal cancer cells.
Accumulating evidences suggest that longnon-coding RNAs (lncRNAs) play functional roles in development of different cancers, including cancer initiation and progression. Metastasis associated lung adenocarcinoma transcript 1(MALAT1) is a well-known lncRNA which was previously shown to be a direct target of miR-125b in bladder cancer (BCa) and to promote cancer progression and invasion. However, little is known whether MALAT1 can also target miR-125b. In the present study, using CRISPR-based technologies and qRT-PCR, we show that MALAT1 is capable of suppressing mature miR-125b and increasing the expression of its target genes (Bcl-2 and MMP-13), but has no effect on pri-miR-125b and pre-miR-125b. We observe that the biotin-labeled MALAT1-RNA probe is able to pull down Ago2 and miR-125b and that the negative regulation of miR-125b by MALAT1 is dependent on Ago2. Importantly, the results of flow cytometry assay and transwell assay reveal that the MALAT1-mediated cancer progression is in part due to specific suppression of miR-125b and activation of its two target genes. All together, these data suggest that the “MALAT1-miR-125b-Bcl-2 / MMP-13” axis plays an important role in the progression of BCa, thereby may provide a potential therapeutic strategy for the treatment of human BCa.
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