Therapeutic inhibition of METTL3/miR-146a-5p-guided NOTCH pathway suppresses bladder cancer progression
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ABSTRACT:
PROVIDER: PRJNA768431 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16193787.fastq.gz | Fastqsanger.gz | |||
| SRR16193788.fastq.gz | Fastqsanger.gz | |||
| SRR16193789.fastq.gz | Fastqsanger.gz | |||
| SRR16193790.fastq.gz | Fastqsanger.gz | |||
| SRR16193791.fastq.gz | Fastqsanger.gz |
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Project description:Bladder cancer characterized by RNA methylation abnormalities and NOTCH pathway dysregulation exhibits high recurrence that remains the major obstacle for bladder cancer treatment. Targeting methyltransferase-like 3 (METTL3) and NOTCH signal is a potential strategy to block bladder cancer progression. However, the underlying mechanisms by which METTL3-manipulated NOTCH signal and its effect on bladder cancer tumorigenesis remain to be clarified. Here we showed that METTL3-guided m6A modification methylated pri-miR-146 at the flaking sequence, which was responsible for the pri-miR-146 maturation. Furthermore, NUMB/NOTCH2 axis was identified as the functional downstream target signal that mediated the pro-survival role of miR-146a-5p in bladder cancer cells. Therapeutically, the polypeptide melittin was demonstrated to induce apoptosis of bladder cancer cells in a METTL3-dependent manner. Importantly, METTL3 and miR-146a-5p were positively correlated with recurrence and poor prognosis of bladder cancer patient. Our studies indicate that METTL3/miR-146a-5p/NUMB/NOTCH2 axis could be a potential therapeutic target for recurrent bladder cancer treatment and METTL3 acts as a fate determinant that controls sensitivity of bladder cancer cells to melittin treatment.
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Project description:MicroRNAs (miRNAs) are small non-coding RNAs that function as modulators of gene expression. We previously showed that miR-146a-5p is upregulated in pancreatic islets treated with pro-inflammatory cytokines and in pancreatic sections from organ donors with type 1 diabetes (T1D). Other studies have associated overexpression of miR-146a-5p with β cell apoptosis and impaired insulin secretion; however, the molecular mechanisms mediating these effects remain elusive. To investigate the role of miR-146a-5p in β cell function, we developed stable MIN6 cell lines transduced with lentiviral vectors to either overexpress or inhibit the expression of miR-146a-5p. Monoclonal cell populations were treated with pro-inflammatory cytokines (IL1β, IFNg, and TNFα) to model T1D in vitro. We found that overexpression of miR-146a-5p increased the cell death of MIN6 cells under inflammatory stress, whereas inhibition of miR-146a-5p reversed these effects. Additionally, inhibition of miR-146a-5p increased mitochondrial DNA copy number, respiration rate, and ATP production, suggesting that miR-146a-5p inhibition improves mitochondrial function. In support of this finding, we also observed that miR-146a-5p is enriched in the mitochondria of MIN6 cells treated with cytokines. Consistently, bioinformatic analysis of RNA sequencing data using MIN6 stable cells showed enrichment of pathways related to insulin secretion, apoptosis, and mitochondrial function when the expression levels of miR-146a-5p were altered. Overall, the findings from our study show for the first time that miR-146a-5p upregulation during inflammatory stress may promote β cell dysfunction and death by suppressing mitochondrial function.
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Project description:Oncogenic mutations in BRAF and NRAS occur in 70% of melanomas. Here we identify a microRNA, miR-146a, that is highly upregulated by oncogenic BRAF and NRAS. Expression of miR-146a increases the ability of human melanoma cells to proliferate in culture and form tumors in mice, whereas knockdown of miR-146a has the opposite effects. We show these oncogenic activities are due to miR-146a targeting the NUMB mRNA, a repressor of Notch signaling. Previous studies have shown that pre-miR-146a contains a single nucleotide polymorphism (C>G rs2910164). We find that the ability of pre-miR-146a/G to activate Notch signaling and promote oncogenesis is substantially higher than that of pre-miR-146a/C. Analysis of melanoma cell lines and matched patient samples indicates that during melanoma progression pre-miR-146a/G is enriched relative to pre-miR-146a/C, resulting from a C-to-G somatic mutation in pre-miR-146a/C. Collectively, our results reveal a central role for miR-146a in the initiation and progression of melanoma.
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Project description:Oncogenic mutations in BRAF and NRAS occur in 70% of melanomas. Here we identify a microRNA, miR-146a, that is highly upregulated by oncogenic BRAF and NRAS. Expression of miR-146a increases the ability of human melanoma cells to proliferate in culture and form tumors in mice, whereas knockdown of miR-146a has the opposite effects. We show these oncogenic activities are due to miR-146a targeting the NUMB mRNA, a repressor of Notch signaling. Previous studies have shown that pre-miR-146a contains a single nucleotide polymorphism (C>G rs2910164). We find that the ability of pre-miR-146a/G to activate Notch signaling and promote oncogenesis is substantially higher than that of pre-miR-146a/C. Analysis of melanoma cell lines and matched patient samples indicates that during melanoma progression pre-miR-146a/G is enriched relative to pre-miR-146a/C, resulting from a C-to-G somatic mutation in pre-miR-146a/C. Collectively, our results reveal a central role for miR-146a in the initiation and progression of melanoma. SKMEL28 melanoma cell line stably expressing either an empty vector or pre-miR146a with either C or G SNP (SKMEL28-FG12, SKMEL28-miR-146a/C and SKMEL28-miR-146a/G) were used to prepare total RNA. Microarray analysis was performed by using biological replicates for each stable cell lines for a total of 6 samples.
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