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METTL3-mediated N6-methyladenosine modification of DUSP5 mRNA promotes gallbladder-cancer progression
Hua-Dong Chen1, Fuxi Li2, Siyun Chen3
1Department of Pediatric Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
Abstract:
N6-methyladenosine (m6A) RNA methylation and its associated methyltransferase METTL3 play an important role in tumorigenesis of a series of tumors. However, dysregulation of METTL3 in gallbladder cancer (GBC) remains obscure. Here, we showed that upregulated METTL3 level predicted poor prognosis and correlated with increased lymphatic metastasis and high TNM stage. Functionally, we found that METTL3 could promote cell proliferation, invasion, and migration of GBC-SD and NOZ cells. Mechanistically, we revealed the METTL3-mediated m6A-modification profile in GBC cells and identified DUSP5 as the downstream gene of METTL3. METTL3 promoted the degradation of DUSP5 mRNA in a YTHDF2-dependent manner. Rescue assays showed that downregulation of DUSP5 could attenuate the knockdown METTL3-mediated inhibition of cell proliferation, invasion, and migration of GBC-SD and NOZ cells. Thus, our finding shows that elevated METTL3 expression contributes to tumor aggression in GBC, suggesting that METTL3 is a possible prognostic predictor and therapeutic target against GBC.
Insights
Elevated METTL3 expression promotes gallbladder cancer (GBC) aggression by accelerating DUSP5 mRNA degradation. This finding suggests METTL3 as a prognostic marker and potential therapeutic target for GBC.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- N6-methyladenosine (m6A) RNA methylation is implicated in tumorigenesis.
- The role of the methyltransferase METTL3 in gallbladder cancer (GBC) is not well understood.
Purpose of the Study:
- To investigate the role and mechanism of METTL3 in gallbladder cancer progression.
- To determine if METTL3 can serve as a prognostic predictor or therapeutic target in GBC.
Main Methods:
- Analysis of METTL3 expression levels in relation to GBC prognosis and clinical features.
- Functional studies assessing METTL3's impact on GBC cell proliferation, invasion, and migration.
- Mechanistic investigation involving m6A profiling, identification of downstream targets, and rescue assays.
Main Results:
- Upregulated METTL3 expression correlated with poor prognosis, increased lymphatic metastasis, and advanced TNM stage in GBC.
- METTL3 promoted GBC cell proliferation, invasion, and migration.
- METTL3 facilitated DUSP5 mRNA degradation in a YTHDF2-dependent manner, and DUSP5 downregulation partially rescued METTL3 knockdown effects.
Conclusions:
- Elevated METTL3 expression drives tumor aggression in gallbladder cancer.
- METTL3 represents a potential prognostic biomarker and therapeutic target for GBC.
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