m6A mRNA methylation regulates CTNNB1 to promote the proliferation of hepatoblastoma

被引：137
作者：
Liu, Li [1 ,4 ]
Wang, Jing [2 ]
Sun, Guifeng [3 ]
Wu, Qiong [5 ]
Ma, Ji [1 ]
Zhang, Xin [1 ]
Huang, Nan [3 ]
Bian, Zhixuan [1 ]
Gu, Song [2 ]
Xu, Min [2 ]
Yin, Minzhi [6 ]
Sun, Fenyong [3 ]
Pan, Qiuhui [1 ]
机构：
[1] Shanghai Jiao Tong Univ, Sch Med, Dept Clin Lab Med, Shanghai Childrens Med Ctr, Shanghai 200127, Peoples R China
[2] Tongji Univ, Dept Clin Lab, Sch Med, Shanghai Peoples Hosp 4, Shanghai 200081, Peoples R China
[3] Shanghai Jiao Tong Univ, Sch Med, Dept Surg, Shanghai Childrens Med Ctr, Shanghai 200127, Peoples R China
[4] Tongji Univ, Dept Clin Lab Med, Shanghai Peoples Hosp 10, Shanghai 200072, Peoples R China
[5] Guangdong Pharmaceut Univ, Sch Pharm, Gaungzhou 510006, Peoples R China
[6] Shanghai Jiao Tong Univ, Sch Med, Dept Pathol, Shanghai Childrens Med Ctr, Shanghai 200127, Peoples R China
来源：
MOLECULAR CANCER | 2019年 / 18卷 / 01期
基金：
中国国家自然科学基金;
关键词：
RNA m(6)A methylation; Wnt; beta-catenin pathway; CTNNB1; Hepatoblastoma; METTL3; DEMETHYLASE; CATENIN; ALKBH5; SUBTYPES; PATHWAY; CELLS; FATE;
D O I：
10.1186/s12943-019-1119-7
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Background N-6-Methyladenosine (m(6)A) modification has been implicated in many biological processes. It is important for the regulation of messenger RNA (mRNA) stability, splicing, and translation. However, its role in cancer has not been studied in detail. Here we investigated the biological role and underlying mechanism of m(6)A modification in hepatoblastoma (HB). Methods We used Reverse transcription quantitative real-time PCR (RT-qPCR) and Western blotting to determine the expression of m(6)A related factors. And we clarified the effects of these factors on HB cells using cell proliferation assay, colony formation, apoptotic assay. Then we investigated of methyltransferase-like 13 (METTL3) and its correlation with clinicopathological features and used xenograft experiment to check METTL3 effect in vivo. m(6)A-Seq was used to profiled m(6)A transcriptome-wide in hepatoblastoma tumor tissue and normal tissue. Finally, methylated RNA immunoprecipitation (MeRIP) assay, RNA remaining assay to perform the regulator mechanism of MEETL3 on the target CTNNB1 in HB. Results In this research, we discovered that m(6)A modifications are increased in hepatoblastoma, and METTL3 is the main factor involved with aberrant m(6)A modification. We also profiled m(6)A across the whole transcriptome in hepatoblastoma tumor tissues and normal tissues. Our findings suggest that m(6)A is highly expressed in hepatoblastoma tumors. Also, m(6)A is enriched not only around the stop codon, but also around the coding sequence (CDS) region. Gene ontology analysis indicates that m(6)A mRNA methylation contributes significantly to regulate the Wnt/beta-catenin pathway. Reduced m(6)A methylation can lead to a decrease in expression and stability of the CTNNB1. Conclusion Overall our findings suggest enhanced m(6)A mRNA methylation as an oncogenic mechanism in hepatoblastoma, METTL3 is significantly up-regulated in HB and promotes HB development. And identify CTNNB1 as a regulator of METTL3 guided m(6)A modification in HB.
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页数：13
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