YTHDF2 reduction fuels inflammation and vascular abnormalization in hepatocellular carcinoma

doi:10.1186/s12943-019-1082-3

	YTHDF2 reduction fuels inflammation and vascular abnormalization in hepatocellular carcinoma
	Hou, Jiajie 1,2,3,4; Zhang, He 1,5; Liu, Jun 6; Zhao, Zhenjun 1; Wang, Jianye 1; Lu, Zhike 6; Hu, Bian 7; Zhou, Jiankui7 ; Zhao, Zhicong 1; Feng, Mingxuan 1; Zhang, Haiyan 4,8; Shen, Bin 9; Huang, Xingxu7 ; Sun, Beicheng 2; He, Chuan 6,10; Xia, Qiang 1
	2019-11-18
发表期刊	MOLECULAR CANCER
EISSN	1476-4598
卷号	18 期号:1
发表状态	已发表
DOI	10.1186/s12943-019-1082-3
摘要	Background Dynamic N-6-methyladenosine (m(6)A) modification was previously identified as a ubiquitous post-transcriptional regulation that affected mRNA homeostasis. However, the m(6)A-related epitranscriptomic alterations and functions remain elusive in human cancer. Here we aim to identify the profile and outcome of m(6)A-methylation in hepatocellular carcinoma (HCC). Results Using liquid chromatography-tandem mass spectrometry and m(6)A-immunoprecipitation in combination with high-throughput sequencing, we determined the m(6)A-mRNA levels in human HCC. Human HCC exhibited a characteristic gain of m(6)A modification in tandem with an increase of mRNA expression, owing to YTH domain family 2 (YTHDF2) reduction. The latter predicted poor classification and prognosis of HCC patients, and highly correlated with HCC m(6)A landscape. YTHDF2 silenced in human HCC cells or ablated in mouse hepatocytes provoked inflammation, vascular reconstruction and metastatic progression. Mechanistically, YTHDF2 processed the decay of m(6)A-containing interleukin 11 (IL11) and serpin family E member 2 (SERPINE2) mRNAs, which were responsible for the inflammation-mediated malignancy and disruption of vascular normalization. Reciprocally, YTHDF2 transcription succumbed to hypoxia-inducible factor-2 alpha (HIF-2 alpha). Administration of a HIF-2 alpha antagonist (PT2385) restored YTHDF2-programed epigenetic machinery and repressed liver cancer. Conclusion Our results have characterized the m(6)A-mRNA landscape in human HCC and revealed YTHDF2 as a molecular 'rheostat' in epitranscriptome and cancer progression.
关键词	m(6)A YTHDF2 HCC Inflammation Vessel normalization IL-11 Serpin E2 HIF-2 alpha antagonism
URL	查看原文
收录类别	SCI ; SCIE
语种	英语
资助项目	Shanghai Education Development Foundation[15CG13]
WOS研究方向	Biochemistry & Molecular Biology ; Oncology
WOS类目	Biochemistry & Molecular Biology ; Oncology
WOS记录号	WOS:000496945100001
出版者	BMC
WOS关键词	CELL-SURVIVAL ; RNA ; METHYLATION ; N-6-METHYLADENOSINE ; PROMOTES ; REVEALS ; RECOGNITION ; TRANSLATION ; EXPRESSION ; PROTEINS
原始文献类型	Article
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/102247
专题	生命科学与技术学院_PI研究组_黄行许组
通讯作者	Hou, Jiajie; He, Chuan; Xia, Qiang
作者单位	1.Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Dept Liver Surg, Shanghai 200127, Peoples R China 2.Nanjing Univ, Med Sch, Dept Hepatobiliary Surg, Affiliated Drum Tower Hosp, Nanjing 210093, Jiangsu, Peoples R China 3.Sun Yat Sen Univ, Dept Hepatobiliary Surg, Canc Ctr, Guangzhou 510060, Guangdong, Peoples R China 4.Sun Yat Sen Univ, State Key Lab Oncol South China, Canc Ctr, Guangzhou 510060, Guangdong, Peoples R China 5.Univ Hong Kong, Dept Surg, Shenzhen Hosp, Shenzhen 518053, Guangdong, Peoples R China 6.Univ Chicago, Dept Chem, Dept Biochem & Mol Biol, Inst Biophys Dynam, 5735 S Ellis Ave, Chicago, IL 60637 USA 7.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 8.QIMR Berghofer Med Res Inst, Immunol Canc & Infect Lab, Herston, Qld 4006, Australia 9.Nanjing Med Univ, Dept Histol & Embryol, Key Lab Reprod Med, Nanjing 211166, Jiangsu, Peoples R China 10.Univ Chicago, Howard Hughes Med Inst, 5841 S Maryland Ave, Chicago, IL 60637 USA
推荐引用方式 GB/T 7714	Hou, Jiajie,Zhang, He,Liu, Jun,et al. YTHDF2 reduction fuels inflammation and vascular abnormalization in hepatocellular carcinoma[J]. MOLECULAR CANCER,2019,18(1).
APA	Hou, Jiajie.,Zhang, He.,Liu, Jun.,Zhao, Zhenjun.,Wang, Jianye.,...&Xia, Qiang.(2019).YTHDF2 reduction fuels inflammation and vascular abnormalization in hepatocellular carcinoma.MOLECULAR CANCER,18(1).
MLA	Hou, Jiajie,et al."YTHDF2 reduction fuels inflammation and vascular abnormalization in hepatocellular carcinoma".MOLECULAR CANCER 18.1(2019).