期刊
MOLECULAR CANCER
卷 18, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s12943-019-1082-3
关键词
m(6)A; YTHDF2; HCC; Inflammation; Vessel normalization; IL-11; Serpin E2; HIF-2 alpha antagonism
资金
- National Key Research and Development Program of China [2017YFC0908102]
- National Natural Science Foundation of China [81871970, 81672801]
- Joint Program of Biomedical Engineering & Medicine in Shanghai Jiaotong University
- Chen Guang Project in Shanghai Municipal Education Commission
- Shanghai Education Development Foundation [15CG13]
- Ludwig Center at the University of Chicago Grant
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据