RNA m6A methylation promotes the formation of vasculogenic mimicry in hepatocellular carcinoma via Hippo pathway
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ORIGINAL PAPER
RNA m6A methylation promotes the formation of vasculogenic mimicry in hepatocellular carcinoma via Hippo pathway Kailiang Qiao1,2 · Yantao Liu1,2 · Zheng Xu1,2 · Haohao Zhang1,2 · Heng Zhang1,2 · Chao Zhang1 · Zhi Chang1,2 · Xinyan Lu1 · Zhongwei Li1 · Ce Luo1 · Yanrong Liu3 · Cheng Yang1,2 · Tao Sun1,2 Received: 22 April 2020 / Accepted: 1 September 2020 © Springer Nature B.V. 2020
Abstract Vasculogenic mimicry (VM) formed by aggressive tumor cells to mimic vasculogenic networks plays an important role in the tumor malignancy of HCC. However, the pathogenesis underlying VM is complex and has not been fully defined. m6A is a common mRNA modification and has many biological effects. However, the relationship between m6A and VM remains unclear. In this research, we found that m6A methyltransferase METTL3 in HCC tissues was positively correlated with VM. The m6A level of mRNA significantly increased in 3D cultured cells treated with VEGFa and was related to VM formation. Transcriptome sequencing analysis of 3D cultured cells with knockdown Mettl3 showed that the Hippo pathway was involved in m6A-mediated VM formation. Further mechanism research indicated that the m6A modification of YAP1 mRNA affected the translation of YAP1 mRNA. In conclusion, m6A methylation plays a key role in VM formation in HCC. METTL3 and YAP1 could be potential therapeutic targets via impairing VM formation in anti-metastatic strategies. Keywords Metastasis · Vasculogenic mimicry · N6-methyladenosine · METTL3 · YAP1 Abbreviations HCC Hepatocellular carcinoma VM Vasculogenic mimicry m6A N6-methyladenosine VEGFa Vascular endothelial growth factor a YAP1 Yes associated protein 1 DEN Diethylnitrosamine METTL3 Methyltransferase-like 3 ALKBH5 AlkB homolog 5 Kailiang Qiao and Yantao Liu contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10456-020-09744-8) contains supplementary material, which is available to authorized users. * Tao Sun [email protected] 1
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, 38 Tongyan Road, Haihe Education Park, Tianjin, China
2
Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China
3
Department of Pathology, Affiliated Hospital of Jining Medical University, Jining Medical University, No.89, Guhuai Road, Rencheng District, Jining, Shandong, China
PAS Periodic acid–Schiff IHC Immunohistochemistry CDH5 Cadherin 5 MMP2 Matrix metallopeptidase 2 MMP9 Matrix metallopeptidase 9 FN1 Fibronectin 1 MeRIP Methylated RNA immunoprecipitation
Introduction Liver cancers are the fourth most common cause of cancerrelated deaths and rank sixth in terms of incident cases worldwide. Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers [1]. Although much progress has been made in the treatment of HCC in recent years, the prognosis of patients with HCC remains very poor. A
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