M6A-mediated upregulation of circMDK promotes tumorigenesis and acts as a nanotherapeutic target in hepatocellular carcinoma

Molecular Cancer

Yongxing Zhang¹  Shanni Li¹  Siyi Tao¹  Xuan Chen¹  Pinjia Liu¹  Zongpeng Chen¹  Yuxin Liu¹  Ashuai Du¹  Cyrollah Disoma¹  Zanxian Xia¹  Yuzheng Zhou¹  Yujie Liao¹  Aroona Razzaq¹  Lunan Xu¹  Shiqin Li¹  Zijun Dong¹  Sixu Liu¹  Qinglong Yang²  Jian Peng³  Qianjun Zhang⁴ 

[1] Department of Cell Biology, School of Life Sciences, Central South University;Department of General Surgery, Guizhou Provincial People’s Hospital;Department of Geriatric Surgery, Xiangya Hospital, Central South University;Institute of Reproduction and Stem Cell Engineering, School of Basic Medical Science, Central South University;

关键词: Hepatocellular carcinoma (HCC);    circRNA;    N6-methyladenosine (m6A);    IGF2BP1;    ATG16L1;    Apoptosis;   

DOI  :  10.1186/s12943-022-01575-z

来源: DOAJ

【 摘 要 】

Abstract Background Emerging evidence suggest the critical role of circular RNAs (circRNAs) in disease development especially in various cancers. However, the oncogenic role of circRNAs in hepatocellular carcinoma (HCC) is still largely unknown. Methods RNA sequencing was performed to identify significantly upregulated circRNAs in paired HCC tissues and non-tumor tissues. CCK-8 assay, colony formation, transwell, and xenograft mouse models were used to investigate the role of circRNAs in HCC proliferation and metastasis. Small interfering RNA (siRNA) was used to silence gene expression. RNA immunoprecipitation, biotin pull-down, RNA pull-down, luciferase reporter assay and western blot were used to explore the underlying molecular mechanisms. Results Hsa_circ_0095868, derived from exon 5 of the MDK gene (named circMDK), was identified as a new oncogenic circRNA that was significantly upregulated in HCC. The upregulation of circMDK was associated with the modification of N6-methyladenosine (m6A) and poor survival in HCC patients. Mechanistically, circMDK sponged miR-346 and miR-874-3p to upregulate ATG16L1 (Autophagy Related 16 Like 1), resulting to the activation of PI3K/AKT/mTOR signaling pathway to promote cell proliferation, migration and invasion. Poly (β-amino esters) (PAEs) were synthesized to assist the delivery of circMDK siRNA (PAE-siRNA), which effectively inhibited tumor progression without obvious adverse effects in four liver tumor models including subcutaneous, metastatic, orthotopic and patient-derived xenograft (PDX) models. Conclusions CircMDK could serve as a potential tumor biomarker that promotes the progression of HCC via the miR-346/874-3p-ATG16L1 axis. The PAE-based delivery of siRNA improved the stability and efficiency of siRNA targeting circMDK. The PAE-siRNA nanoparticles effectively inhibited HCC proliferation and metastasis in vivo. Our current findings offer a promising nanotherapeutic strategy for the treatment of HCC. Graphical Abstract

【 授权许可】

Unknown