Nanoparticles targeting at methylases with high correlation to N6-methyladenosine-related lncRNA signatures as potential therapy of kidney clear cell carcinoma

作者：Chen, Ruixuan; Ouyang, Ping; Su, Licong; Xu, Xi; Lian, Penghu; Li, Yanqin; Gao, Qi; Zhang, Yifan; Nie, Sheng; Luo, Fan; Xu, Ruqi; Zhang, Xiaodong; Li, Xiaoxi; Cao, Yue; Gao, Peiyan; Kang, Juanjuan^*; Wu, Jun^*; Li, Lu^*

来源：CHINESE CHEMICAL LETTERS, 2022, 33(10): 4610-4616.

DOI：10.1016/j.cclet.2022.03.074

• Nanoparticle
• Methylation
• Long noncoding RNA
• Clear cell renal carcinoma
• Immunotherapy

Clear cell renal cell carcinoma (ccRCC) is a heterogeneous malignancy with poor prognosis. Methylation of the N-6 position of adenosine (m(6)A), the most common epigenetic modification in both messenger RNAs and noncoding RNAs, has been reported to regulate the initiation and progression of ccRCC. However, whether and how m(6)A-related long noncoding RNAs (m(6)ArlncRNAs) signify the progression of ccRCC remain unclear. We found m(6)ArlncRNAs are effective signatures illustrating immune landscape and risk stratification in ccRCC. We identified two differently expressed m(6)ArlncRNAs (DEm(6)ArlncRNAs), AC008870.2 and EMX2OS, as independent risk factors for overall survival of ccRCC patients, by applying stringent variable selection procedure to data from the Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma project. The risk score generated from the DEm(6)ArlncRNA expression categorizes patients into either high or low-risk groups, between which, enrichment analysis indicated an enrichment in immunerelated pathways. Under different DEm(6)ArlncRNA transcription pattern, the two risk groups differ in immune cell population composition and expression levels of therapy targeting genes. Nanoparticle is satisfactory strategy to delivering therapeutic drugs. For further clinical translation, we designed a novel nanoparticle delivery system packaged STM2457 (STM@8P4 NPs), which selectively inhibits AC008870.2-correlated m(6)A writer. STM@8P4 NPs loaded drug successfully with uniform particle size, long-term stability and high release efficiency. STM@8P4 NPs can easily enter ccRCC cells and showed a highly efficient ccRCC killing activity in vitro. Our results therefore indicate that m(6)ArlncRNAs expression can depict tumor microenvironment, predict prognosis for ccRCC patient and give hint to therapeutic strategies in ccRCC.

• 单位
  中山大学; 中国医学科学院; 南方医科大学; 中国医学科学院北京协和医院