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

Abstract

Clear cell renal cell carcinoma (ccRCC) is a heterogeneous malignancy with poor prognosis. Methylation of the N6 position of adenosine (m6A), 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 m6A-related long noncoding RNAs (m6ArlncRNAs) signify the progression of ccRCC remain unclear. We found m6ArlncRNAs are effective signatures illustrating immune landscape and risk stratification in ccRCC. We identified two differently expressed m6ArlncRNAs (DEm6ArlncRNAs), 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 DEm6ArlncRNA expression categorizes patients into either high or low-risk groups, between which, enrichment analysis indicated an enrichment in immune-related pathways. Under different DEm6ArlncRNA 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 m6A 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 m6ArlncRNAs expression can depict tumor microenvironment, predict prognosis for ccRCC patient and give hint to therapeutic strategies in ccRCC.