SiRNA-based delivery nanoplatform attenuates the CRC progression via HIF1α-AS2

Abstract

Colorectal cancer (CRC) is one of the most common malignancies and the leading causes of cancer-related deaths in the world. However, the molecular mechanisms of colorectal carcinogenesis and metastasis remain unknown. Long non-coding RNAs (lncRNAs) have been implicated to be in the initiation and malignant progression of CRC. In this study, we identified a novel oncogenic lncRNA HIF1α-AS2 in CRC patients by combination with lncRNA microarray and qRT-PCR. HIF1α-AS2 is upregulated progressively in adjacent non-tumor tissues to adenoma to CRC and contributes to CRC aggressive phenotypes. RNA-sequence assays and luciferase reporter assays were performed to reveal that upregulation of lncRNA HIF1α-AS2 may lead to the increased expression of HIF1α via competitively binding to miR-155–5p, miR-340–5p, miR-580–5p and miR-590–3p in CRC initiation, whereas HIF1α may work as a cellular sponge to directly interact with the RMRP promoter to promote RMRP transcription determined by chromatin immunoprecipitation and RNA-sequence assays. Data from RNA Binding Protein Immunoprecipitation and mass spectrometry revealed that RMRP-mediated an increased level of IGF2 expression promotes CRC progression and metastasis by competitively sponging IGF2R. Lastly, we developed mPEG-DSPE liposomes encapsulated with siRNA HIF1α-AS2, which exhibited desirable physicochemical properties along with narrow well-dispersion stability and significantly prevented the progression of CRC, indicating that mPEG-DSPE-liposome-encapsulated HIF1α-AS2 siRNA might be a potential biomarker and therapeutic target for CRC therapy.