Engineered exosomes for co‐delivery of PGM5‐AS1 and oxaliplatin to reverse drug resistance in colon cancer

• Published in: Journal of cellular physiology 2022-01, Vol.237 (1), p.911-933
• Main Authors: Hui, Bingqing, Lu, Chen, Wang, Jing, Xu, Yetao, Yang, Yuchen, Ji, Hao, Li, Xiaofei, Xu, Lingyan, Wang, Jiawei, Tang, Weiwei, Wang, Keming, Gu, Yanhong
• Format: Article
• Language: English
• Subjects: Alternative splicing; Antisense RNA; Antisense therapy; Cell proliferation; Cell Proliferation - genetics; Colon; Colon cancer; Colonic Neoplasms - drug therapy; Colonic Neoplasms - genetics; Colorectal cancer; Colorectal carcinoma; Drug Resistance; engineered exosomes; Exosomes; Exosomes - genetics; Exosomes - metabolism; Fluorescence; Fluorescence in situ hybridization; Gene expression; Gene Expression Regulation, Neoplastic - genetics; Gene sequencing; Genes; GFI1B; Humans; Immunoprecipitation; In Situ Hybridization, Fluorescence; Metastases; MicroRNAs - genetics; MicroRNAs - metabolism; Nucleic acids; Oxaliplatin; Oxaliplatin - pharmacology; PGM5‐AS1; Regulatory mechanisms (biology); Reporter gene; Ribonucleic acid; RNA; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Serine-Arginine Splicing Factors - genetics; Serine-Arginine Splicing Factors - metabolism; Splicing; Transcription; Transcriptomes
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.30566

Oxaliplatin resistance inevitably occurs in almost all cases of metastatic colorectal cancer (CRC), and it is important to study the roles of lncRNAs and their specific regulatory mechanisms in oxaliplatin resistance. Exosomes are increasingly designed for drug or functional nucleic acid delivery due to their properties, thereby improving the effectiveness of cancer therapy. The results of this study show that the low expression of PGM5 antisense RNA 1 (PGM5‐AS1) in colon cancer is induced by transcription inhibitor, GFI1B. PGM5‐AS1 prevents proliferation, migration, and acquired oxaliplatin tolerance of colon cancer cells. Exosomes encapsulating oxaliplatin and PGM5‐AS1 can reverse drug resistance. For identifying differentially expressed target genes regarding PGM5‐AS1, RNA transcriptome sequencing was performed. The mechanism by which PGM5‐AS1 regulates its target genes was explored by performing experiments such as fluorescent in situ hybridization assay, dual‐luciferase reporter gene assay, and RNA immunoprecipitation. The results show that by recruiting SRSF3, PGM5‐AS1 activates alternate splicing to downregulate PAEP expression. For hsa‐miR‐423‐5p, PGM5‐AS1 can also act as a sponge to upregulate the NME1 expression. GFI1B inhibits the transcription of PGM5 antisense RNA 1 (PGM5‐AS1), which recruits SRSF3 to downregulate PAEP and competitively binds with hsa‐miR‐423‐5p to upregulate NME1 to suppress the malignant phenotype of colorectal cancer (CRC). Engineered exosomes co‐delivering PGM5‐AS1 and oxaliplatin reverses drug resistance in CRC.