EVs delivery of miR-1915-3p improves the chemotherapeutic efficacy of oxaliplatin in colorectal cancer

• Published in: Cancer chemotherapy and pharmacology 2021-12, Vol.88 (6), p.1021-1031
• Main Authors: Xiao, Zhenhuan, Liu, Yun, Li, Qun, Liu, Qinyuan, Liu, Yong, Luo, Yan, Wei, Songzhi
• Format: Article
• Language: English
• Subjects: 6-Phosphofructo-2-kinase; Animal models; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Cancer; Cancer Research; Cell adhesion; Cell Proliferation; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Combinatorial analysis; Drug resistance; Drug Resistance, Neoplasm; E-cadherin; Exosomes - metabolism; Exosomes - transplantation; Extracellular vesicles; Gene expression; Humans; Hydrolase; Kinases; Medicine; Medicine & Public Health; Mesenchyme; Mice; MicroRNAs; MicroRNAs - administration & dosage; MicroRNAs - genetics; miRNA; Oncology; Original Article; Overexpression; Oxaliplatin; Oxaliplatin - pharmacology; Pharmacology/Toxicology; Ribonucleic acid; RNA; Sensitivity; Tumor Cells, Cultured; Ubiquitin; Western blotting; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-021-04348-5

Purpose Oxaliplatin is a crucial component of the combinatorial chemotherapeutic standard of care for advanced colorectal cancer (CRC). Unfortunately, a serious barrier to effective oxaliplatin treatment is drug resistance due to epithelial-mesenchymal transitioning (EMT). Interestingly, stable oxaliplatin-resistant CRC cell lines show differential expression of miR-1915-3p; thus, this microRNA may represent a potential modifier of oxaliplatin resistance in CRC cells. Methods miR-1915-3p was over-expressed in oxaliplatin-resistant CRC cells and a non-tumorigenic intestinal cell line (FHC) via lentiviral transduction. Extracellular vesicles (EVs) were purified from transduced FHC cells and co-incubated with CRC cells. Expression levels of miR-1915-3p and other RNA species were assessed by RT-qPCR, while protein expression levels were assessed by Western blotting. The effects of miR-1915-3p on CRC viability were evaluated by proliferation, apoptosis assays, and Transwell assays. Effects of miR-1915-3p over-expression on in vivo oxaliplatin sensitivity was tested via murine xenograft models. Results miRNA-1915-3p decreased EMT marker expression in oxaliplatin-resistant CRC cell lines and in vivo. FHC cells were able to produce and secrete miR-1915-3p-containing EVs, which we employed to mediate miR-1915-3p delivery to oxaliplatin-resistant CRC cells and increase their oxaliplatin sensitivity in vivo and in vitro. Mechanistically, miR-1915-3p overexpression downregulated the EMT-promoting oncogenes 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and ubiquitin carboxyl-terminal hydrolase 2 (USP2) as well as upregulated E-cadherin (a cell adhesion mediator). miR-1915-3p’s effects on chemosensitivity and EMT were mediated by its regulation of PFKFB3 and USP2. Conclusion Exosomal delivery of miR-1915-3p can improve the chemotherapeutic efficacy of oxaliplatin in CRC cells by suppressing the EMT-promoting oncogenes PFKFB3 and USP2.