RETRACTED ARTICLE: Exosome-transmitted miR-128-3p increase chemosensitivity of oxaliplatin-resistant colorectal cancer

Abstract

BackgroundOxaliplatin resistance is a major challenge for treatment of advanced colorectal cancer (CRC). Both acquisition of epithelial-mesenchymal transition (EMT) and suppressed drug accumulation in cancer cells contributes to development of oxaliplatin resistance. Aberrant expression of small noncoding RNA, miR-128-3p, has been shown to be a key regulator in tumorigenesis and cancer development. However, its roles in the progression of CRC and oxaliplatin-resistance are largely unknown.MethodsOxaliplatin-resistant CRC and normal intestinal FHC cells were transfected with a miR-128-3p expression lentivirus. After transfection, FHC-derived exosomes were isolated and co-cultured with CRC cells. miR-128-3p expression in resistant CRC cells, FHC cells, and exosomes was quantified by quantitative real-time PCR (RT-qPCR). The mRNA and protein levels of miR-128-3p target genes in resistant CRC cells were quantified by RT-qPCR and western blot, respectively. The effects of miR-128-3p on CRC cell viability, apoptosis, EMT, motility and drug efflux were evaluated by CCK8, flow cytometry, Transwell and wound healing assays, immunofluorescence, and atomic absorption spectrophotometry. Xenograft models were used to determine whether miR-128-3p loaded exosomes can re-sensitize CRC cells to oxaliplatin in vivo.ResultsIn our established stable oxaliplatin-resistant CRC cell lines, in vitro and vivo studies revealed miR-128-3p suppressed EMT and increased intracellular oxaliplatin accumulation. Importantly, our results indicated that lower miR-128-3p expression was associated with poor oxaliplatin response in advanced human CRC patients. Moreover, data showed that miR-128-3p-transfected FHC cells effectively packaged miR-128-3p into secreted exosomes and mediated miR-128-3p delivery to oxaliplatin-resistant cells, improving oxaliplatin response in CRC cells both in vitro and in vivo. In addition, miR-128-3p overexpression up-regulated E-cadherin levels and inhibited oxaliplatin-induced EMT by suppressing Bmi1 expression in resistant cells. Meanwhile, it also decreased oxaliplatin efflux through suppressed expression of the drug transporter MRP5.ConclusionOur results demonstrate that miR-128-3p delivery via exosomes represents a novel strategy enhancing chemosensitivity in CRC through negative regulation of Bmi1 and MRP5. Moreover, miR-128-3p may be a promising diagnostic and prognostic marker for oxaliplatin-based chemotherapy.Electronic supplementary materialThe online version of this article (10.1186/s12943-019-0981-7) contains supplementary material, which is available to authorized users.

<p>Exosome-Delivered c-Met siRNA Could Reverse Chemoresistance to Cisplatin in Gastric Cancer</p>

“…38,39 Exosomes with miR-128-3p increase chemosensitivity of oxaliplatin in drug-resistant colorectal cancer. 40 Exosomedelivered nucleic acid and proteins partly facilitate the resistance of breast cancer. 41 Exosomes derived from HEK293 could deliver siRNA that target PKL-1 and reduce expression of PLK-1 in bladder cancer cells.…”

Exosomal miRNA-128-3p from mesenchymal stem cells of aged rats regulates osteogenesis and bone fracture healing by targeting Smad5

“…Furthermore, miR-128-3p was demonstrated to inhibit glioma cell proliferation and differentiation through the IRS-1/PI3K/AKT signaling pathway [69]. Exosome-transmitted miR-128-3p could also exert its anticancer effect by increasing the chemosensitivity of oxaliplatin-resistant colorectal cancer [70]. However, as far as we know, there have been no reports about the specific role of miR-128-3p in the MSCs osteogenic differentiation and bone fracture healing process.…”

Exosomal circular RNA sorting mechanisms and their function in promoting or inhibiting cancer (Review)

“…CircATP8B4 was demonstrated to promote glioma radioresistance by serving as a miR-766 sponge, and circATP8B4 in EVs may be a potential biomarker for glioma radioresistance. It was reported that exosome-transmitted miRNA may promote chemosensitivity in multiple cancer types such as colorectal cancer and head and neck cancer (124,125), and recent studies have revealed that circRNAs mediate chemotherapy resistance in various types of cancer such as ovarian cancer and thyroid carcinoma (126)(127)(128). Hence, there is a novel hypothesis that exosomal circRNAs are influence chemotherapy resistance, but this still requires further experimental confirmation (Fig.…”