Cancer-Derived Exosomal miR-651 as a Diagnostic Marker Restrains Cisplatin Resistance and Directly Targets ATG3 for Cervical Cancer

• Published in: Disease markers Vol. 2021; pp. 1 - 16
• Main Authors: Zhu, Xiaofan, Long, Ling, Xiao, He, He, Xuan
• Format: Journal Article
• Language: English
• Published: United States Hindawi 2021; John Wiley & Sons, Inc
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis; Autophagy-Related Proteins - genetics; Autophagy-Related Proteins - metabolism; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cancer; Cancer therapies; CD63 antigen; CD81 antigen; CD9 antigen; Cell culture; Cell Proliferation; Cervical cancer; Cervix; Chemical compounds; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Diagnostic systems; Drug resistance; Drug Resistance, Neoplasm; Exosomes; Exosomes - genetics; Female; Gene Expression Regulation, Neoplastic; Humans; Membranes; MicroRNAs; MicroRNAs - genetics; Pharmacology; Prognosis; Proteins; Radiation therapy; Surgery; Tumor Cells, Cultured; Tumors; Ubiquitin-Conjugating Enzymes - genetics; Ubiquitin-Conjugating Enzymes - metabolism; Uterine Cervical Neoplasms - drug therapy; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - pathology; United States > US; China; Japan
• ISSN: 0278-0240; 1875-8630; 1875-8630
• DOI: 10.1155/2021/1544784

Objective. Cancer-derived exosomes can facilitate drug resistance in cervical cancer. However, the mechanisms remain elusive. Herein, we observed the roles of exosomal miR-651 in cisplatin resistance of cervical cancer. Methods. Circulating miR-651 was detected in cervical cancer and healthy individuals. The diagnostic efficacy was determined. When transfected with miR-651 mimics, cisplatin resistance, apoptosis, and proliferation were assessed. The cancer-derived exosomes were separated and identified. We observed the uptake of PKH67-labeled exosomes by HeLa/S cells. After coculture with exosomes secreted by HeLa/S or HeLa/DDP cells, malignant behaviors were examined in HeLa/S cells. The interactions between ATG3 and miR-651 were validated by dual luciferase report. Biological behaviors were investigated for HeLa/S cells cocultured with exosomes secreted by miR-651 mimic-transfected HeLa/DDP cells. Results. Downregulated circulating miR-651 was found in cancer subjects than healthy individuals. It possessed high sensitivity and accuracy in diagnosing cervical cancer (AUC=0.9050). Lower miR-651 expression was confirmed in HeLa/DDP than HeLa/S cells. Forced miR-651 lessened cisplatin resistance and proliferation and elevated apoptosis in HeLa cells. ATG3 was a direct target of miR-651. The exosomes isolated from HeLa cells were rich in CD63, CD9, and CD81 proteins, thereby identifying the isolated exosomes. Exosomes secreted by HeLa/DDP cells can be absorbed by HeLa/S cells. When being cocultured with exosomes secreted by HeLa/DDP cells, malignant behaviors of HeLa/S cells were enhanced, which were ameliorated by miR-651 mimic exosomes. Conclusion. Our findings showed that cancer-derived exosomal miR-651 restrained cisplatin resistance and directly targeted ATG3, indicating that exosomal miR-651 could be a therapeutic agent.