Abstract
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.
Highlights
Cervical cancer is a major killer that seriously threatens women’s health [1]
The current treatment strategy is neoadjuvant chemotherapy followed by surgery for chemotherapy-sensitive patients, while insensitive patients are directly converted to radiotherapy [7]
To investigate the roles of miR-651 on cisplatin resistance of cervical cancer, this study firstly examined its levels in cervical cancer cells
Summary
Cervical cancer is a major killer that seriously threatens women’s health [1]. the application of cervical cancer vaccine can effectively reduce the incidence of cervical cancer, mortality as well as morbidity of this malignancy still ranks fourth among women worldwide [2]. The current treatment methods for cervical cancer are comprehensive such as surgery, chemotherapy, radiotherapy, and immunotherapy [3]. Not all subjects can achieve satisfactory outcomes, especially for subjects with advanced stages [4,5,6]. The current treatment strategy is neoadjuvant chemotherapy followed by surgery for chemotherapy-sensitive patients, while insensitive patients are directly converted to radiotherapy [7]. If there are indicators that can effectively predict the sensitivity of patients to chemotherapy, this part of the patients who are not sensitive to chemotherapy can save the time and expense of neoadjuvant chemotherapy and directly transfer to radiotherapy to obtain better outcomes [8]. Continuing to study the pathogenesis of cervical cancer, looking for specific therapeutic targets and markers for predicting
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