Abstract
Radioresistance prevails as one of the largest obstacles in the clinical treatment of nasopharyngeal carcinoma (NPC). Meanwhile, tumor-derived extracellular vesicles (TEVs) possess the ability to manipulate radioresistance in NPC. However, its mechanism remains to be further explored. Therefore, the current study set out to explore the mechanism of microRNA (miR)-142-5p delivered by TEVs in regard to the radiosensitivity of NPC. Firstly, peripheral blood samples were collected from patients with radioresistance and radiosensitivity, followed by RT-qPCR detection of miR-142-5p expression. A dual-luciferase reporter assay was carried out to elucidate the targeting relationship of miR-142-5p with HGF and EGF. In addition, radiotherapy-resistant NPC cell models were established by screening NPC cells with gradient increasing radiation exposure, and co-incubated with EVs isolated from miR-142-5p mimic-transfected NPC cells, followed by overexpression of HGF and EGF. Moreover, cell viability was detected by means of MTS, cell proliferation with a colony formation assay, cell apoptosis with flow cytometry, and expression patterns of related genes with the help of Western blot analysis. NPC xenotransplantation models in nude mice were also established by subcutaneous injection of 5-8FR cells to determine apoptosis, tumorigenicity, and radiosensitivity in nude mice. It was found that miR-142-5p was poorly expressed in peripheral blood from NPC patients with radioresistance. Mechanistic experimentation illustrated that miR-142-5p inversely targeted HGF and EGF to inactivate the HGF/c-Met and EGF/EGFR pathways, respectively. NPC cell apoptosis was observed to be augmented, while their radioresistance and proliferation were restricted by EVs-miR-142-5p or HGF silencing, or EGF silencing. Furthermore, EVs-miR-142-5p inhibited growth and radioresistance and accelerated the apoptosis of radiotherapy-resistant NPC cells in nude mice by inhibiting the HGF/c-Met and EGF/EGFR pathways. Collectively, our findings indicated that TEVs might inhibit the HGF/c-Met and EGF/EGFR pathways by delivering miR-142-5p into radiotherapy-resistant NPC cells to enhance radiosensitivity in NPC.
Highlights
Nasopharyngeal carcinoma (NPC) is an epithelial tumor originating from the nasopharyngeal mucosal lining, which is featured by obvious geographical distribution and particular prevalence in East and Southeast Asia [1]
Low expression of miR-142-5p was associated with poor prognosis in NPC patients with radioresistance In order to further elucidate the relationship between miR-142-5p and radioresistance, we adopted gradient increasing radiation screening to construct NPC cell models of radioresistance (5-8FR and CNE-3R, Fig. 2A)
Radiotherapy is lauded as the gold standard for NPC treatment, while the recent strides made in disease control and survival in NPC patients can be partly attributed to the advent of intensity-modulated radiation therapy (IMRT) [17]
Summary
Nasopharyngeal carcinoma (NPC) is an epithelial tumor originating from the nasopharyngeal mucosal lining, which is featured by obvious geographical distribution and particular prevalence in East and Southeast Asia [1]. Significant advancements have been made in radiotherapy techniques for the treatment of NPC, while concurrent chemotherapy is widely used for localized diseases [3]. The overall prognosis of NPC has improved remarkably over the past decades with the advent of imaging (more accurate disease staging), radiotherapy, chemotherapy, and targeted therapies [4]. Amongst the various therapeutic approaches, intensity-modulated radiation therapy (IMRT), the current gold-standard treatment for NPC, achieves good tumor coverage and healthy tissue sparing, resulting in dose escalation and decent local control in the majority of patients [5]. Radioresistance may cause local failure to contribute to residual or recurrent tumors in some patients, which is the principal cause of NPC treatment failure [4]. It would be prudent to elucidate the underlying mechanism of radioresistance during NPC
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