Abstract
miR-203 is a tumor suppressor that is disregulated in numerous malignancies including nasopharyngeal carcinoma (NPC). However, the role of miR-203 in suppressing tumor stemness, chemotherapy resistance as well as its molecular mechanisms are unclear. In this study, we observed that miR-203 suppressed cell migration, invasion, tumor stemness, and chemotherapy resistance to cisplatin (DDP) in vitro and in vivo. miR-203 exerted these effects by targeting ZEB2 and downstream epithelial-mesenchymal transition (EMT) and tumor stemness signals. Interestingly we observed that miR-203 expression was directly suppressed by ZEB2 via targeting its promoter, which significantly reduced cell migration, invasion, tumor stemness, and chemotherapy resistance in NPC cells. Finally, we found that miR-203 was negatively correlated with ZEB2 expression in NPC tissues and tumor spheres. Our data demonstrate a directly negative feedback loop between miR-203 and ZEB2 participating in tumor stemness and chemotherapy resistance, highlighting the therapeutic potential of targeting this signal for NPC chemotherapy.
Highlights
Nasopharyngeal carcinoma (NPC) is a type of malignant head and neck cancer derived from the nasopharyngeal epithelium, and one of the most common malignancies in Southern China and Southeast Asia
Epstein-Barr virus-encoded microRNA nasopharyngeal carcinoma BART1 induces tumour metastasis by regulating PTEN-dependent pathways in NPC while miR-23 targets IL-8/Stat3 pathway sensitizing NPC cells to irradiation [1, 2]. miR-744 was observed to inhibit ARHGAP5 and induced NPC progression and metastasis in NPC [3]. miR-3188 is induced by Foxo1 through PI3K/AKT/c-Jun signaling which suppresses NPC cell growth via targeting mTOR [4]. miR-184 induced by PDCD4 directly inhibits c-Myc and Bcl-2, which suppresses NPC cell growth and induces apoptosis [5]
More studies have demonstrated that miR-203 is a key tumor suppressor participating in the pathogenesis of many tumors including nasopharyngeal carcinoma
Summary
Nasopharyngeal carcinoma (NPC) is a type of malignant head and neck cancer derived from the nasopharyngeal epithelium, and one of the most common malignancies in Southern China and Southeast Asia. MiR-3188 is induced by Foxo through PI3K/AKT/c-Jun signaling which suppresses NPC cell growth via targeting mTOR [4]. MiR-184 induced by PDCD4 directly inhibits c-Myc and Bcl-2, which suppresses NPC cell growth and induces apoptosis [5]. MiR203 has been found to directly target IL8/AKT signaling suppressing NPC radioresistance. Suppression for tumor stemness and chemotherapy resistance mediated by miR203 has not been reported in the context of NPC. As an oncogenic transcription factor [9, 10], it has been reported to induce EMT and tumor stemness by regulating E-cadherin and miR-200 family members by binding to the promoter of these genes [11,12,13]. ZEB2 promoted NPC metastasis [14, 15], the precise molecular mechanisms exerting this effect have not been determined
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