Abstract
Approximately 30% of patients with Epstein-Barr virus (EBV)-positive advanced nasopharyngeal carcinoma (NPC) display chemoresistance to cisplatin-based regimens, but the underlying mechanisms are unclear. The Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1), a functional homologue of the tumor necrosis factor receptor family, contributes substantially to the oncogenic potential of EBV through the activation of multiple signaling pathways, and it is closely associated with a poorer prognosis for NPC. Recent studies show that EBV infection can induce the expression of many cellular miRNAs, including microRNA-21, a biomarker for chemoresistance. However, neither a link between LMP1 expression and miR-21 upregulation nor their cross talk in affecting chemoresistance to cisplatin have been reported. Here, we observed that stable LMP1-transformed NPC cells were less sensitive to cisplatin treatment based on their proliferation, colony formation, the IC50 value of cisplatin and the apoptosis index. Higher levels of miR-21 were found in EBV-carrying and LMP1-positive cell lines, suggesting that LMP1 may be linked to miR-21 upregulation. These data were confirmed by our results that exogenous LMP1 increased miR-21 in both transiently and stably LMP1-transfected cells, and the knock down of miR-21 substantially reversed the resistance of the NPC cells to cisplatin treatment. Moreover, the proapoptotic factors programmed cell death 4 (PDCD4) and Fas ligand (Fas-L), which were negatively regulated by miR-21, were found to play an important role in the program of LMP1-dependent cisplatin resistance. Finally, we demonstrated that LMP1 induced miR-21 expression primarily by modulating the PI3K/AKT/FOXO3a signaling pathway. Taken together, we revealed for the first time that viral LMP1 triggers the PI3K/Akt/FOXO3a pathway to induce human miR-21 expression, which subsequently decreases the expression of PDCD4 and Fas-L, and results in chemoresistance in NPC cells.
Highlights
Nasopharyngeal carcinoma (NPC), which is prevalent in Southeast China and Southeast Asia, is closely associated with Epstein-Barr virus (EBV) infection, primarily due to the latent membrane protein 1 (LMP1) oncogene of EBV
To explore whether LMP1 has an effect on miR-21, we first detected the level of miR-21 in NPC and lymphoblastoid cell lines
We examined miR-21 expression after the transient transfection of the LMP1 plasmid into NPC cells. qRT-PCR and immunoblotting demonstrated that the transient transfection of LMP1 into CNE2 or HONE1 cells increased LMP1 expression at the mRNA and protein levels
Summary
Nasopharyngeal carcinoma (NPC), which is prevalent in Southeast China and Southeast Asia, is closely associated with Epstein-Barr virus (EBV) infection, primarily due to the LMP1 oncogene of EBV. NPC is sensitive to radiotherapy and chemotherapy, and can be cured at a rate as approximately 70% [1,2]. The metastatic NPCs usually develop resistance after 6 cycles of cisplatin-based chemotherapy [4]. The copy number of EBV DNA is reported to be elevated in patients with metastatic NPC, indicating the revival or more active proliferation of the virus [5,6]. It is unclear whether the activity of EBV in NPC cells is responsible for the resistance of the cancer cells to cisplatin-based chemotherapy
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