No abstract

Genomic instability facilitates the evolution of cells, tissues, organs, and species. The progression of human malignancies can be regarded as the accumulation of genomic instability, which confers a high evolutionary potential for tumor cells to adapt to continuous changes in the tumor microenvironment. Nasopharyngeal carcinoma (NPC) is a head-and-neck squamous-cell carcinoma closely associated with Epstein–Barr virus (EBV) infection. NPC progression is driven by a combination of accumulated genomic instability and persistent EBV infection. Here, we present a review of the key characteristics of genomic instability in NPC and the profound implications of EBV infection. We further discuss the significance of profiling genomic instability for the assessment of disease progression and treatment efficacy, as well as the opportunities and challenges of targeted therapies for NPC based on its unique genomic instability.

Distant metastasis remains the primary cause of treatment failure and suggests a poor prognosis in nasopharyngeal carcinoma (NPC). Epithelial-mesenchymal transition (EMT) is a critical cellular process for initiating a tumor invasion and remote metastasis. Our previous study showed that the blockage of the stromal interaction molecule 1 (STIM1)-mediated Ca2+ signaling blunts the Epstein–Barr virus (EBV)-promoted cell migration and inhibits the dissemination and lymphatic metastasis of NPC cells. However, the upstream signaling pathway that regulates the STIM1 expression remains unknown. In this follow-up study, we demonstrated that the miRNA-185-5p/STIM1 axis is implicated in the regulation of the metastatic potential of 5–8F cells, a highly invasive NPC cell line. We demonstrate that the knockdown of STIM1 attenuates the migration ability of 5–8F cells by inhibiting the epidermal growth factor receptor (EGFR) phosphorylation-induced switch from E- to N-cadherin in vitro. In addition, the STIM1 knockdown inhibited the locoregional lymphatic invasion of the 5–8F cells in mice. Furthermore, we identified miRNA-185-5p as an upstream regulator that negatively regulates the expression of STIM1. Our findings suggest that the miRNA-185-5p/STIM1 axis regulates the invasiveness of NPC cell lines by affecting the EGFR activation-modulated cell adhesiveness. The miRNA-185-5p/STIM1 axis may serve as a potentially effective therapeutic target for the treatment of NPC.

Background Stromal interaction molecule 1 (STIM1)-mediated Ca 2+ signaling regulates tumor angiogenesis in nasopharyngeal carcinoma (NPC), an Epstein-Barr virus (EBV)-related human malignancy. However, the mechanism by which STIM1 modulates the endothelial functional phenotypes contributing to tumor angiogenesis remains elusive.Methods We explored the intercellular communication via exosomal biomolecules released by EBVinfected NPC cells and delivered to endothelial cells (ECs). The NPC cell-derived exosomes were isolated via differential centrifugation and observed with transmission electron microscopy. Exosome particle size was assessed by nanoparticle tracking analysis (NTA). Uptake of exosomes by recipient ECs was detected by uorescent labeling of the exosomes with PKH26. Tumor angiogenesis-associated pro les were characterized by determining cell proliferation, migration, tubulogenesis, and permeability in human umbilical vein endothelial cells (HUVECs). Activation of the Akt/ERK pathway was elucidated by detecting the phosphorylation level using western blotting. A chick embryo chorioallantoic membrane (CAM) xenograft model was employed to study tumor-associated neovascularization in vivo. Results The NPC cell-derived exosomes harboring EBV-encoded latent membrane protein 1 (LMP1) promoted proliferation, migration, tubulogenesis, and permeability by activating the Akt/ERK pathway in ECs. STIM1 silencing reduced LMP1 enrichment in NPC cell-derived exosomes, thereby reversing its prooncogenic effects in an Akt/ERK pathway-dependent manner. Furthermore, STIM1 knockdown in NPC cells blunted tumor-induced vascular network formation and inhibited intra-tumor neovascularization in the chorioallantoic membrane (CAM) xenograft model. Conclusion STIM1 regulates tumor angiogenesis by controlling exosomal EBV-LMP1 delivery to ECs in the NPC tumor microenvironment. Blocking exosome-mediated cell-to-cell horizontal transfer of EBVassociated oncogenic signaling molecules may be an effective therapeutic strategy for NPC.

Background Stromal interaction molecule 1 (STIM1)-mediated Ca2+ signaling regulates tumor angiogenesis in nasopharyngeal carcinoma (NPC), an Epstein-Barr virus (EBV)-related human malignancy. However, the mechanism by which STIM1 modulates the endothelial functional phenotypes contributing to tumor angiogenesis remains elusive. Methods We explored the intercellular communication via exosomal biomolecules released by EBV-infected NPC cells and delivered to endothelial cells (ECs). The NPC cell-derived exosomes were isolated via differential centrifugation and observed with transmission electron microscopy. Exosome particle size was assessed by nanoparticle tracking analysis (NTA). Uptake of exosomes by recipient ECs was detected by fluorescent labeling of the exosomes with PKH26. Tumor angiogenesis-associated profiles were characterized by determining cell proliferation, migration, tubulogenesis, and permeability in human umbilical vein endothelial cells (HUVECs). Activation of the Akt/ERK pathway was elucidated by detecting the phosphorylation level using western blotting. A chick embryo chorioallantoic membrane (CAM) xenograft model was employed to study tumor-associated neovascularization in vivo. Results The NPC cell-derived exosomes harboring EBV-encoded latent membrane protein 1 (LMP1) promoted proliferation, migration, tubulogenesis, and permeability by activating the Akt/ERK pathway in ECs. STIM1 silencing reduced LMP1 enrichment in NPC cell-derived exosomes, thereby reversing its pro-oncogenic effects in an Akt/ERK pathway-dependent manner. Furthermore, STIM1 knockdown in NPC cells blunted tumor-induced vascular network formation and inhibited intra-tumor neovascularization in the chorioallantoic membrane (CAM) xenograft model. Conclusion STIM1 regulates tumor angiogenesis by controlling exosomal EBV-LMP1 delivery to ECs in the NPC tumor microenvironment. Blocking exosome-mediated cell-to-cell horizontal transfer of EBV-associated oncogenic signaling molecules may be an effective therapeutic strategy for NPC.