Nasopharyngeal carcinoma (NPC) is one of the most common malignancies of the head and neck. It arises from the nasopharynx epithelium and is associated with high morbidity and mortality. Long non‐coding RNA (lncRNA) have been reported to regulate gene interaction and play critical roles in carcinogenesis and progression. LncRNA‐ROR, a recently identified lncRNA, has been shown to be involved in initiation, progression and metastasis of several tumors, including hepatocellular carcinoma, breast cancer and glioma. However, whether lncRNA‐ROR is associated with the progression of NPC remains unknown. Resistance to radiotherapy and chemotherapy is the primary cause of NPC patients’ death. In this study, we found that lncRNA‐ROR was significantly upregulated in NPC tissues compared with normal tissues. Next, our study proved that lncRNA‐ROR was highly associated with the proliferation, metastasis and apoptosis of NPC. The enrichment of lncRNA‐ROR played a critucal functional role in chemoresistance. The mechanism by which NPC resists chemotherapy might be that lncRNA‐ROR suppress p53 signal pathway. Taken together, these data suggested that lncRNA‐ROR played an important role in the progression of NPC; thereby it might become a therapeutic target and reduce chemoresistance for NPC.
Exosomes are nano-vesicles secreted by tumor cells. Exosomes can transfer complex biological information and induce a diverse signaling response in a wide array of pathological conditions, such as hypoxia. Hypoxia is associated with aggressive phenotypes and poor outcomes in nasopharyngeal carcinoma (NPC) patients. Here, we analyzed the role of exosomes from hypoxic NPC cells in enhancing the metastases of normoxic cells in a hypoxia-induced factor-1α (HIF-1α)-dependent manner. HIF-1α rapidly accumulates and trans-activates hundreds of genes, such as matrix metalloproteinases (MMPs). We found that MMP-13 was over-expressed in exosomes and cells under hypoxic conditions. HIF-1α depletion in hypoxic CNE2 cells led to decreased MMP-13 levels in exosomes and significantly reduced cell migration and invasion. Moreover, exosomal MMP-13 significantly up-regulated Vimentin expression while decreasing E-cadherin levels in CNE2 cells in vitro and in vivo. Furthermore, MMP-13 levels were closely associated with HIF-1α expression (r = 0.679, P < 0.001), lymph node metastasis, clinical stage (all P < 0.05) and poor prognosis in NPC patients (P < 0.01). In conclusion, our findings suggest that the hypoxic exosomes were loaded with MMP-13, which could enhance migration and invasiveness and induce microenvironment changes to promote NPC aggressiveness.
Nasopharyngeal carcinoma (NPC) is a squamous epithelial cancer, arising from the nasopharynx epithelium. It has high morbidity and mortality. PFKFB3 as a glycolytic activator has been implicated in the progression of multiple types of tumor. PFKFB3 can be contributed to the progression and metastasis of cancer. However, whether PFKFB3 is associated with the progression of NPC remains unknown. We postulated that PFKFB3 promotes proliferation, migration and angiogenesis in nasopharyngeal carcinoma. In this study, we found that PFKFB3 was significantly up-regulated in NPC tissues and cell lines compared with normal control. Our study proved that PFKFB3 can regulate the proliferation, metastasis and apoptosis of NPC. By the way, the NPC-derived exosomes come from and CNE2-derived exosomes are enriched in PFKFB3. The enrichment of PFKFB3 played a crucial functional role in promotes HUVECs proliferation, migration and angiogenesis. And tumor angiogenesis is closely related to the proliferation and metastasis of tumor. In conclusion, our findings demonstrate that PFKFB3 could act not only as a clinical biomarker for angiogenesis but also as a therapeutic target to overcome angiogenesis, enhancing the clinical benefits of angiogenesis therapy in NPC patients.
Dysregulated microRNAs (miRNAs) are involved in carcinoma progression, metastasis, and poor prognosis. We demonstrated that in nasopharyngeal carcinoma (NPC), transactivated MIR106A-5p promotes a malignant phenotype by functioning as a macroautophagy/autophagy suppressor by targeting BTG3 (BTG anti-proliferation factor 3) and activating autophagy-regulating MAPK signaling. MIR106A-5p expression was markedly increased in NPC cases based on quantitative real-time PCR, miRNA microarray, and TCGA database analysis findings. Moreover, MIR106A-5p was correlated with advanced stage, recurrence, and poor clinical outcomes in NPC patients. In addition to three-dimensional cell culture assays, zebrafish and BALB/c mouse tumor models revealed that overexpressed MIR106A-5p targeted BTG3 and accelerated the NPC malignant phenotype by inhibiting autophagy. BTG3 promoted autophagy, and its expression was correlated with poor prognosis in NPC. Attenuation of autophagy, mediated by the MIR106A-5p-BTG3 axis, occurred because of MAPK pathway activation. MIR106A-5p overexpression in NPC was due to increased transactivation by EGR1 and SOX9. Our findings may lead to novel insights into the pathogenesis of NPC.
SOX4, which belongs to the sex-determining region Y-related high-mobility group (SRY) box family, plays a critical role in embryonic development, cell fate decision, differentiation, and tumor development. Nasopharyngeal carcinoma (NPC) is one of the most common cancers in China and Southeast Asia. However, the molecular mechanisms of this disease remain unknown. In the present study, we used immunohistochemistry to investigate the correlation between the expression of SOX4 with clinicopathologic variables as well as patients prognosis of NPC. We found overexpression of SOX4 was correlated with clinical stages, lymph node metastasis, and Ki-67 expression in NPC (P < 0.05). Besides, patients who expressed higher levels of SOX4 had poorer survival rate (P < 0.05). Then, in vitro studies, we took serum starvation-refeeding experiment and knocked down the expression of SOX4 with siRNA to demonstrate that SOX4 could promote proliferation of NPC nonkeratinizing cell line CNE2. The regulation of SOX4 on cell migration was determined by the transwell migration assay and wounding healing assay. Besides, we also found SOX4 could promote epithelial-mesenchymal transition (EMT) of CNE2 cells and decrease their cisplatin sensitivity. Our data suggested that SOX4 might play an important role in regulating NPC progression and would provide a potential therapeutic strategy for NPC.
Insulin-like growth factor-binding protein-3 (IGFBP3) is an N-linked glycosylated, phosphorylated protein, which has been reported to regulate cancer progression and metastasis. However, the role of IGFBP3 in tumor metastasis remains under debate. Nasopharyngeal carcinoma (NPC) is a highly metastatic head and neck cancer. And it fails to achieve the desired therapeutic efficacy in patients with metastasis, while the role of IGFBP3 in NPC is still unclear. In this study, we first used immunohistochemistry to explore the expression of IGFBP3 in NPC tissues. We found that IGFBP3 was significantly elevated in NPC and its expression level was correlated with N classification, distant metastasis, and TNM clinical stage (all P < 0.05). Patients with high expression of IGFBP3 had poorer survival rate (P < 0.05). In addition, we found that downregulation of IGFBP3 inhibited cell migration and adhesion by Transwell migration assay, wounding healing assay, and cell adhesion assays in vitro. Besides, NPC cells stimulated with recombinant IGFBP3 accelerated migration and adhesion. These data suggest overexpression of IGFBP3 promotes tumor metastasis in NPC, which makes it a potential therapeutic target.
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