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Nucleosome assembly protein 1-like 1 (NAP1L1) is significantly involved in the development of various cancers. However, its role in the molecular mechanism of nasopharyngeal carcinoma (NPC) remains undetermined. In this study, we detected the upregulated expression of NAP1L1 mRNA and protein levels by quantitative polymerase chain reaction and Western blot analysis in NPC cell lines. Results of the immunohistochemistry analysis of NPC tissue biopsies showed that upregulated NAP1L1 protein expression promoted NPC progression and negatively correlated with poor prognosis in NPC patients. Suppression of NAP1L1 expression by small interfering RNA (siRNA) or small hairpin RNA (shRNA) methods significantly decreased cell proliferation in vivo and in vitro. Mechanism analysis revealed that the regulation of cell growth was enriched by Gene Set Enrichment Analysis based on RNA sequencing data. Cell cycle-induced genes CCND1 and E2F1 were downregulated in NAP1L1 knockdown NPC cells. Reduced NAP1L1 suppressed the recruitment of hepatoma-derived growth factor (HDGF) and decreased its expression. Knockdown of HDGF reduced the expression of c-JUN, a key oncogenic transcription factor that can induce the expression of cyclin D1 (CCND1), reducing cell cycle progression and suppressing cell growth in NPC. Transfecting HDGF or c-JUN could reverse the growth-suppressive effects in NAP1L1-downregulated NPC cells. The data obtained in this study suggest that NAP1L1 acts as a potential oncogene by activating HDGF/c-JUN/CCND1 signaling in NPC., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Nasopharyngeal carcinoma (NPC) is a malignant tumor originating from the superior mucosal epithelium of the nasopharynx. However, effective therapies for NPC are still required. Reducing Hedgehog signaling pathway has been shown to suppress tumor growth. In this study, we attempted to explore whether Jervine (JV), an inhibitor of Hedgehog signaling, had anti-cancer effects on NPC, and the underlying mechanisms. Our findings showed that JV treatments markedly reduced the proliferation of NPC cells in a dose- and time-dependent manner. Cell cycle arrest in G2/M phase was significantly enhanced by JV, along with evident DNA damage. Moreover, JV treatment effectively induced apoptosis in NPC cells through improving Caspase-3 activation. Furthermore, ROS production and mitochondrial impairments were detected in JV-incubated NPC cells with elevated releases of Cyto-c from mitochondria. JV also dramatically triggered autophagy through blocking AKT/mTOR and increasing AMPK signaling pathways. Intriguingly, we showed that JV-induced apoptosis was mainly via an autophagy-dependent manner. In addition, the expression levels of SHH, PTCH1, SMO and GLI1 were markedly suppressed in NPC cells, demonstrating the hindered Hedgehog signaling. Importantly, we found that JV-induced apoptosis and autophagy were closely associated with the blockage of Hedgehog signaling. Our in vivo studies confirmed the anti-cancer effects of JV on NPC through inducing autophagy, as evidenced by the markedly reduced tumor growth rate and weight without side effects and toxicity. Taken together, JV may be a promising and effective agent for human NPC treatment through repressing Hedgehog signaling pathway and inducing autophagic cell death., (Copyright © 2020. Published by Elsevier Masson SAS.)

Nasopharyngeal carcinoma (NPC) is a common malignant tumor in Southern China and South-East Asia. Regardless of initiative high response to radiotherapy, parts of patients still have relapses and metastases. It is reported that epidermal growth factor receptor (EGFR) is highly expressed in most of NPC and is a poor prognostic factor. Targeting EGFR therapies including monoclonal antibodies and EGFR tyrosine kinase inhibitors (EGFR-TKIs), offer different benefits and toxicities for patients with NPC. Herein, we summarize the clinical evidence of anti-EGFR therapies in the management of NPC and provide a direction for the treatment and research of NPC in the future., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Long non-coding RNA (lncRNA) has been proposed to regulate tumorigenesis, however, the role of small nucleolar RNA host gene 8 (SNHG8) in nasopharyngeal carcinoma (NPC) remains unclear., Methods: Levels of SNHG8 in NPC tissues and cells were analyzed with real-time quantitative PCR method. Cell counting kit-8 assay, colony formation assay, wound-healing assay, and transwell invasion assay were performed to detect cell viability, migration, and invasion. Luciferase activity assay and RIP assay were performed to explore relationships among SNHG8, microRNA-656-3p (miR-656-3p), and special AT-rich sequence-binding protein 1 (SATB1)., Results: We found SNHG8 level was increased expression in NPC tissues and cells.In vitro assays revealed that SNHG8 stimulates NPC cell proliferation, colony formation, cell migration, and cell invasion. In vivo assay confirmed knockdown of SNHG8 could hamper tumor growth. Furthermore, we showed SNHG8 serves as a sponge for miR-656-3p to regulate SATB1 expression, and participated in NPC progression., Conclusions: In summary, our work indicated the importance of SNHG8 in NPC progression, which provided novel treatment methods for NPC., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The promoting roles of the long non-coding RNA (lncRNA) MACC1-AS1 have been indicated in gastric and pancreatic cancer, however, its roles in nasopharyngeal carcinoma (NPC) progression are never been revealed. In this work, it was shown that lncRNA MACC1-AS1 was highly expressed in NPC tissues and cells relative to the adjacent tissues and nasal mucosa cells, respectively. Additionally, MACC1-AS1 expression was positively correlated with the high rate of lymph node metastasis and large tumor size. in vitro and in vivo experiments revealed that MACC1-AS1 knockdown reduced the stemness of NPC cells, which was indicated by the decrease of sphere-forming ability, ALDH1 activity, stemness marker expression and tumor-initiating capacity. Mechanistic research showed that MACC1-AS1 antagonized the activity of miR-145, which could target Smad2. In turn, smad2 directly bound to MACC1-AS1 promoter and thus increased MACC1-AS1 expression. Notably, knockdown of miR-145 or overexpression of Smad2 rescued the inhibition of MACC1-AS1 knockdown on the stemness of NPC cells. Therefore, these results demonstrate a novel MACC1-AS1/miR-145/Smad2 negative loop responsible for NPC cell stemness., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Background: Nasopharyngeal carcinoma (NPC) is common in Southern China. The molecular mechanism underlying NPC genesis and progression has been comprehensively investigated, but the key gene (s) or pathway (s) pertaining to NPC are unidentified., Methods: We explored some key genes and pathways involved in NPC through using meta-analysis of deposited expression of microarray data of NPC. The expression of proliferating cell nuclear antigen clamp associated factor (PCLAF) was determined by real-time PCR and western blots. CCK-8 assay, colony formation assay, transwell migration assay, cell wound healing assay, cell cycle analysis and cell apoptosis were carried out to assess biological behaviors caused by downregulation and overexpression of PCLAF in vitro. CHIP was utilized to determine the direct upstream regulatory transcription factors of PCLAF., Results: PCLAF was the key gene of NPC, which was significantly up-regulated in NPC cell line compared to the normal nasopharyngeal cell line. Additionally, in vitro assay has demonstrated the down-regulation and overexpression of PCLAF, resulted in significantly suppressed and enhanced NPC proliferation, metastasis and invasion respectively. Furthermore, the up-regulation of PCLAF in NPC is induced by direct binding of dysregulated NF-κB p50/RelB complex to the promoter of PCLAF., Conclusion: Our results offer a strategy for re-using the deposited data to find the key genes and pathways involved in pathogenesis of cancer. Our study has provided evidence of supporting the role of PCLAF in NPC genesis and progression., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Emerging evidence suggests that cinobufagin, an active ingredient in Venenum Bufonis, inhibits cell proliferation in several tumor cells. However, the anti-tumor effect of cinobufagin on nasopharyngeal carcinoma and the underlying molecular mechanisms are still unclear. In this study, we found that cinobufagin significantly inhibits the proliferation of nasopharyngeal carcinoma HK-1 cells. Further analyses demonstrated that cinobufagin induces cell cycle arrest at the S phase in HK-1 cells through downregulating the levels of CDK2 and cyclin E. Moreover, cinobufagin significantly downregulates the protein level of Bcl-2 and upregulates the levels of Bax, subsequently increasing the levels of cytoplasmic cytochrome c, Apaf-1, cleaved PARP1, cleaved caspase-3, and cleaved caspase-9, leading to HK-1 apoptosis. Furthermore, we found that cinobufagin significantly increases ROS levels and decreases the mitochondrial membrane potential in HK-1 cells. Collectively, these data imply that cinobufagin induces cell cycle arrest at the S phase and induces apoptosis through increasing ROS levels, thereby inhibiting cell proliferation in HK-1 cells. Therefore, cinobufagin is a promising bioactive agent that may contribute to the development of treatment strategies of nasopharyngeal carcinoma., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The enhancement of the anticancer activity by disulfiram (DSF) chelated with copper (DSF/Cu 2+ ) has been investigated recently, while the underlying molecular mechanisms still need to be fully elucidated. Chloride channel-3 (ClC-3) is over-expressed in a variety of cancers and involves multiple tumor biological events. However, whether the over-expression of ClC-3 in tumor cells affects the sensitivity of anti-tumor drugs remains unclear. Here, we showed that the involvement of ClC-3 chloride channel in the selective cytotoxicity of DSF/Cu 2+ in the poorly-differentiated nasopharyngeal carcinoma. The EC 50 of DSF alone and DSF/Cu 2+ in activating the Cl - channel were 95.36 μM and 0.31 μM in the CNE-2Z cells, respectively. DSF/Cu 2+ exhibited a positive correlation between the induction of the Cl - currents and the inhibition of cell proliferation. DSF/Cu 2+ increased the ClC-3 protein expression and induced the cell apoptosis. Cl - channel blockers, NPPB and DIDS, and ClC-3 siRNA partially inhibited the cell apoptosis, and depleted the Cl - currents induced by DSF/Cu 2+ in CNE-2Z cells. However, these effects could not be observed in the normal nasopharyngeal epithelium NP69-SV40 T cells. In vivo, the transplanted human nasopharyngeal carcinoma tumors size in the DSF/Cu 2+ group decreased about 73.2% of those in the solvent control group. The chloride blockers partially inhibited the antitumor action of DSF/Cu 2+ . These data demonstrated that the selective cytotoxicity of DSF/Cu 2+ may relate to its selective activation of ClC-3 Cl - channel pathways in CNE-2Z cells. ClC-3 Cl - channel can be viewed as a new and promising target for the treatment of nasopharyngeal carcinoma., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Nasopharyngeal carcinoma (NPC) is a malignant tumor in South China, characterized with high death rate. If untreated, NPC cells will be invasiveness and then spread to other tissues. In clinical practice, however, lack of early effective screening to prevent the NPC development. Therefore, candidate biomarker for detecting NPC is developing urgently. In current study, human NPC data and samples were collected for tests, followed by cell culture study. As results, Epstein-Barr virus (EBV)-based human NPC sections showed increased expressions of heat shock protein 90 (Hsp90), protein kinase B (AKT), and Hsp90 levels were positively expressed than those in cytokeratin 19 (CK19). The clinical data showed unchanged contents of blood cancer markers. In cell line study, Hsp90-treated cells (CNE1, 5-8 F) resulted in promoted cellular growth and proliferation. Additionally, proliferative proteins of cellular extracellular regulated protein kinase (Erk1/2), phospho-Erk1/2 (Thr202+Tyr204), B-cell lymphoma-2 (Bcl-2), AKT, phospho-AKT (Ser473), Ki-67 were up-regulated in Hsp90 treatments, while the apoptotic protease activating factor-1 (Apaf1) were down-regulated. Followed by treatment with Hsp90 inhibitor, the NPC cells exhibited inhibited cellular proliferation and growth, induced cell apoptosis, reduced proliferative proteins of Erk1/2, phospho-Erk1/2 (Thr202+Tyr204), AKT, phospho-AKT (Ser473), Bcl-2, Ki-67, and elevated Apaf1 expression. In conclusion, the current findings obtained from this study demonstrate that Hsp90 effectively promotes cell proliferation through activating carcinomatous ERK1/2, phospho-Erk1/2 (Thr202+Tyr204), AKT, phospho-AKT (Ser473) expressions in NPC cells. Briefly, Hsp90 may be a promising biomarker to screen NPC, including early stage., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The inhibitory effects of limonin have been disclosed in various tumors, however, its roles in nasopharyngeal carcinoma (NPC) progression are never been revealed. In the current work, we collected NPC cells with a higher stemness compared with bulk cells through isolating the side population (SP) cells. It was found that limonin exhibited a stronger inhibitory effect on SP cells than that in bulk cells, which was evident by a lower IC50 value. Additionally, limonin attenuated the stemness and migration ability of SP cells with the higher stemness, characterized as decreasing the spheroid formation ability, expression of stemness markers and migration ability. Moreover, the proportion of SP cells in G0 phase was remarkably higher than that in bulk cells. Notably, upon limonin treatment, the proportion of SP cells in G0 was decreased and S/G2/M increased. Furthermore, limonin enhanced the radiosensitivity of NPC cells. The mechanistic studies based on RNA-sequencing analysis revealed that limonin inhibited the gene transcription driven by Stat3 (signal transducer and activator of transcription 3) and an activator of Stat3 (Colivelin or IL-6) rescued the inhibitory effects of limonin. Therefore, these results demonstrate that limonin could reduce the stemness of NPC cells and thus the radiosensitivity through suppressing Stat3 transcriptional activity., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Nasopharyngeal carcinoma (NPC) is the most common type of malignancy of the neck and head in Southeast Asia and North Africa. Long noncoding RNA (LncRNA) Differentiation antagonizing nonprotein coding RNA (DANCR) has been reported to exert oncogenic functions in various malignant tumors. However, whether DANCR is involved in NPC tumorgenesis and its underlying mechanisms are still unknown. In the current study, we investigated the expression and biological functions of DANCR in NPC cells and found that DANCR is highly expressed in NPC cells and IL-6 stimulation upregulates DANCR expression through an STAT3-dependent manner. Besides, DANCR knockdown attenuates IL-6-induced proliferation and invasion of NPC cells. Furthermore, DANCR specifically interacts with STAT3 to promote STAT3 activation in NPC cells. Moreover, DANCR knockdown evidently decreases IL-6 induced the association between STAT3 and JAK1 in NPC cells. In addition, we also found that DANCR also indirectly binds to JAK1 through interacting with STAT3 under IL-6 stimulation in NPC cells. Taken together, the present study for the first time demonstrates that DANCR, acting as an oncogene in NPC, promotes NPC progression by interacting with STAT3 and enhancing JAK1 binding to STAT3 to strengthen IL-6/JAK1/STAT3 signaling, suggesting that it may be a potential target to be used as a novel strategy to develop NPC therapeutics., (Copyright © 2019. Published by Elsevier Masson SAS.)

The incidence of nasopharyngeal carcinoma (NPC) in China is relatively higher than that throughout the rest of the world, and NPC is geographically distributed. Long non-coding RNA (lncRNA) plays a key role in the development of tumors. Recent studies have found that the lncRNA Ewing sarcoma-associated transcript 1 (EWSAT1) is highly expressed in various tumors and also in NPCs. The isoflavone calycosin, which is a typical Chinese herbal medicine, can inhibit the growth of breast cancer, colorectal cancer, osteosarcoma and other cancers. The aim of our study was to select NPCs that were sensitive to calycosin and whether calycosin had an effect on NPC cells. If it does, are the effects related to a high expression of EWSAT1? We also verified that EWSAT1 was highly expressed in NPC cells. At the same time, we found that calycosin inhibited the growth of NPC cell lines. To further determine whether the effect of calycosin on NPC cells was related to EWSAT1, we used NPC cells with different concentrations of calycosin and found that the expression of EWSAT1 decreased significantly with increasing concentrations of calycosin and that the expression of downstream factors and pathways were also affected. It was demonstrated that calycosin affected NPC cell growth by regulating EWSAT1 and its downstream pathway. In addition, we overexpressed EWSAT1 and found that the increased expression of EWSAT1 weakened the growth inhibitory effect of calycosin on NPC cells., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)