Nasopharyngeal carcinoma (NPC) is a unique epithelial malignancy arising from the superior aspect of the pharyngeal mucosal space, associated with latent Epstein-Barr virus infection in most cases. The capacity to characterize cancer genomes in unprecedented detail is now providing insights into the genesis and molecular underpinnings of this disease. Herein, we provide an overview of the molecular aberrations that likely drive nasopharyngeal tumor development and progression. The contributions of major Epstein-Barr virus-encoded factors, including proteins, small RNAs, and microRNAs, along with their interactions with pathways regulating cell proliferation and survival are highlighted. We review recent analyses that clearly define the role of genetic and epigenetic variations affecting the human genome in NPC. These findings point to the impact of DNA methylation and histone modifications on gene expression programs that promote this malignancy. The molecular interactions that allow NPC cells to evade immune recognition and elimination, which is crucial for the survival of cells expressing potentially immunogenic viral proteins, are also described. Finally, the potential utility of detecting host and viral factors for the diagnosis and prognosis of NPC is discussed. Altogether, the studies summarized herein have greatly expanded our knowledge of the molecular biology of NPC, yet much remains to be uncovered. Emerging techniques for using and analyzing well-annotated biospecimens from patients with NPC will ultimately lead to a greater level of understanding, and enable improvements in precision therapies and clinical outcomes.

Nasopharyngeal Cancer: Molecular Landscape

Abstract Head and neck cancer (HNC) is malignant, genetically complex and difficult to treat and is the sixth most frequent cancer, with tobacco, alcohol and human papillomavirus being major risk factors. Based on epigenetic data, HNC is remarkably heterogeneous, and treatment remains challenging. There is a lack of significant improvement in survival and quality of life in patients with HNC. Over half of HNC patients experience locoregional recurrence or distal metastasis despite the current multiple traditional therapeutic strategies and immunotherapy. In addition, resistance to chemotherapy, radiotherapy and some targeted therapies is common. Therefore, it is urgent to explore more effective and tolerable targeted therapies to improve the clinical outcomes of HNC patients. Recent targeted therapy studies have focused on identifying promising biomarkers and developing more effective targeted therapies. A well understanding of the pathogenesis of HNC contributes to learning more about its inner association, which provides novel insight into the development of small molecule inhibitors. In this review, we summarized the vital signaling pathways and discussed the current potential therapeutic targets against critical molecules in HNC, as well as presenting preclinical animal models and ongoing or completed clinical studies about targeted therapy, which may contribute to a more favorable prognosis of HNC. Targeted therapy in combination with other therapies and its limitations were also discussed. 

/pdf/targeted-therapy-for-head-and-neck-cancer-signaling-pathways-18kworv0.pdf

Targeted therapy for head and neck cancer: signaling pathways and clinical studies

Nasopharyngeal carcinoma (NPC) is a malignant epithelial carcinoma of the head and neck region which mainly distributes in southern China and Southeast Asia and has a crucial association with the Epstein–Barr virus. Based on epidemiological data, both incidence and mortality of NPC have significantly declined in recent decades grounded on the improvement of living standard and medical level in an endemic region, in particular, with the clinical use of individualized chemotherapy and intensity-modulated radiotherapy (IMRT) which profoundly contributes to the cure rate of NPC patients. To tackle the challenges including local recurrence and distant metastasis in the current NPC treatment, we discussed the implication of using targeted therapy against critical molecules in various signal pathways, and how they synergize with chemoradiotherapy in the NPC treatment. Combination treatment including targeted therapy and IMRT or concurrent chemoradiotherapy is presumably to be future options, which may reduce radiation or chemotherapy toxicities and open new avenues for the improvement of the expected functional outcome for patients with advanced NPC.

/pdf/advances-in-targeted-therapy-mainly-based-on-signal-pathways-34hcvrm3yw.pdf

Advances in targeted therapy mainly based on signal pathways for nasopharyngeal carcinoma.

Recent discoveries have led to the development of novel ideas and techniques that have helped elucidate the correlation between epigenetics and tumor biology. Nowadays, the field of tumor genetics has evolved to include a new type of regulation by epigenetics. An increasing number of studies have demonstrated the importance of DNA methylation and hydroxymethylation in specific genes in the progression of cervical cancer. Determining the methylation and hydroxymethylation profiles of these genes will help in the early prevention and diagnosis, monitoring recurrence, prognosis, and treatment of patients with cervical cancer. In this review, we focus on the significance of aberrant DNA methylation and hydroxymethylation in cervical cancer and the use of these epigenetic signatures in clinical settings.

DNA Methylation and Hydroxymethylation in Cervical Cancer: Diagnosis, Prognosis and Treatment.

Circular RNAs play an important role in tumor genesis and progression, but they have not been sufficiently studied in patients with nasopharyngeal carcinoma (NPC).The circular RNA, circCAMSAP1, was screened in NPC cells by RNA sequencing analysis. The expression of circCAMSAP1 in NPC tissues was examined by real-time quantitative polymerase chain reaction (RT-qPCR) and in situ hybridization. Wound-healing, transwell, MTT and flow cytometry assays, and nude mouse tumor models were used to explore the effect of circCAMSAP1 on proliferation and metastasis of NPC in vitro or in vivo. The downstream proteins regulated by circCAMSAP1 were screened using mass spectrometry. The interaction between circCAMSAP1 and the SERPINH1 mRNA was identified using the circular RNA immunoprecipitation method and the luciferase reporter assay. The interaction between SERPINH1 and transcription factor c-Myc was verified through Co-immunoprecipitation (Co-IP) and immunofluorescence. The effect of c-Myc on the generation of circCAMSAP1 was examined through RT-qPCR and chromatin immunoprecipitation. Finally, the splicing factors that promote the production of circCAMSAP1 were explored by RT-qPCR and RNA immunoprecipitation (RIP).We found that circCAMSAP1 was highly expressed in NPC tissues and promoted NPC proliferation and metastasis. Additionally, circCAMSAP1 promoted SERPINH1 expression through improved SERPINH1 mRNA stability by binding to the 3'-untranslated region (3'UTR) of SERPINH1. Highly expressed SERPINH1 reduced the ubiquitination-degradation rate of c-Myc, causing increased tumorigenesis. Meanwhile, c-Myc, cooperating with splicing factor 10 (SRSF10), could also promote CAMSAP1 pre-mRNA transcription and back-splicing, forming a positive feedback of circCAMSAP1 production, resulting in the proliferation and metastasis of NPC.Our findings revealed that circCAMSAP1 promotes NPC proliferation and metastasis by binding to the 3'UTR of SERPINH1, suggesting that the positive feedback of circCAMSAP1-SERPINH1-c-Myc may serve as a prognostic biomarker or therapeutic target in patients with NPC. 

/pdf/splicing-factor-derived-circular-rna-circcamsap1-accelerates-1y4uyayu.pdf

Splicing factor derived circular RNA circCAMSAP1 accelerates nasopharyngeal carcinoma tumorigenesis via a SERPINH1/c-Myc positive feedback loop

Aberrant activation of the Wnt/β-catenin signaling pathway is an important factor in the development of nasopharyngeal carcinoma (NPC). Previous studies have demonstrated that the developmental gene sex-determining region Y (SRY)-box 1 (SOX1) inhibits cervical and liver tumorigenesis by interfering with the Wnt/β-catenin signaling pathway. However, the role of SOX1 in NPC remains unclear. This study investigates the function of SOX1 in NPC pathogenesis. Down-regulation of SOX1 was detected in NPC cell lines and tissues. Besides, quantitative methylation-specific polymerase chain reaction revealed that SOX1 promoter was hypermethylated in NPC cell lines. Ectopic expression of SOX1 in NPC cells suppressed colony formation, proliferation and migration in vitro and impaired tumor growth in nude mice. Restoration of SOX1 expression significantly reduced epithelial-mesenchymal transition, enhanced cell differentiation and induced cellular senescence. Conversely, transient knockdown of SOX1 by siRNA in these cells partially restored cell proliferation and colony formation. Notably, SOX1 was found to physically interact with β-catenin and reduce its expression independent of proteasomal activity, leading to inhibition of Wnt/β-catenin signaling and decreased expression of downstream target genes. SOX1 decreases the expression of β-catenin in a proteasome-independent manner and reverses the malignant phenotype in NPC cells.

/pdf/sox1-down-regulates-b-catenin-and-reverses-malignant-n83dj6yzg2.pdf

SOX1 down-regulates β-catenin and reverses malignant phenotype in nasopharyngeal carcinoma.

OBJECTIVE To investigate the radiosensitizing effect and its mechanism of 3-MA in human hypopharynx cancer cells. METHODS 5 mmol/L of 3-MA combined with 2 Gy or 4 Gy of X-ray was utilized to deal with Fadu cells, and the cell livability (cloning efficiency) and DNA lesion severity (tail moment) of each groups was examined by clonogenic survival assay and comet assay, then differences were compared between groups by independent-sample T test. Fadu cells were then treated with different dose of 3-MA (1, 2, 5, 10 mmol/L), the alteration of cell cycle distribution was detected by flow cytometer, and differences among groups were analyzed through one-way analysis of variance. The expression of p62 and cyclinB1 in each group was examined by western blot. RESULTS The livability and DNA lesion severity of cells treated with 3-MA alone showed no notable variation. Compared with non-3-MA groups, the cloning efficiency of cells treated with 3-MA decreased much more after irradiated with 2 Gy or 4 Gy of X-ray (t = 13.41 or 13.98, P < 0.001), and the cells showed a more serious DNA lesion (t = 7.07 or 6.91, P < 0.001). The G2/M percentages of cells in the control group and groups treated with 1, 2, 5, 10 mmol/L of 3-MA were 17.10 ± 1.20, 23.30 ± 2.3, 39.90 ± 3.12, 58.47 ± 1.65, 76.13 ± 3.51 and differences among groups were statistically significant (F = 278.4, P < 0.05). The expression of p62 in cells treated with 3-MA showed a dose-dependent increase, while cyclinB1 showed a dose-dependent decrease. CONCLUSIONS The autophagy inhibitor 3-MA could enhance radiosensitivity of human hypopharynx cancer cells by inducing G2/M arrest and enhancing irradiation-induced DNA damage.

[Mechanism of radiosensitization of 3-methyladenine in human hypopharynx cancer cells].

CO2 transoral laser microsurgery for early glottic carcinoma with anterior commissure involvement.

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SOX1 down-regulates β-catenin and reverses malignant phenotype in nasopharyngeal carcinoma.

[Mechanism of radiosensitization of 3-methyladenine in human hypopharynx cancer cells].

CO2 transoral laser microsurgery for early glottic carcinoma with anterior commissure involvement.