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Epstein‐Barr virus (EBV) is a tumorigenic virus that can cause various human malignancies such as nasopharyngeal carcinoma (NPC) and gastric cancer (GC). EBV encodes 44 mature micro (mi)RNAs, mostly exhibiting oncogenic properties and promoting cancer progression. However, we have previously found that one EBV‐encoded miRNA, namely EBV‐miR‐BART6‐3p, acts as a tumor suppressor by inhibiting metastasis and invasion. Here, we report that EBV‐miR‐BART6‐3p inhibits the proliferation of EBV‐associated cancers, NPC, and GC, by targeting and downregulating a long non‐coding RNA (lncRNA), LOC553103. Through proteomics analysis, we determined that stathmin (STMN1) is affected by EBV‐miR‐BART6‐3p and LOC553103. Further, via RNA immunoprecipitation and luciferase reporter assay, we confirmed that LOC553103 directly binds and stabilizes the 3′UTR region of STMN1 mRNA. These results indicate that the EBV‐miR‐BART6‐3p/LOC553103/STMN1 axis regulates the expression of cell cycle‐associated proteins, which then inhibit EBV‐associated tumor cell proliferation. These findings provide potential targets or strategies for novel EBV‐related cancer treatments, as well as contributes new insights into the understanding of EBV infection‐related carcinogenesis. [ABSTRACT FROM AUTHOR]

Human SPLUNC1 can suppress nasopharyngeal carcinoma ( NPC) tumor formation; however, the correlation between SPLUNC1expression and NPC patient prognosis has not been reported. In the present study, we used a large-scale sample of 1015 tissue cores to detect SPLUNC1 expression and its association with patient prognosis. SPLUNC1 expression was reduced in NPC samples compared to nontumor nasopharyngeal epithelium tissues. Positive expression of SPLUNC1 in NPC predicted a better prognosis (disease-free survival, P = 0.034; overall survival, P = 0.048). Cox's proportional hazards model revealed that SPLUNC1 could be a significant prognostic factor affecting disease-free survival ( P = 0.027). A c DNA micro-array analyzed by significant analysis of micro-array (SAM) and ingenuity pathway analysis (IPA) revealed that an indirect interaction existed between SPLUNC1 and retinoic acid (RA) in the cancer regulatory network. To further investigate the molecular mechanisms involved, we utilized several bioinformatics tools and identified 12 retinoid X receptors heterodimer binding sites in the promoter region of the SPLUNC1 gene. The transcriptional activity of the SPLUNC1 promoter was up-regulated significantly by all-trans-retinoic acid ( ATRA). SPLUNC1 and retinoic acid receptor expression were induced significantly by ATRA, and removal of ATRA led to a progressive loss of SPLUNC1 and retinoic acid receptor expression. ATRA inhibited proliferation and induced the differentiation of NPC cells. Interestingly, over-expression of SPLUNC1 sensitized NPC cells to ATRA, whereas knockdown of SPLUNC1 in HNE1 cells increased cell viability. Under SPLUNC1 knockdown conditions, differentiation was reversed by ATRA treatment. We concluded that SPLUNC1 could potentially predict prognosis for NPC patients and play an important role in ATRA-induced growth inhibition and differentiation in NPC cells. [ABSTRACT FROM AUTHOR]

Epstein‐Barr virus (EBV) infection leads to cancers with an epithelial origin, such as nasopharyngeal cancer and gastric cancer, as well as multiple blood cell‐based malignant tumors, such as lymphoma. Interestingly, EBV is also the first virus found to carry genes encoding miRNAs. EBV encodes 25 types of pre‐miRNAs which are finally processed into 44 mature miRNAs. Most EBV‐encoded miRNAs were found to be involved in the occurrence and development of EBV‐related tumors. However, the function of EBV‐miR‐BART12 remains unclear. The findings of the current study revealed that EBV‐miR‐BART12 binds to the 3'UTR region of Tubulin Polymerization‐Promoting Protein 1 (TPPP1) mRNA and downregulates TPPP1, thereby promoting the invasion and migration of EBV‐related cancers, such as nasopharyngeal cancer and gastric cancer. The mechanism underlying this process was found to be the inhibition of TPPP1 by EBV‐miRNA‐BART12, which, in turn, inhibits the acetylation of α‐tubulin, and promotes the dynamic assembly of microtubules, remodels the cytoskeleton, and enhances the acetylation of β‐catenin. β‐catenin activates epithelial to mesenchymal transition (EMT). These two processes synergistically promote the invasion and metastasis of tumor cells. To the best of our knowledge, this is the first study to reveal the role of EBV‐miRNA‐BART12 in the development of EBV‐related tumors as well as the mechanism underlying this process, and suggests potential targets and strategies for the treatment of EBV‐related tumors. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC) is a unique EBV‐associated subtype of head and neck cancer, which has the highest incidence in Southern China and eastern South Asia. The interaction between genetic risk factors and environmental challenge, have been considered to contribute to the development of nasopharyngeal carcinogenesis. Constitutive activation of NF‐κB signaling has been seen in NPC tissues and is associated with unfavorable prognosis. Recently, several whole exome sequencing study consistently revealed that high frequency mutations of NF‐κB pathway negative regulators is common in nasopharyngeal carcinoma, which reinforce the importance of NF‐κB driving oncogenesis. This review focuses on the current state of research in role of NF‐κB in NPC carcinogenesis. We summarized the newly identified loss of function (LOF) mutations on NF‐κB negative regulators leading to it's activation bypass LMP‐1 stimulation. We discussed the critical role of NF‐κB activation in immortalization and transformation of nasopharygeal epithelium. We also depicted how NF‐κB signaling mediated chronic inflammation contribute to persistent EBV infection, immune evasion of EBV infected cells, metabolic reprogramming, and cancer stem cells (CSCs) formation in NPC. Lastly, we discussed the clinical resonance of targeting NF‐κB for NPC precise therapy. [ABSTRACT FROM AUTHOR]