SIMULTANEOUSLY BOTH EXPRESSION OF LMP-1 AND METHYLATION OF E-CADHERIN: MOLECULAR BIOMARKER IN STAGE IV OF NASOPHARYNGEAL CARCINOMA PATIENTS
Lao TD1, Truong PK1, Thieu HH1, Nguyen DH2, Nguyen MT3, Le TAH1,*
*Corresponding Author: Associate Professor Thuy A.H. Le, Department of Pharmaceutical and Medical Biotechnology, Ho Chi Minh City Open University, 35-37 Ho Hao Hon Street, Ho Chi Minh City, Vietnam. Tel.: +84-905-784-471. E-mail: thuy.lha@ou.edu.vn
page: 57

DISCUSSION

In this study, we pointed out the significantly high expression of LMP-1 in NPC biopsy samples, accounting for 76.34%, compared to no expression in non-cancerous samples. The increased expression of LMP-1 was strongly associated with NPC risk, with statistical significance, based on the calculated OR value of 638.73 (p <0.05). Thus, all these results imply that the oncogenic role of LMP-1 in NPC was well evaluated in this case/control. According to the etiological factor, as previously reported, LMP-1 is an integral membrane protein that plays a key role in EBV-mediated oncogenesis involved in many signal pathways, including nuclear factor-κ-light-chain-enhancer of activated B cells (NF-κB), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein (MAP) pathway [20-22]. Moreover, LMP-1 is capable of inducing a range of phenotypic changes in epithelial cells [23]. In the latent stage of NPC, the expression of LMP-1 are expressed in EBV-associated malignant type II, exemplified by NPC, contribute to cell survival, and NPC metastasis [11,24]. Thus, the LMP-1 gene, which encoded the LMP-1 protein, performed the oncogenic function in the case of EBVassociated malignancies, including NPC, has been identified as the meaningful diagnosis biomarker as well as potential therapeutic molecule target for NPC. Additionally, the finding of LMP-1 characteristics was again confirmed in the current case-control study, and it may open up the treatment approach for NPC therapy based on the inhibitor of LMP-1 expression in EBV-associated NPC. The inactivation of the E-cadherin gene through the methylation of its promoter has been postulated as the metastasis-associated factor of NPC development and progression [14-17,25]. In this study, the methylation of the E-cadherin gene was examined by the nested-MSP method, which shows an advantage in the hypermethylation analysis by increased MSP sensitivity of approximately 50-fold [26]. Here, we found that the hypermeth-ylation of the E-cadherin gene promoter in 73.12% NPC biopsy samples, which was significantly higher than in control samples, accounting for 30.00%. This frequency of methylated E-cadherin gene in the current study was similar to that previously reported by Niemhom et al. [15], Ayadi et al. [16], and higher than the study by Ran et al. [17]. Even though the differences in E-cadherin methylation frequencies exist, they met the common point where the methylation of the E-cadherin gene was significantly associated with the risk of NPC based on the calculated OR (OR >1.0, p <0.05). Therefore, we believe that the aberrant methylation of the E-cadherin gene is significant in NPC and may serve as the promising biomarker that could be potentially used for diagnosis of NPC. To answer whether or not there was the association between the expression of LMP-1 and methylation of E-cadherin in NPC tumorigenesis, the statistical analysis was performed between the expression of LMP-1 and E-cadherin methylation in 93 clinical NPC biopsy samples. Our results reported that there was strongly correlation between the LMP-1 expression and E-cadherin methylation in NPC samples (p <0.0001). Especially, the status of both gene positive was significantly associated with the stage of NPC, in which the highest frequency of 37.63% (35 of 93) NPC samples were positive for both LMP-1 expression and methylation of E-cadherin was observed. Additionally, in the stage IV, we found that in case of LMP-1-positive samples, 35 cases of 37 samples (counting for 94.60%) were positive for methylation of E-cadherin. Whereas, we found that 7 of 15 cases (counting for 46.67%), 19 of 33 cases (counting for 57.58%) in the stage II and stage 4, respectively, were positive for both genes. Therefore, it could be concluded that the expression of LMP-1 and methylation of E-cadherin are more likely to be positive in the stage IV than the early stage of NPC. Based on these finding, it could be induced that the expression of LMP-1, which profound effects on the proliferation of NPC cells as well as the highly invasive, malignant growth of NPC tumors, and addition of epigenetics change, methylation of E-cadherin, a main key mediator of cell-cell adhesion, are likely to be a major contributing factor to the advance stage of nasopharyngeal tumor. These finding was similar to pervious study, the LMP-1 have an ability to down regulation of expression of E-cadherin through the pathway of E-cadherin/β-catenin, in our study the inactivation of E-cadherin caused by the epigenetics event, resulting in enhancement of invasive capacity of metastasis of NPC cells [27]. E-cadherin, which is the important factor responsible for the development and metastasis of nasopharyngeal tumor, may combine to act in a complex sequential process of nasopharyngeal tumorigenesis that culminates in metastasis of EBV-infected tumor cells. Therefore, these combination testing will be used as a parameter in the diagnosis of NPC in further studies. In this study, the E-cadherin gene has been reported to be a candidate therapeutic target in human cancers, such as hepatocellular carcinoma [28], nasopharyngeal cancer [17], breast cancer [29]. Especially, growing evidence supported epigenetics drug (epi-drug) has been generated and developed to explore the epigenetics reversion to treat human cancers. Giving the example, the inhibitors of DNA meth-ylation drugs, such as 5-azacytidine, 5-aza-2-deoxycytidine, etc. acts as a potent inhibitor of the DNA demeth-ylase, enzymes that catalyze the process of DNA methylation [30]. In other study, they reported that 5-aza-2-deoxycytidine could restore the E-cadherinsilenced lung cancer and metastasis of cancer cell [31]. Concerning to viral therapy, as reported, LMP-1 gene, and its encoded protein play an oncogenic role in NPC, including the proliferation as well as the metastasis of NPC cells, whereby evidence of its expression can only be inferred by its inhibition being detrimental to the growth of the cell, therefore, LMP1 may be a value therapeutic molecule target in the treatment of EBV associated disease, including NPC [32]. Therefore, the re-activation of E-cadherin, especially combined with viral therapy, will be a candidate therapeutic target in NPC. This study is believed to show the relationship between LMP-1 expression, E-cadherin gene methylation reinforced the basis for pursuing LMP1 and E-cadherin as a therapeutic molecule target in NPC. As reported, the striking different expression of LMP-1 and aberrant methylation of E-cadherin, therefore, towards to activation of tumor suppressive E-cadherin and/ or inhibition of oncogenic LMP-1 expression may open up the molecule-biomarker for the development of therapeutics for NPC. This suggested a clinical trial could be performed on the group of NPC patients with advance stage to improve their survival and recovery. Therefore, it is necessary to design such a study to consider the effect treatment on two criteria described above by the treatment which focused on each molecular target or both targets. Conclusions. Our data indicated that the LMP-1 expression and E-cadherin methylation were significantly correlated with the risk of NPC. The frequency of LMP-1 expression and E-cadherin methylation were higher in NPC biopsy samples, counting for 76.34% and 73.12%, respectively, compared to non-cancerous samples. Additionally, the strong association between the LMP-1 expression and E-cadherin methylation was observed in NPC samples. The status of both gene positive was sig nificantly associated with the stage of NPC, in which the highest frequency of 37.63% (35 of 93) NPC samples were positive for both LMP-1 expression and methylation of E-cadherin, was reported. In summary, the authors of this paper demonstrated that the relationship between LMP-1 expression, E-cadherin gene methylation reinforced the basis for pursuing LMP1 and E-cadherin as a molecule biomarker in NPC. Acknowledgments. We wish to express our thanks to the research project sponsored by Ho Chi Minh City Department of Science and Technology, Vietnam; Ho Chi Minh City Open University, Vietnam. We also thank all the recruited participants in this work and all the staff members of Otorhinolaryngology in Cho Ray Hospital, Ho Chi Minh City, for collecting the samples used in these studies. Declaration of Interest. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. Funding. This project is funded by Ho Chi Minh City Department of Science and Technology [Grant No. 42/2017/HD-SKHCN] and Ho Chi Minh City Open University [Grant No. 2018.02.1].



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