PATHOGENESIS

Epstein Barr Virus has tumorigenic potential due to a unique set of latent genes. Latent genes
predominantly expressed in NPC are latent membrane proteins (LMP1, LMP2A, and LMP2B)
and EBV-determined nuclear antigens (EBNA1 and EBNA2).1 The principal oncogene, LMP1 is
required for cell immortalization and is present in 80%to 90%of NPC tumors. LMP1 molecule
directly activate a number of signaling pathways including nuclear factor kappa-Beta (NF-B),
mitogen-activated protein (MAP) kinases, and phosphoinositol-3-kinase (PI3K).2 Although the
basic role of LMP1 is to prevent apoptosis, it also involved in suppressing immunogenic
responses against NPC; for example, LMP1 has intrinsic T-cell inhibitory properties and
mediates downregulation of CD99, an important component of the anti-NPC immune response.
LMP1-positive cells have greater mobility, leading to higher metastatic potential and faster
disease progression.3,4 The importance of LMP1 in tumorigenesis is illustrated by inhibition of
LMP1 results in increased tumor cell sensitivity to chemotherapy.57 Less is known about LMP2
and EBNA than LMP1. LMP2A downregulates the NF-B transcription factor and can decrease
LMP1 expression. Additionally, LMP2A expression causes NPC cells to become migratory and
invasive.8,9 EBNA1 binds the EBV genome to host chromosomes, and mediates equal
partitioning of viral DNA into daughter cells.1,10

Figure 2. Mechanisms of Epstein-Barr virus (EBV) latent proteins in

nasopharyngeal carcinoma (NPC) development.1
NPC development begins with the upregulation of pathways that promote cellular proliferation:
Akt pathway, mitogen-activated protein kinases (JNK, ERK), Wnt pathway, and EGFR
signaling. Subsequent increases of transcription factors such as NF-B and -catenin lead to
cellular proliferation via cell cycle dysregulation (high c-myc, cyclin D1, and cyclin E
expression) and inhibition of tumor suppressors (p16,p27, and wild-type p53). NF-kappa-beta
which is overexpressed in almost all NPC leads to a plethora of cellular effects, affecting among
other things proliferation and apoptosis. In addition, cell adhesion abilities are compromised
because of low E-cadherin levels and high expression of MMPs. Also, antiapoptotic mechanisms
such as bcl-2, survivin, and telomerase are upregulated.1

Regarding tumor suppressors, increased levels of p53 are present in NPC cells and high p53
levels correlate with high LMP1 levels. However, TP53 mutations are relatively rare in NPC and
the majority of expressed p53 is wild type. Importantly, the wild-type p53 in NPC fail to induce
apoptosis and this is believed to be due to low levels of p14 (via promoter hypermethylation) and
excessN-p63 (a mutated version of p63).11,12

Figure 101. Overview molecular mechanis of nasopharyngeal carcinoma

1. Chou J, Lin Y-C, Kim J, et al. NASOPHARYNGEAL CARCINOMAREVIEW OF

 THE MOLECULAR MECHANISMS OF TUMORIGENESIS. Head Neck.
2008;30(7):946-963. doi:10.1002/hed.20833.

2. Mainou BA, Raab-Traub N. LMP1 Strain Variants: Biological and Molecular Properties. J
Virol. 2006;80(13):6458-6468. doi:10.1128/JVI.00135-06.

3. Ozyar E, Ayhan A, Korcum AF, Atahan IL. Prognostic role of Ebstein-Barr virus latent
membrane protein-1 and interleukin-10 expression in patients with nasopharyngeal
carcinoma. Cancer Invest. 2004;22(4):483-491.
http://www.ncbi.nlm.nih.gov/pubmed/15565804. Accessed March 12, 2017.

4. Liu L-T, Peng J-P, Chang H-C, Hung W-C. RECK is a target of EpsteinBarr virus latent
membrane protein 1. Oncogene. 2003;22(51):8263-8270. doi:10.1038/sj.onc.1207157.

5. Keryer-Bibens C, Pioche-Durieu C, Villemant C, et al. Exosomes released by EBV-

infected nasopharyngeal carcinoma cells convey the viral latent membrane protein 1 and
the immunomodulatory protein galectin 9. BMC Cancer. 2006;6:283. doi:10.1186/1471-
2407-6-283.

6. Mei Y-P, Zhou J-M, Wang Y, et al. Silencing of LMP1 Induces Cell Cycle Arrest and
Enhances Chemosensitivity Through Inhibition of AKT Signaling Pathway in EBV-
Positive Nasopharyngeal Carcinoma Cells. Cell Cycle. 2007;6(11):1379-1385.
doi:10.4161/cc.6.11.4274.

7. Kim HS, Kim JS, Kim JS, et al. The association between CD99 and LMP-1 expression in
nasopharyngeal carcinoma. Exp Oncol. 2006;28(1):40-43.
http://www.ncbi.nlm.nih.gov/pubmed/16614706. Accessed March 12, 2017.

8. Stewart S, Dawson CW, Takada K, et al. Epstein-Barr virus-encoded LMP2A regulates

viral and cellular gene expression by modulation of the NF-kappaB transcription factor
pathway. Proc Natl Acad Sci U S A. 2004;101(44):15730-15735.
doi:10.1073/pnas.0402135101.

9. Pegtel DM, Subramanian A, Sheen T-S, Tsai C-H, Golub TR, Thorley-Lawson DA.
Epstein-Barr-virus-encoded LMP2A induces primary epithelial cell migration and
invasion: possible role in nasopharyngeal carcinoma metastasis. J Virol.
 2005;79(24):15430-15442. doi:10.1128/JVI.79.24.15430-15442.2005.

10. Yates JL, Warren N, Sugden B. Stable replication of plasmids derived from Epstein-Barr
virus in various mammalian cells. Nature. 313(6005):812-815.
http://www.ncbi.nlm.nih.gov/pubmed/2983224. Accessed March 12, 2017.

11. Kwong J, Lo K-W, To K-F, Teo PML, Johnson PJ, Huang DP. Promoter hypermethylation
of multiple genes in nasopharyngeal carcinoma. Clin Cancer Res. 2002;8(1):131-137.
http://www.ncbi.nlm.nih.gov/pubmed/11801549. Accessed March 12, 2017.

12. Crook T, Nicholls JM, Brooks L, ONions J, Allday MJ. High level expression of N-p63:
a mechanism for the inactivation of p53 in undifferentiated nasopharyngeal carcinoma
(NPC)? Oncogene. 2000;19(30):3439-3444. doi:10.1038/sj.onc.1203656.