Nasopharyngeal carcinoma--review of the molecular mechanisms of tumorigenesis

Abstract

Nasopharyngeal carcinoma (NPC) is a head and neck cancer rare throughout most of the world but common in certain geographic areas, such as southern Asia. While environmental factors and genetic susceptibility play important roles in NPC pathogenesis, the Epstein-Barr virus in particular has been implicated in the molecular abnormalities leading to NPC. There is upregulation of cellular proliferation pathways such as the Akt pathway, mitogen-activated protein kinases, and the Wnt pathway. Cell adhesion is compromised due to abnormal E-cadherin and beta-catenin function. Aberrations in cell cycle are due to dysregulation of factors such as p16, cyclin D1, and cyclin E. Anti-apoptotic mechanisms are also upregulated. There are multiple abnormalities unique to NPC that are potential targets for novel treatments.

FIGURE 1

Overview of the molecular mechanisms involved in nasopharyngeal carcinoma (NPC) development. 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-κB and β-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). 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., Stimulatory effect; , inhibitory effect; orange color indicates apoptosis regulators; light blue color indicates cell adhesion proteins; yellow color indicates cell cycle regulators; dark blue color indicates proliferative pathways; green color indicates transcription factors; purple color indicates tumor suppressors; EGFR, epidermal growth factor receptor; ERK, extracellular signal related kinase; JNK, c-Jun N-terminal kinase; LMP1, latent membrane protein 1; MMP, matrix metalloproteinase; NPC, nasopharyngeal carcinoma; PTEN, phosphatase and tensin homolog; PI3K, phosphoinositol-3-kinase; RASSF, Ras association domain family; WIF, Wnt inhibitory factor; WT p53, wild-type p53. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

FIGURE 2

Mechanisms of Epstein-Barr virus (EBV) latent proteins in nasopharyngeal carcinoma (NPC) development. NPC tumorigenesis depends on the activity of latent proteins LMP1 and 2 and EBNA 1 and 2. The majority of cancer development is propagated by LMP1, which is responsible for the activation of various molecular pathways (see Figure 1) and immune evasion. LMP1 is regulated positively by LMP2 and negatively by EBNA 2. The other functions of LMP2 include mediation of tumor cell survival and invasion. Finally, EBNA 1 is critical for viral DNA partitioning during replication. , Stimulatory effect; , inhibitory effect; LMP, latent membrane protein; EBNA, EBV-determined nuclear antigen. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]