Mechanisms of cell immortalization mediated by EB viral activation of telomerase in nasopharyngeal carcinoma

Abstract

Nasopharyngeal carcinoma (NPC) is a common cancer in Southern China and Southeast Asia. The disease is a poorly differentiated carcinoma without effective cure, and the mechanism underlying its development remains largely unknown. Of several factors identified in NPC aetiology in recent years, Epstein-Barr virus (EBV) infection has emerged to be most important. In almost all NPC cells, EBV uses several intracellular mechanisms to cause oncogenic evolution of the infected cells. One such mechanism by which EBV infection induces cellular immortalization is believed to be through the activation of telomerase, an enzyme that is normally repressed but becomes activated during cancer development. Studies show that greater than 85% of primary NPC display high telomerase activity by mechanisms involving EBV infection, consistent with the notion that EBV is commonly involved in inducing cell immortalization. More recently, different EBV proteins have been shown to activate or inhibit the human telomerase reverse transcriptase gene, by modulating intracellular signalling pathways. These findings suggest a new model with a number of challenges towards our understanding, molecular targeting and therapeutic intervention in NPC.

Estrogen deficiency leads to telomerase inhibition, telomere shortening and reduced cell proliferation in the adrenal gland of mice

“…Recently, studies have shown that estrogen stimulates the activity of the enzyme telomerase and gene expression of telomerase reverse transcriptase (TERT) in cancer cell cultures (reviewed in [4,5]). Telomerase is required to maintain the structures of chromosomal ends (telomeres) for continuous cell division in human embryonic development and cancer (reviewed in [6][7][8]). Telomerase interacts with telomeric DNA and other telomere binding proteins, catalyzing telomeric DNA reverse transcription to lengthen telomeres and capping the telomere ends [9][10][11].…”

DNA Epstein-Barr virus (EBV) sebagai biomaker diagnosis karsinoma nasofaring

“…5 NPC merupakan tumor endemis di Asia Selatan terutama pada pria dan sangat jarang ditemui di bagian lain dunia. Predileksi umur dekade 5, 6, dan 7 meskipun dapat pula terjadi pada dekade 2 dan 3.…”

“…5,6 Terpapar banyak karsinogen lingkungan berperan dalam kecenderungan peningkatan insiden kanker. 9 Penelitian patogenesis NPC yang telah dilakukan akhir-akhir ini bertujuan untuk mengetahui peran kombinasi faktor lingkungan dan genetik dan dinyatakan bahwa ada hubungan antara profil human leukocyte antigen (HLA) pada populasi Cina yang mengindikasikan kerentanan genetik.…”

“…Penelitian membuktikan bahwa >85% NPC primer menunjukkan aktivitas telomerase yang tinggi melalui mekanisme yang terlibat dalam infeksi EBV yang menyebabkan immortalitas sel. 5 Infeksi EBV ditemukan pada karsinoma in situ nasofaring yang diduga merupakan lesi prekursor dari NPC. Penemuan ini menyatakan bahwa infeksi EBV terjadi sebelum pertumbuhan invasif dimulai.…”

Potential Therapeutic Molecular Targets for Nasopharyngeal Carcinoma

“…EBNA2 has been shown to be able to functionally replace the intracellular region of Notch in the regulation of gene expression of B cells by targeting CBF1 and localizing the coactivators p300, PCAF, and CBP to the promoter (109,122,250,280,306,321). In normal cells, CBF-1 is bound by Notch to regulate the expression of cellular genes involved in cell proliferation (14,187). Lee et al have demonstrated that like Notch, EBNA2 can block orphan nuclear receptor Nur77-mediated apoptosis through interaction between its amino acids 123-147 conserved domain and Nur77 (158).…”