Nasopharyngeal carcinoma (NPC) is a head and neck cancer arising from nasopharynx epithelium. It differs from other cancer types due to a very unique pattern of geographical and ethnic distribution. Every year, most of the new NPC cases were reported in east and southeast parts of Asia. Cantonese population in southern China shows around 10-20 fold higher incidence rate of NPC than the rest of the world. It has been proposed that genetic susceptibility, environmental exposure to carcinogens as well as early infection by Epstein-Barr virus (EBV) are three major etiological factors related to NPC development.

MicroRNA deregulation is involved in the initiation and progression of human cancers. In this study, I tried to uncover those microRNAs with tumor suppressive functions but s...[ Read more ]

Nasopharyngeal carcinoma (NPC) is a head and neck cancer arising from nasopharynx epithelium. It differs from other cancer types due to a very unique pattern of geographical and ethnic distribution. Every year, most of the new NPC cases were reported in east and southeast parts of Asia. Cantonese population in southern China shows around 10-20 fold higher incidence rate of NPC than the rest of the world. It has been proposed that genetic susceptibility, environmental exposure to carcinogens as well as early infection by Epstein-Barr virus (EBV) are three major etiological factors related to NPC development.

MicroRNA deregulation is involved in the initiation and progression of human cancers. In this study, I tried to uncover those microRNAs with tumor suppressive functions but silenced in NPC. Through Taqman qPCR-based microRNA microarray screening, I found two microRNAs, miR-376a and miR-708, that were downregulated in both NPC-derived cell lines and in a large fraction of NPC biopsies. I found that miR-376a was silenced in NPC mainly by promoter hypermethylation, whereas mR-708 was silenced by other mechanisms including histone modifications. I found that re-expression of miR-376a and miR-708 in NPC cell lines suppressed cell growth and migration in cell culture models. Moreover, over-expression of miR-708 in NPC cells was found to induce apoptosis. In addition, I also found that miR-376a and miR-708 overexpressing stable NPC cells could hardly form solid tumor in nude mice. At the molecular levels, I found that EZRIN and MYC serve as direct targets of miR-376a, while IKK2 serves as the target of miR-708. All three target proteins have known oncogenic properties and are known to be associated with various cancers. Thus, my work demonstrated that both miR-376a and miR-708 are tumor suppressive miRNAs that are downregulated in NPC.

EBV-encoded latent infection membrane protein 1 (LMP1) is known to have oncogenic properties and is indispensable for EBV-induced human B cell transformation. When expressed in host cells, LMP1 potently activates both mitogen-activated protein kinase pathways and NF-kappaB pathways. Two critical regions, namely CTAR1 and CTAR2, of the carboxyl-terminus of LMP1 are responsible for its signaling effects. LMP1 activates both canonical and non-canonical NF-kappaB pathways. Previous work done by us and others has identified the key signaling molecules involved in the LMP1-induced canonical NF-kappaB pathway. However, it remains unclear how LMP1 activates the non-canonical NF-kappaB pathway. Here, I demonstrated that LMP1 utilizes both CTAR1 and CTAR2 domains to activate the pathway by differentially targeting TRAF2, TRAF3, and cIAPs, all being known critical negative regulators of NIK, a key upstream kinase in the non-canonical NF-kappaB pathway. Firstly, LMP1 disrupts the stable complex between TRAF2-cIAPs and TRAF3-NIK by competing for binding to TRAF2 and TRAF3 respectively. Secondly, LMP1 promotes rapid cIAP degradation via both autophagy- and proteasome-dependent mechanisms with the former being the predominant mechanism. As inappropriate activation of the non-canonical NF-kappB pathway is known to contribute to human malignancies, my work helps explain the oncogenic properties of LMP1.