Nasopharyngeal Carcinoma (NPC) is one of the most common cancers among Chinese living in southern China, Hong Kong, Singapore and Taiwan. The cause of the disease is quite complex, and the molecular mechanisms involved in the pathogenesis of NPC still are not yet well defined. Although it was proposed that Epstein-Barr virus (EBV) is closely associated with NPC pathogenesis, but recently many studies have reported that EBV behaves more likely as progression factors but not initiation factors. The purpose of this research was to find out the genes associated with NPC pathogenesis. Using cDNA microarray analysis of mRNA expression between NPC cell lines and normal nasal mucosal epithelial cells, SOX5 gene expression was found significantly increased in NPC cell lines by quantitative RT-PCR and Western blot analysis. In our previous studies of the function of SOX-5 gene in NPC, we found that Chemokine (CC motif) of ligand 28 (CCL28) was also significantly increased in NPC cell lines, especially in NPC-TW03 line which is a lymphoepitheliomatous carcinoma of nasopharynx (LE-NPC). In 50 cases of LE-NPC biopsy specimens we found that about 46% of cases revealed high expression of CCL28 protein in some tumor cells. To further identify the relationship between SOX5 and CCL28, we performed some investigation to clarify this condition. We found that SOX5 and CCL28 gene expressions could be reciprocally regulated in NPC cells and suggested that CCL28 may be a critical factor for the formation of LE-NPC. To study the role of CCL28 in the molecular pathogenesis of LE-NPC and its functions, we constructed a stable pBIG2i-CCL28 transfected NPC cell lines. We found that tumor cells could be up-regulated to express CCL28 mRNA and protein remarkably in those transfectants. This gene could promote tumor cell migration, proliferation, invasion, and attract lymphocytes especially B cells in vitro. In addition, EBV-immortalized B cells can also be attracted by CCL28. On the other hand, EBV could infect the CCL28 transfectants and replicate in the cells. However, in SCID mice bearing CCL28 transfected NPC xenograft, the tumor growth and metastatic activity were slightly to moderately increased by this gene, but it has failed to attract mouse lymphocytic infiltration, probably due to the dissimilarity of CCL28 molecular structure between human and mouse species. Also, cDNA microarray analysis of CCL28 overexpressed NPC cells showed a group of oncogenes up-regulated and some oncosuppressor genes down-regulated. It is concluded that CCL28 gene may play a role to promote the formation of lymphoepitheliomatous carcinoma of nasopharynx (LE-NPC) and as an oncogene in NPC pathogenesis to promote LE-NPC migration, proliferation and invasion in addition to it chemotactic property.