Abstract 3006: The CCL28 oncogene in NPC pathogenesis.
Authors: Lin Chin-Tarng , Chen Yi-Ying , Wu Cheng-Der , Huang Dah-yeou , Kuo Yuan-Sung 
Published: August 2014

CCL28 Gene plays a role as an oncogene in the pathogenesis of Lymphoepitheliomatous Carcinoma of Nasopharynx

Nasopharyngeal Carcinoma (NPC) is one of the most common cancers among Chinese living in southern China, Hong Kong, Singapore and Taiwan. 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 a progression factor but not an initiation factor. 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. 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 Type III NPC biopsy specimens it was found that about 46% of cases revealed high expression of CCL28 protein in their tumor cells. To further identify the relationship between SOX5 and CCL28, 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 line. 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; furthermore, CCL28 could enhance IgA anti EBV-VCA production from the EBV infected-B 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, such as IFI6 (Interferon L-inducible Protein 6, a survival protein) up-regulated and some oncosuppressor genes such as GPR68 (a G-protein-couple receptor 68) (a tumor metastasis suppressor gene) down-regulated. It is concluded that CCL28 gene may play a role to promote the formation of LE-NPC and as an oncogene in NPC pathogenesis to promote LE-NPC migration, proliferation and invasion in addition to its chemotactic property to attract B cell migration and to enhance IgA anti EBV-VCA production from the EBV+ B cells.

Citation Format: Chin-Tarng Lin, Yi-Ying Chen, Cheng-Der Wu, Dah-yeou Huang, Yuan-Sung Kuo. The CCL28 oncogene in NPC pathogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3006. doi:10.1158/1538-7445.AM2013-3006