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TSLC1 Is a Tumor Suppressor Gene Associated with Metastasis in Nasopharyngeal Carcinoma

¹ Department of Biology and Center for Cancer Research, Hong Kong University of Science and Technology, Kowloon, Hong Kong (SAR), People's Republic of China; The Departments of ² Clinical Oncology and ³ Anatomy, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China; ⁴ State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University, Guangzhou, People's Republic of China; ⁵ Genetics Branch, National Cancer Institute, National Naval Medical Center, Bethesda, Maryland; ⁶ Tumor Suppression and Functional Genomics Project, National Cancer Center Research Institute, Tokyo, Japan; ⁷ Microbiology and Tumor Biology Center, Center for Genomics and Bioinformatics, Karolinska Institute, Stockholm, Sweden; and ⁸ Department of Microbiology and Molecular Genetics, University of California, Irvine, California

Requests for reprints: Maria Li Lung, Department of Biology, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong (SAR), People's Republic of China. Phone: 852-2358-7307; Fax: 852-2358-1559; E-mail: bomaria{at}ust.hk.

In up to 87% of nasopharyngeal carcinoma (NPC) clinical tumor specimens, there was either down-regulation or loss of TSLC1 gene expression. Using a tissue microarray and immunohistochemical staining, the frequency of down-regulated or loss of expression of TSLC1 in metastatic lymph node NPC was 83% and the frequency of loss of expression of TSLC1 was 35%, which was significantly higher than that in primary NPC (12%). To examine the possible growth-suppressive activity of TSLC1 in NPC, three NPC cell lines, HONE1, HNE1, and CNE2, were transfected with the wild-type TSLC1 gene cloned into the pCR3.1 expression vector; a reduction of colony formation ability was observed for all three cell lines. A tetracycline-inducible expression vector, pETE-Bsd, was also used to obtain stable transfectants of TSLC1. There was a dramatic difference between colony formation ability in the presence or absence of doxycycline when the gene is shut off or expressed, respectively, with the tetracycline-inducible system. Tumorigenicity assay results show that the activation of TSLC1 suppresses tumor formation in nude mice and functional inactivation of this gene is observed in all the tumors derived from tumorigenic transfectants. Further studies indicate that expression of TSLC1 inhibits HONE1 cell growth in vitro by arresting cells in G₀-G₁ phase in normal culture conditions, whereas in the absence of serum, TSLC1 induced apoptosis. These findings suggest that TSLC1 is a tumor suppressor gene in NPC, which is significantly associated with lymph node metastases. (Cancer Res 2006; 66(19): 9385-92)