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Functional Analysis of a Cell Cycle–Associated, Tumor-Suppressive Gene, Protein Tyrosine Phosphatase Receptor Type G, in Nasopharyngeal Carcinoma

¹ Department of Biology and Center for Cancer Research, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong (SAR), People's Republic of China; ² City of Hope, Beckman Research Institute, Department of Biology, Duarte, California; ³ Cancer Biology and Pharmacology, Genome Institute of Singapore, Biomedical Sciences Institutes, Singapore; ⁴ State Key Laboratory of Oncology in Southern China and Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China; ⁵ Department of Clinical Oncology and ⁶ Department of Anatomy, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China; ⁷ Department of Microbiology, Tumor and Cell Biology, 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.

Key Words: PTPRG • nasopharyngeal carcinoma • tumor suppressor gene • microcell-mediated chromosome transfer • microarray, pRB, cyclin D1

Functional studies to identify the potential role of a chromosome 3p14-21 gene, protein tyrosine phosphatase receptor type G (PTPRG), were performed. PTPRG was identified as a candidate tumor suppressor gene (TSG) in nasopharyngeal carcinoma (NPC) by differential gene profiling of tumorigenic and nontumorigenic NPC chromosome 3 microcell hybrids (MCH). Down-regulation of this gene was found in tumor segregants when compared with their corresponding tumor-suppressive MCHs, as well as in NPC cell lines and tumor biopsies. Promoter hypermethylation and loss of heterozygosity were found to be important mechanisms contributing to PTPRG silencing. PTPRG overexpression in NPC cell lines induces growth suppression and reduced anchorage-independent growth in vitro. This is the first study to use a tetracycline-responsive vector expression system to study PTPRG stable transfectants. Results indicate its ability to induce significant tumor growth suppression in nude mice under conditions activating transgene expression. These studies now provide functional evidence indicating critical interactions of PTPRG in the extracellular matrix milieu induce cell arrest and changes in cell cycle status. This is associated with inhibition of pRB phosphorylation through down-regulation of cyclin D1. These novel findings enhance our current understanding of how PTPRG may contribute to tumorigenesis. [Cancer Res 2008;68(19):8137–45]