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G₁₂-Mediated Pathway Promotes Invasiveness of Nasopharyngeal Carcinoma by Modulating Actin Cytoskeleton Reorganization

¹ Graduate Institute of Life Sciences, National Defense Medical Center; Departments of ² Radiation Oncology and ³ Otolaryngology and Head and Neck Surgery, Tri-Service General Hospital, Taipei, Taiwan; Divisions of ⁴ Molecular and Genomic Medicine and ⁵ Biostatistics and Bioinformatics, National Health Research Institutes, Miaoli, Taiwan; and ⁶ Biomedical Engineering Department, Ming Chuan University, Taoyuan County, Taiwan

Requests for reprints: Jyh-Lyh Juang, Division of Molecular and Genomic Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan. Phone: 886-37-246-166, ext. 35308; Fax: 886-37-586-459; E-mail: Juang{at}nhri.org.tw.

Key Words: nasopharyngeal carcinoma • G₁₂ • IQGAP1 • metastasis • EMT

The molecular mechanisms behind the aggressiveness of nasopharyngeal carcinoma (NPC), a highly invasive and metastatic head and neck malignancy, have not been made clear. In this study investigating these mechanisms, guanine nucleotide-binding protein ₁₂ subunit (G₁₂) signaling was found by microarray analysis to be increased in primary NPC cells and NPC-derived cell lines. Using small interfering RNA to knock down G₁₂ in NPC cells resulted in a reduction in cell migration and invasion as well as a reversal in fibroblastoid morphology. Using microarray analysis, we also found a reduction in expression of key actin dynamics regulators and several epithelial-to-mesenchymal transition–related genes in G₁₂-depleted NPC cells. Knocking down one of those genes, IQ motif containing GTPase activating protein 1, reduced the migration and formation of adherens junctions and reversed the fibroblastoid morphology of NPC cells, as knocking down G₁₂ was found to do. Immunohistochemical analysis found NPC tumors to have significantly greater levels of G₁₂ protein than the normal basal epithelial cells. Quantitative real-time PCR analysis revealed a significant correlation between G₁₂ mRNA levels and NPC lymph node metastasis. Together, our findings support a model in which activation of G₁₂ signaling promotes tumorigenesis and progression of NPC by modulating actin cytoskeleton reorganization and expression of epithelial-to-mesenchymal transition–related genes. [Cancer Res 2009;69(15):6122–30]