G(alpha)12-mediated pathway promotes invasiveness of nasopharyngeal carcinoma by modulating actin cytoskeleton reorganization.
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 alpha(12) subunit (G(alpha)(12)) 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 G(alpha)(12) 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 G(alpha)(12)-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 G(alpha)(12) was found to do. Immunohistochemical analysis found NPC tumors to have significantly greater levels of G(alpha)(12) protein than the normal basal epithelial cells. Quantitative real-time PCR analysis revealed a significant correlation between G(alpha)(12) mRNA levels and NPC lymph node metastasis. Together, our findings support a model in which activation of G(alpha)(12) signaling promotes tumorigenesis and progression of NPC by modulating actin cytoskeleton reorganization and expression of epithelial-to-mesenchymal transition-related genes. =
Liu
Shu-Chen
SC
Department of Radiation Oncology, Graduate Institute of Life Sciences, National Defense Medical Center, Tri-Service General Hospital, Taipei, Taiwan.
Jen
Yee-Min
YM
Jiang
Shih Sheng
SS
Chang
Junn-Liang
JL
Hsiung
Chao A
CA
Wang
Chih-Hung
CH
Juang
Jyh-Lyh
JL
D000199:Actins / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D003599:Cytoskeleton / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D046228:Microarray Analysis; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D020703:ras GTPase-Activating Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
D000199:Actins; C101203:IQ motif containing GTPase activating protein 1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D020703:ras GTPase-Activating Proteins; D044365:GTP-Binding Protein alpha Subunits, G12-G13