Gα12-Mediated Pathway Promotes Invasiveness of Nasopharyngeal Carcinoma by Modulating Actin Cytoskeleton Reorganization

Abstract

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 A 12 subunit (GA 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 GA 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 GA 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 GA 12 was found to do. Immunohistochemical analysis found NPC tumors to have significantly greater levels of GA 12 protein than the normal basal epithelial cells. Quantitative real-time PCR analysis revealed a significant correlation between GA 12 mRNA levels and NPC lymph node metastasis. Together, our findings support a model in which activation of GA 12 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]

Upregulation of SOX9 in Lung Adenocarcinoma and Its Involvement in the Regulation of Cell Growth and Tumorigenicity

“…Methods for proteins separation by SDS-PAGE and Western blotting were as previously described (21). The primary antibodies used were rabbit anti-SOX9 antibody (Chemicon AB5535, 1:4,000; ref.…”

“…The immunohistochemistry (IHC) staining was done using a rabbit anti-SOX9 antibody (Chemicon AB5535, 1:50) following protocol previously described (21). The immunoreactivity pattern and histologic appearance of all tissue microarray slides were examined and scored by two independent pathologists.…”

Gα 12/13 Induction of CYR61 in Association With Arteriosclerotic Intimal Hyperplasia

“…Whereas a deficiency of CYR61 results in a defect in vessel bifurcation, 7 increased CYR61 expression induces a set of genes responsible for adhesion, migration, proliferation, angiogenesis, and inflammation. 8,9 Of the G-protein families, the G␣ 12 family that comprises G␣ 12 and G␣ 13 as members (also referred as the gep oncogenes) plays a role in oncogenic transformation, tumor growth, and tumor progression. 10 Moreover, G␣ 12 and G␣ 13 are upregulated in various human tumor tissues.…”

“…8,9 Of the G-protein families, the G␣ 12 family that comprises G␣ 12 and G␣ 13 as members (also referred as the gep oncogenes) plays a role in oncogenic transformation, tumor growth, and tumor progression. 10 Moreover, G␣ 12 and G␣ 13 are upregulated in various human tumor tissues. [11][12][13] They differ in terms of the abilities to couple to different GPCRs and ligands, recruit different signaling pathways, and stimulate mitogenic pathways.…”

“…10 Moreover, G␣ 12 and G␣ 13 are upregulated in various human tumor tissues. [11][12][13] They differ in terms of the abilities to couple to different GPCRs and ligands, recruit different signaling pathways, and stimulate mitogenic pathways. 14,15 Unlike the case of G␣ 12 deficiency, G␣ 13 deficiency impairs angiogenesis and results in intrauterine death of mice.…”