Mechanism of Cancer Cell Adaptation to Metabolic Stress PROTEOMICS IDENTIFICATION OF A NOVEL THYROID HORMONE-MEDIATED GASTRIC CARCINOGENIC SIGNALING PATHWAY
Mechanism of Cancer Cell Adaptation to Metabolic Stress PROTEOMICS IDENTIFICATION OF A NOVEL THYROID HORMONE-MEDIATED GASTRIC CARCINOGENIC SIGNALING PATHWAY
复制标题
癌细胞适应代谢应激的机制 新型甲状腺激素介导的胃致癌信号通路的蛋白质组学鉴定
DOI：
10.1074/mcp.m800195-mcp200
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发表时间：
2009-01-01
影响因子：
7
通讯作者：
Huang, Canhua
中科院分区：
文献类型：
--
作者：
Liu, Rui;Li, Zhenjun;Huang, Canhua
Gastric cancer is the second most common cancer worldwide and has a poor prognosis. To determine the mechanism of adaptation to metabolic stress in cancer cells, we used gastric cancer as a model system to reveal the potential signaling pathways involved. Two-dimensional polyacrylamide gel electrophoresis coupled with ESI-Q-TOF MS/MS analysis was used to identify differentially expressed proteins between gastric tumor tissues and the corresponding noncancerous tissues. In total, 107 spots with significant alteration (+/- over 2-fold, p < 0.05) were positively identified by MS/MS analysis. Altered expression of representative proteins was validated by RT-PCR and Western blotting. Cluster analysis of the changed proteins revealed an interesting group of metabolic proteins, which suggested accumulation of triiodothyronine (T-3; the major functional component of thyroid hormone) and overexpression of hypoxia-induced factor (HIF) in gastric carcinoma. These observations were further confirmed by electrochemiluminescence immunoassay and immunohistochemistry. T-3-induced expression of HIF1-alpha and vascular endothelial growth factor was further verified using a gastric cancer cell line and in vivo mouse model. Because the early accumulation of HIF1-alpha was found to be independent of de novo transcription, we also found that the cytosolic cascade phosphatidylinositol 3-kinase/Akt pathway sensitive to T-3 stimulus was involved. Furthermore we demonstrated that T-3-induced overexpression of HIF1-alpha was mediated by fumarate accumulation and could be enhanced by fumarate hydratase inactivation but inhibited by 2-oxoglutarate. These results provide evidence for alteration of metabolic proteins and dysfunction of thyroid hormone regulation in gastric tumors, and a novel thyroid hormone-mediated tumorigenic signaling pathway is proposed. Our findings are considered a significant step toward a better understanding of adaptations to metabolic stress in gastric carcinogenesis. Molecular & Cellular Proteomics 8:70-85, 2009.
