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Peng Zhang, Chunli Wang, Tao Ma, Shengyi You General Surgery Department, General Hospital of Tianjin Medical University, Tianjin, People’s Republic of China Background: The PI3K family participates in multiple signaling pathways to regulate cellular functions. PI3K/Akt signaling pathway plays an important role in tumorigenesis and development. O-GlcNAcylation, a posttranslational modification, is thought to modulate a wide range of biological processes, such as transcription, cell growth, signal transduction, and cell motility. O-GlcNAcylation is catalyzed by the nucleocytoplasmic enzymes, OGT and OGA, which adds or removes O-GlcNAc moieties, respectively. Abnormal O-GlcNAcylation has been implicated in a variety of human diseases. However, the role of O-GlcNAcylation in tumorigenesis and progression of cancer is still under-investigated. Understanding the O-GlcNAc-associated molecular mechanism might be significant for diagnosis and therapy of cancer. Methods: Human thyroid anaplastic cancer 8305C cells were used to evaluate the role of O-GlcNAcylation in tumorigenesis and progression of cancer. The global O-GlcNAc level of intracellular proteins was up-regulated by OGA inhibitor Thiamet-G treatment or OGT overexpression. Cell proliferation was assessed by MTT assay. Invasion in vitro was determined by Transwell assay, and phosphorylation of Akt1 at Ser473 was assessed by Western blot for activity of Akt1. PI3K-specific inhibitor LY294002 and RNA interference of Akt1 were used to investigate the impact of PI3K/Akt signaling on the regulation of O-GlcNAcylation during tumor progression. Results: Cell models with remarkably up-regulated O-GlcNAcylation were constructed, and then cell proliferation and invasion were determined. The results indicated that the proliferation was not affected by OGA inhibition or OGT overexpression, while the invasion of 8305C cells with OGA inhibition or OGT overexpression was obviously increased. Akt1 activity was stimulated by elevated O-GlcNAcylation by mediating phosphorylation at Ser473. The enhanced invasion of thyroid cancer cells by Thiamet-G treatment or OGT overexpression was significantly depressed by PI3K inhibitor LY294002. Moreover, silence of Akt1 remarkably attenuated the increase of cell invasion induced by Thiamet-G treatment, but the invasion was still higher compared to Akt1-silenced only cells. In other words, Thiamet-G restored the invasion of Akt1-silenced thyroid cancer cells, but it was still lower relative to Thiamet-G-treated only cells. Conclusion: Taken together, our findings suggested that O-GlcNAcylation enhanced the invasion of thyroid anaplastic cancer cells partially by PI3K/Akt signaling, which might be a potential target for the diagnosis and treatment of thyroid anaplastic cancer. Keywords: O-GlcNAcylation, thyroid anaplastic cancer, invasion, PI3K/Akt, Akt1 |
