| Summary: | 碩士 === 國立成功大學 === 生物化學暨分子生物學研究所 === 103 === The multifunctional cytokine transforming growth factor β (TGF-β) regulates a complicated signaling network. In cancer progression, TGF-β exerts its tumor-suppressive role by inducing cell-cycle arrest and apoptosis at early stages. Nevertheless, at the late stages of cancer, TGF-β promotes tumor progression by enhancing migration and invasion to induce epithelial-mesenchymal transition (EMT). EMT has been shown to be a critical mechanism of tumor cell metastatic dissemination by endowing cells with a more motile, invasive potential. Prothymosin α (ProT) is an acidic nuclear protein and an important regulator of cell proliferation, transcription, chromatin remodeling, and immunomodulation. We found immunohistochemically that ProT expression was associated with cancer progression. At the early stage, ProT was overexpressed in the nucleus and during disease progression ProT expression was decreased and its nuclear expression was even lost. Therefore, we hypothesized that nuclear ProT may play a pivotal role in interrupting TGF-β signaling, resulting in inducing EMT. We found that TGF-β-induced downregulation of E-cadherin and upregulation of Snail and N-cadherin could be supressed by ProT overexpression in A549 cells. Moreover, we demonstrated that ProT could antagonize TGF-β signaling through enhancing Smad7 acetylation and stability. We further showed that Smad7 disrupted the binding of Smad2 to the promoter of Snail1, a TGF-β-induced EMT-associated regulator, leading to downregulating Snail1 expression. In addition, we found that human lung cancer A549 cells overexpressing PoT exhibited lower metastatic potential than parental A549 cells in NOD/SCID mice. In human lung cancer specimens, there was an inverse correlation between nuclear ProT and Snail expression. In conclusion, nuclear ProT expression enhances Smad7 acetylation to antagonize TGF-β signaling, which competes the Smad2-binding site on the Snail1 promoter to reduce Snail1 expression and inhibit TGF-β-induced EMT.
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