Methyl-CpG-Binding Protein 2 Drives Furin/TGF-β1/Smad Loop to Promote Epithelial-Mesenchymal Transition in Pancreatic Cancer Cells

Abstract

Methyl-CpG binding protein 2 (MeCP2) has been characterized as an oncogene in several types of cancer. However, its precise role in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Hence, this study was to evaluate the potential role of MeCP2 in pancreatic cancer progression. We found that MeCP2 was up-regulated in pancreatic cancer tissues, and enhanced the abilities of migration, invasion and proliferation in pancreatic cancer cells, and promoted tumorigenesis. Further evidence revealed that MeCP2 remarkably increased mesenchymal markers of Vimentin, N-cadherin, and Snail, and down-regulated epithelial marker expression of E-cadherin and ZO-1, indicating that MeCP2 promotes Epithelial-mesenchymal transition (EMT). Also, we found that MeCP2 improved the expression of Furin, and activated TGF-β1, and raised the levels of p-Smad2/3. Importantly, we demonstrated that MeCP2, as a coactivator, enhanced Samd3 binding to the promoter of furin to improve its transcription. Therefore, it is noted that MeCP2/Smads drives the expression of Furin to activate TGF-β1 and in turn phosphorates Smad2/3, which forms a positive feedback loop to promote EMT in pancreatic cancer cells. Funding Statement: This study was supported by grants from the Natural Science Foundation of China [81672402, 81472333, 81301693]; Natural Science Foundation of Jiangsu Provincal, China [BK20171305]; Research Programs of Jiangsu Provincial Commission of Health and Family Planning, China [H201434]; the Graduate Research and Innovation Projects of Jiangsu Province [5561280022]. Declaration of Interests: The authors declared that there were no conflicts of interest. Ethics Approval Statement: The protocol was approved by the Institutional Animal Care and Use Committee of Jiangsu University, Zhenjiang, China.