Abstract
14-3-3zeta protein is well-known in many cellular processes and has been identified as an oncogene. However, 14-3-3zeta has not been reported previously to be a secretable protein and its secretion involved in tumor biology is still unclear. Therefore, the objective of this study is to investigate the secretion machenism of 14-3-3zeta and its effect on lung cancer progression. First, secreted 14-3-3zeta of lung cancer cells was detected by purification of the conditioned medium. Next, an immunofluorescent staining showed that the purified GFP-tagged 14-3-3zeta was taken up and transported into the cytosol and nucleus of lung cancer cells. Uptake of secretable protein by the cells is major through endocytosis. Owing to intracellular EGFR plays an important role in lung cancer, we first examined the interaction between 14-3-3zeta and EGFR. A co-immunoprecipitation assay showed that 14-3-3zeta bound to EGFR in a highly invasive lung cancer cell line. An immunofluorescent staining also revealed that GFP-tagged 14-3-3zeta might be co-localized with EGFR. In previously study, 14-3-3zeta will regulate Cyclin D1 (CCND1) expression. Therefore, we speculate that 14-3-3zeta could be transported to nucleus then binding to cyclin D1 promoter. By using luciferase assay we found that 14-3-3zeta would regulate cyclin D1 promoter activity through TCF-4 and EGFR binding site. We also observed that cobble-like appearance of CL1-0 cells was replaced by a neuron-like morphology in presence of the conditioned medium from 14-3-3zeta transfectants; also, the EMT marker E-cadherin was down-regulated. Furthermore, we discovered that 14-3-3zeta protein could be secreted through microvesicle (MVs) then be uptaken by other epithelia cells. Taken together, we propose that 14-3-3zeta could be secreted with MVs and taken up by other cancer cells. While uptake by cells, 14-3-3zeta could interact with EGFR to induce EMT, as well as be transported to nucleus to regulate cyclin D1 expression.
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