Upregulation of MUC1 by its novel activator 14-3-3ζ promotes tumor invasion and indicates poor prognosis in lung adenocarcinoma.

Abstract

Lung adenocarcinoma (LAC) is currently the predominant histological subtype of lung cancer. Despite recent advancement in targeted therapies, the average 5-year survival rate is only 15%, highlighting the need to identify previously unrecognized molecular events that propel cancer development. Herein, we showed knockdown of 14-3-3ζ suppresses cell proliferation, migration and invasion capability of A549 and H1299 cells. MUC1 was then identified as a novel target of 14-3-3ζ protein. Overexpression of MUC1 is found to induce epithelial-mesenchymal transition and promote metastasis of lung cancer cells, while knockdown of 14-3-3ζ can completely abolish the oncogenic function of MUC1.Furthermore, we unraveled a novel mechanism that 14-3-3ζ activates NF-κB signaling pathway, and therefore enhanced MUC1/NF-κB feedback loop to upregulate MUC1 expression. From a clinical point of view, we evaluated the expression of14-3-3ζ and MUC1 in GSE68465 datasets, in which high expression of14-3-3ζ and MUC1 emerged as poor prognostic factors in LAC patients. In conclusion, we provide novel evidence that 14-3-3ζ regulates MUC1 through MUC1/NF-κB feedback loop. 14-3-3ζ and MUC1 is a promising prognostic biomarker for lung cancer patients and therapeutic targeting of 14-3-3ζ and MUC1 may be a potential treatment option for patients with LAC.