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|標題:||A Novel Function of YWHAZ/b-Catenin Axis in Promoting Epithelial–Mesenchymal Transition and Lung Cancer Metastasis||作者:||Chen, Ching-Hsien
|Project:||Molecular Cancer Research, Volume 10, Issue 10, page(s) 1319–1331.||摘要:||
YWHAZ, also known as 14-3-3zeta, has been reportedly elevated in many human tumors, including non–small
cell lung carcinoma (NSCLC) but little is known about its specific contribution to lung cancer malignancy.
Through a combined array-based comparative genomic hybridization and expression microarray analysis, we
identified YWHAZ as a potential metastasis enhancer in lung cancer. Ectopic expression of YWHAZ on low
invasive cancer cells showed enhanced cell invasion, migration in vitro, and both the tumorigenic and metastatic
potentials in vivo. Gene array analysis has indicated these changes associated with an elevation of pathways relevant
to epithelial–mesenchymal transition (EMT), with an increase of cell protrusions and branchings. Conversely,
knockdown of YWHAZ levels with siRNA or short hairpin RNA (shRNA) in invasive cancer cells led to a reversal
of EMT. We observed that high levels of YWHAZ protein are capable of activating b-catenin–mediated
transcription by facilitating the accumulation of b-catenin in cytosol and nucleus. Coimmunoprecipitation assays
showed a decrease of ubiquitinated b-catenin in presence of the interaction between YWHAZ and b-catenin. This
interaction resulted in disassociating b-catenin from the binding of b-TrCP leading to increase b-catenin stability.
Using enforced expression of dominant-negative and -positive b-catenin mutants, we confirmed that S552
phosphorylation of b-catenin increases the b-catenin/YWHAZ complex formation, which is important in promoting
cell invasiveness and the suppression of ubiquitnated b-catenin. This is the first demonstration showing
YWHAZ through its complex with b-catenin in mediating lung cancer malignancy and b-catenin protein stability.
|Appears in Collections:||生物醫學研究所|
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