Role of P63 in cell migration and cancer metastasis
Villafañe, Johann Sebastian Bergholz
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The p53-related p63 protein is expressed as multiple isoforms involved in diverse biological functions, including cell proliferation, survival, apoptosis, differentiation, senescence, and aging. An inverse correlation between p63 expression and cancer progression in a variety of human cancers suggests that p63 functions as a metastasis suppressor. Here, we show that the predominant isoform of p63, ΔNp63α, plays a major role in inhibiting cell migration, invasion, and cancer metastasis by modulating Extracellular signal-regulated protein kinase 1 and 2 (Erk1/2) signaling. We profiled gene expression in human breast cancer Hs-578T cells stably expressing wild type ΔNp63α, or a mutant derivative defective in DNA binding or protein-protein interaction. We observed that wild type ΔNp63α, but not the mutant derivatives, up-regulated Mitogen-activated Protein (MAP) Kinase Phosphatase 3 (MKP3), a negative regulator of Erk1/2 signaling. Accordingly, exogenous ΔNp63α expression in breast cancer MDA-MB-231 cells up-regulated MKP3 expression, decreased nuclear levels of phosphorylated Erk1/2, and down-regulated Matrix Metalloprotease 1 and 9 (MMP1/9) expression. In addition, ΔNp63α inhibited cancer cell invasion, which was significantly rescued by disrupting MKP3 expression. Conversely, pan-p63 knockdown in mammary epithelial MCF-1OA and head and neck squamous cell carcinoma FaDu cells resulted in decreased MKP3 expression and concomitant higher levels of Erk1/2 phosphorylation, while Mek1/2 phosphorylation levels were not affected. Consistently, pan-p63 knockdown led to increased cell motility and invasion, which was reversed either by reintroduction of the ΔNp63α isoform alone, but not by other isoforms, or by expression of MKP3. Interestingly, p63 ablation-induced cell motility is dependent on Erk2, but not Erk1 expression. Moreover, we found that both p63 and MKP3 expression is usually decreased in invasive breast carcinoma, indicating a clinical correlation between p63 and MKP3 down-regulation and cancer progression. Finally, we found that reduced p63 expression in Her2/Neu-transformed MCF-1OA cells dramatically increased metastatic frequency to the lungs in a mouse model of breast cancer. Taken together, these results not only reveal a novel molecular pathway by which p63 plays an important pathological role in cancer metastasis, but also contribute to the design of therapeutic strategies in the treatment of cancer.
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