Abstract
ARF couples with TP53 in a canonical signaling pathway to activate cellular senescence for tumor suppressive function under oncogenic insults. However, the mechanisms on aberrant elevation of ARF in cancers are still poorly understood. We previously showed that ARF (p14ARF in human and p19Arf in mouse) elevation correlates with PTEN loss and stabilizes SLUG to reduce cell adhesion in prostate cancer (PCa). Here we report that ARF is essential for MMP7 expression, E-Cadherin decrease and the anchorage loss to the extracellular matrix (ECM) in PCa in vitro and in vivo. We found that Mmp7 is aberrantly elevated in cytosol and nucleus of malignant prostate tumors of Pten/Trp53 mutant mice. Interestingly, p19Arf deficiency strikingly decreases Mmp7 levels but increases E-Cadherin in Pten/Trp53/p19Arf mice. ARF knockdown markedly reduces MMP7 in human PCa cells. Conversely, tetracycline-inducible expression of ARF increases MMP7 with a decrease of E-Cadherin in PCa cells. Importantly, MMP7 physically binds ARF to show the co-localization in nucleus. Co-expression of MMP7 and ARF promotes cell migration, and MMP7 knockdown decreases wound healing in PCa cells. Furthermore, MMP7 elevation correlates with ARF expression in advanced human PCa. Our findings reveal for the first time that the crosstalk between ARF and MMP7 in nucleus contributes to ECM network in tumor microenvironments in vivo, implicating a novel therapeutic target for advanced PCa treatment.
Highlights
Prostate cancer (PCa) is the second leading cause of cancer-related deaths among men in Western countries and the emerging threat to men in Asian countries [1, 2]
Given that matrix metalloproteinases (MMPs) genes are primarily involved in extracellular matrix (ECM) and cell adhesion, our results indicate that ARF may activate tumor microenvironments through MMP
Since Mmp7 was dramatically decreased by p19Arf loss in vivo, we decided to investigate the crosstalk between ARF and MMP7 in human prostate cancer (PCa) cells and to further explore whether ARF increases ECM regulator proteins for PCa progression
Summary
Prostate cancer (PCa) is the second leading cause of cancer-related deaths among men in Western countries and the emerging threat to men in Asian countries [1, 2]. Aberrations of multiple oncogenic pathways contribute to the initiation and progression of PCa [3,4,5,6]. ARF (p14ARF in human and p19Arf in mouse) elevation is found in PTENdeficient human PCa [9] and various cancer cell lines [10,11,12]. Induction of the canonical ARF pathway halts cancer progression through coupling with TP53 to induce cellular senescence and inhibiting ribosomal RNA transcription and processing, response to DNA damage and autophagy initiation [14, 15]. ARF elevation is associated with the triggering of oncogenic pathways, which in turn results in additional alterations of molecular cascades for cancer progression
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