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Published on: November 19, 2019
MMP7 interacts with ARF in nucleus to potentiate tumor microenvironments for prostate cancer progression in vivo
Yingqiu Xie1, Wenfu Lu2, Shenji Liu2
1Department of Biology, School of Science and Technology, Nazarbayev University, Astana, 010000, Republic of Kazakhstan.
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.
Insights
Aberrant ARF elevates MMP7, decreasing E-Cadherin and promoting prostate cancer (PCa) progression. This ARF-MMP7 nuclear interaction highlights a new therapeutic target for advanced PCa.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- ARF (Alternative Reading Frame) protein is crucial for tumor suppression via cellular senescence.
- Aberrant ARF elevation in cancers, particularly prostate cancer (PCa), is poorly understood.
- Previous work linked ARF elevation to PTEN loss and reduced cell adhesion in PCa.
Purpose of the Study:
- To elucidate the mechanisms behind aberrant ARF elevation in PCa.
- To investigate the role of ARF in regulating MMP7 expression and E-Cadherin levels.
- To explore the functional consequences of the ARF-MMP7 interaction in PCa progression and therapeutic potential.
Main Methods:
- Utilized mouse models (Pten/Trp53 mutant mice, Pten/Trp53/p19Arf mice) to study Mmp7 expression and E-Cadherin.
- Employed ARF knockdown and inducible ARF expression in human PCa cell lines.
- Performed co-localization and binding assays for ARF and MMP7.
- Assessed cell migration and wound healing in vitro.
- Correlated ARF and MMP7 expression in advanced human PCa tissues.
Main Results:
- ARF is essential for MMP7 expression, E-Cadherin decrease, and anchorage loss in PCa.
- Mmp7 is aberrantly elevated in malignant prostate tumors of Pten/Trp53 mutant mice.
- p19Arf deficiency reduced Mmp7 and increased E-Cadherin in mice.
- ARF knockdown decreased MMP7, while ARF induction increased MMP7 and decreased E-Cadherin in human PCa cells.
- MMP7 physically binds ARF, co-localizing in the nucleus.
- Co-expression of MMP7 and ARF promoted cell migration; MMP7 knockdown impaired wound healing.
- MMP7 elevation correlated with ARF expression in advanced human PCa.
Conclusions:
- ARF directly drives MMP7 expression, contributing to E-Cadherin loss and ECM remodeling in PCa.
- The nuclear interaction between ARF and MMP7 is a key mechanism in PCa progression.
- Targeting the ARF-MMP7 axis presents a novel therapeutic strategy for advanced prostate cancer.
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