MMP7 interacts with ARF in nucleus to potentiate tumor microenvironments for prostate cancer progression in vivo

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.

Neferine inhibits proliferation and migration of human prostate cancer stem cells through p38 MAPK/JNK activation

“…MMP7 (Xie et al, 2016) and MMP9 (Erdogan et al, 2016) Slug and Snail genes are master regulator of EMT that contributes to PCa progression and metastasis (Jethwa et al, 2008;Jin et al, 2010).…”

Nuclear matrix metalloproteinases: functions resemble the evolution from the intracellular to the extracellular compartment

“…However, we found that MMP-7 localizes in the nucleus of prostate cancer cells with pro-enzyme form. 16 These data suggest that MMPs may undergo differential modifications during nuclear translocation. In conclusion, NLS-mediated import may link MMP to Importin proteins 16 and ARF-mediated protein modification may link MMP to SUMOylation, as we, our collaborators and other labs reported.…”

“…We and our collaborators found that MMP-7 nuclear translocation and stability requires ARF-mediated tumor microenvironment for cell migration by disruption of cell adhesions. 16 Co-overexpression of MMP-7 and ARF resulted in greater cell migration, whereas knockdown of MMP-7 decreased wound healing ability of cells in prostate cancer. 16 Thus nuclear MMPs may promote cell migration greater than extracellular MMPs.…”

“… 35–37 Studies by our collaborators showed that MMP-7 nuclear localization induces more aggressive migration. 16 In detail, nuclear MMP-7 interacts with ARF, an upstream regulator of MDM2–p53–p21 pathway, which facilitates the cellular senescence. 38 ARF-mediated stabilization of p53 is through disruption of MDM2, an E3 ubiquitin ligase for p53.…”

“…Recent studies have shown that the tumorigenesis role of ARF in cancer independent of p53. 16 Under PTEN/p53 double null or mutation condition, ARF may exert p53-independent function. We and our collaborators found that MMP-7 nuclear translocation and stability requires ARF-mediated tumor microenvironment for cell migration by disruption of cell adhesions.…”