title: 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.
authors.affiliation: Department of Biology, School of Science and Technology, Nazarbayev University, Astana, 010000, Republic of Kazakhstan.
authors.forename: Yingqiu
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN, 37208, USA.
authors.forename: Wenfu
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN, 37208, USA.
authors.forename: Shenji
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN, 37208, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN, 37208, USA.
authors.forename: J Shawn
authors.initials: JS
authors.lastname: Goodwin
authors.affiliation: Department of Surgery, Meharry Medical College, Nashville, TN, 38208, USA.
authors.forename: Sandeep Anantha
authors.initials: SA
authors.lastname: Sathyanarayana
authors.affiliation: School of Graduate Studies and Research, Meharry Medical College, Nashville, TN, 37208, USA.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Pratap
authors.affiliation: Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN, 37208, USA.
authors.forename: Zhenbang
authors.initials: Z
authors.lastname: Chen
mesh_terms: D015820:Cadherins / Q000032:analysis; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism*; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D059016:Tumor Microenvironment; D025803:Tumor Suppressor Protein p14ARF / Q000502:physiology*
chemical_list: D015820:Cadherins; D025803:Tumor Suppressor Protein p14ARF; D020783:Matrix Metalloproteinase 7
keywords: ARF; MMP7; prostate cancer; tumor microenvironments