MMP7 interacts with ARF in nucleus to potentiate tumor microenvironments for prostate cancer progression in vivo
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Yingqiu Xie1, Wenfu Lu2, Shenji Liu2, Qing Yang2, J. Shawn Goodwin2, Sandeep Anantha Sathyanarayana3, Siddharth Pratap4, Zhenbang Chen2
1Department of Biology, School of Science and Technology, Nazarbayev University, Astana, 010000, Republic of Kazakhstan
2Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN, 37208, USA
3Department of Surgery, Meharry Medical College, Nashville, TN, 38208, USA
4School of Graduate Studies and Research, Meharry Medical College, Nashville, TN, 37208, USA
Yingqiu Xie, email: [email protected]
Zhenbang Chen, email: [email protected]
Keywords: MMP7, ARF, tumor microenvironments, prostate cancer
Received: January 19, 2016 Accepted: June 12, 2016 Published: June 23, 2016
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.
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