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Falconer et al. MT-MMPs in prostate cancer

protein level resulted from inhibition of IGF-1R (using in codon 388 of the human FGFR4 gene has been
picropodophyllin) in PC3N cells. Increased IGF-1R, linked to poor prognosis in prostate cancer patients.
when activated by IGF-1, led to increased MT1-MMP This SNP results in Gly388 being transformed to Arg
expression and activity following treatment of LNCaP in the transmembrane domain of the receptor, leading
cells with synthetic androgen R1881. to prolonged FGFR4 receptor activation [46] . MT1-
MMP and FGFR4 were found to be co-expressed in
Reversion-inducing cysteine-rich protein with the tumor edges and prostate carcinoma: MT1-MMP
Kazal motifs (RECK), originally found to suppress upregulation was observed in cancer cells (9 of 14)
transformation caused by the oncogene KRAS, and/or reactive stroma (9 of 14), whereas FGFR4
is a glycoprotein tumor suppressor which inhibits expression was mainly found in the tumor cells.
metastasis and angiogenesis [39] . Previous studies FGFR4-R388 was shown to enhance MT1-MMP-
have identified RECK as an inhibitor of various MMPs, mediated prostate cancer cell invasion. FGFR4 was
including MT1-MMP [40] . Rabien et al. [41] identified thus also identified as playing a role in MT1-MMP-
RECK expression in prostate cancer cell lines and dependent ECM degradation and tumor progression
tissue and observeda significant decrease in malignant involving EMT in vivo [47] .
tissue. Significantly, RECK overexpression led to
a dramatic reduction in tumor cell invasion and a MT1-MMP has additionally been associated with
[48]
decrease of pro-/active MT1-MMP expression (up to oxidative stress in prostate cancer cell lines. Nguyen et al.
53% of control). described how expression of MT1-MMP increased
oxidative DNA damage via reactive oxygen species
Filiz and Dass [42] demonstrated decreased expression (ROS) in LNCaP and in DU145 cells, causing oxidative
of MT1-MMP associated with reduced pigment stress. The study confirmed the findings of others in
epithelium-derived factor (PEDF).The authors demonstrating that MT1-MMP is associated with a
noted that PEDF had been previously found to be more aggressive phenotype as illustrated by increased
downregulated in prostate cancer patients (specifically cell migration, invasion and anchorage-independent
in high-grade PIN, the most likely precursor of cell growth. Use of the scavenger N-acetylcysteine to
prostate cancer) [43] . PEDF was examined for effects block ROS activity inhibited the MT1-MMP-mediated
on PC3 cells, with increased adhesion to ECM increase in cell migration and invasion. The authors
protein collagen-I and decreased expression of additionally suggested a role for β1-integrins in
phosphorylated FAK observed. Tumor cell invasion facilitating cell adhesion to matrix proteins, and that
through collagen-I was also reduced. These findings this was necessary for induction of ROS in MT1-MMP-
were attributed to the decreased expression of MT1- expressing prostate cancer cells.
MMP.
PTEN (phosphatase and tensin homologue deleted
Increased expression of both MT1-MMP and LIM on chromosome ten) is a phosphatase enzyme
kinase 1 (LIMK1) in prostate tumor tissues was involved in regulation of PI3K-Akt pathway signalling
reported by Tapia et al. [44] . LIMK1 is a downstream and thus cancer progression. Most metastatic
effector of Rho signalling, modulates actin dynamics prostate cancers exhibit loss-of-function mutations or
and is overexpressed in prostate cancer cells, deletions of this key tumor suppressor [49] . Kim et al. [50]
where it promotes invasion and metastasis. Results considered the role of PTEN inactivation on MT-MMP
showed that treatment with ilomastat (broad-spectrum expression in prostate cancer. Mouse PTEN null
hydroxamate-based MMP inhibitor) reduced LIMK1- cells exhibited up-regulation of MT1-MMP and MT3-
induced invasion of benign prostate epithelial cells MMP gene expression (and the associated increased
(BPH-1 cells) suggesting that the process is mediated migration and invasion), and increased MT1-MMP
by MMPs, notably MT1-MMP. Increased MT1-MMP protein expression in vivo. Interestingly, the MT1-MMP
expression in cells overexpressing LIMK1 was also displayed by PTEN null cells exhibited a slow rate of
reported, along with transcriptional activation and turnover, which was thought to be due to differential
localisation of protein to the plasma membrane. LIMK1 O-glycosylation of the MT1-MMP hinge region
was shown to physically associate with MT1-MMP and modulating enzyme stability. MT1-MMP expression
to co-localise with it in Golgi vesicles, thereby enabling in PTEN null cells was additionally determined to be
transport of MT1-MMP to the cell surface [44] . regulated by PI3K/Akt but not MAPK signalling, as
determined by inhibitors of those pathways. A role for
FGFR4 expression and polymorphism has been linked downstream pathway mTORC1 (positively regulates
to prostate cancer progression and drug resistance [45] . translation thereby promoting protein synthesis [51] ) was
In particular, a single nucleotide polymorphism (SNP) predicted, given the upregulation of MT-MMP protein

320 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ December 12, 2017