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Spencer et al. J Cancer Metastasis Treat 2022;8:2 https://dx.doi.org/10.20517/2394-4722.2021.174 Page 7 of 15

downregulation of OS metastasis in HOS-143B cells was attributed to a decrease in MMP-2 expression,
[44]
which is not in line with previous studies in breast and prostate cancer cell lines , with the authors noting
that the decrease in MMP-2 seen could be attributed to an increase in MMP-2 secretion into the medium
which went un-monitored in this study.

The aberrant expression of microRNAs (miRNAs) has been implicated in cancer progression . MiRNAs
[25]
regulate gene expression through the induction of mRNA degradation or by translational regression. The
ability of miRNAs to simultaneously target multiple genes increases their likelihood of success as
[46]
therapeutic agents. Xie et al. , investigated the expression of miR-302b and the mechanism by which it
promotes cell invasion and migration in OS cell lines. The overexpression of miR-146b-5p was shown to
suppress cell proliferation and increase apoptosis in OS cell lines (HOS-143B and MG-63) . Mimics of
[47]
miR-302b were shown to suppress the mRNA and protein levels of MT1-MMP and MMP-2 through the
targeting of the Runx2 gene, while the treatment of cells with an miR-302b inhibitor produced the opposite
effect.

Alternatively, Elenjord et al. utilised ribozyme-transfected cell clones of OHS to determine the effect of
[48]
collagen 1 expression on MMP activity in the absence/presence of S100 calcium-binding protein A4
(S100A4). Previous work demonstrated that reducing S100A4 in OS cell lines, both in vitro and in vivo,
reduced their invasive and metastatic capacity through downregulation of MMPs and TIMPs [49,50] . In
addition, a study by Loennechen et al. showed that colchicine induced MT1-MMP expression in an
[51]
S100A4-independent manner, with higher levels of MT1-MMP observed upon induction of microtubule
rearrangements following exposure to colchicine, as observed in both control and transfected cell lines. The
authors were able to demonstrate that activation of proMMP-2 by MT1-MMP was mediated by TIMP-1 in
OHS cells (control pHβ-1, II-11a and II-11b). Another study evaluated the effect of R1881, a synthetic
androgen analogue, on the expression of several MMPs and their endogenous inhibitors in LNCaP
(prostatic adenocarcinoma) and OHS cells. TIMP-2 was shown to be inhibited in a time-dependent manner
in MT1-MMP deficient LNCaP cells, which also correlated with an increase in the levels of prostate-specific
antigen. In these cells, the mRNA levels of other MMPs (MMP-1, -2, -9, MMP-14 and TIMP-1) were not
detected. An elevation in the expression of MMP-14 mRNA was seen when LNCaP cells were co-cultured
with OHS cells. In this co-culture, the proteolytic activity of the MT1-MMP/TIMP-2/MMP-2 complex was
unaffected by R1881 suggesting that this complex may provide an androgen-independent route for the
development of bone metastases from prostate carcinoma .
[52]
Lysophosphatidic acid (LPA) plays an important role in tumour cell invasion by promoting ECM
degradation through the regulation of downstream targets. Investigation of the effect that LPA has on Rho,
Rho-associated protein kinase (ROCK), MMPs and TIMPs, revealed that following high-dose treatment
with LPA mRNA and protein levels of Rho, ROCK, MT1-MMP and TIMP-2 were reduced. Interestingly
low dose LPA treatment resulted in increased mRNA levels of these proteins. Selective inhibition of Rho
prevented LPA-mediated reduction in MT1-MMP and TIMP-2. Matsumoto et al. speculated that the
[27]
Rho-ROCK pathway might be involved in MMP-2 activation through regulating MT1-MMP and TIMP-2
levels.

MMPs also play an important role in inflammatory processes potentiating the activity of inflammatory
proteins, which result in the activation of many downstream signalling pathways, including JNK/c-jun .
[53]
The ability of Dz13, a DNA enzyme, to downregulate c-Jun has been shown to have a direct effect on OS
progression in HOS-143B and SJSA-1 cells and resulted in an increased doxorubicin sensitivity in Saos-2
cells [54-56] . Tan et al. investigated the relationship between Dz13 and MMP expression in OS. A dose-
[57]