In vivo studies using athymic nude mice injected with CWR22Rv1 (22Rv1) PCa epithelial cells and CAF cells ± ERα also confirmed that mice coimplanted with PCa cells and CAF ERα+ cells had less tumor foci in the pelvic lymph nodes, less metastases, and tumors showed less angiogenesis, MMP3, and MMP9 (an MMP3 downstream target) positive staining.
MT1-MMP and its substrates pro-MMP-2 and pro-MMP-9 are often overexpressed in a variety of cancers including prostate cancer and the expression levels correlate with the grade of malignancy in prostate cancer cells.
Whereas MMP-1 was overexpressed in NAP epithelial glands and progressively decreased from PIN to CaP, MMP-7, MMP-9 and MT1-MMP were more strongly expressed in CaP than in PIN and NAP tissue.
Furthermore, in-silico results indicated that the expression of MMP-9 in cancer tissue was higher than that in normal tissue in prostate cancer (Transcripts Per Kilobase Million (TPM) = 7.14 vs. 1.36, P < 0.001), bladder cancer (TPM = 14.2 vs. 2.47, P < 0.001), kidney renal clear cell carcinoma (TPM = 7.43 vs. 1.61, P < 0.001), kidney renal papillary cell carcinoma (TPM = 5.52 vs. 1.74, P = 0.002).
To investigate the mechanisms involved in PCa (prostate cancer) metastasis and CXCR4 (CXC chemokine receptor-4)-mediated VEGF (vascular endothelial growth factor) and MMP-9 (matrix metalloproteinase-9) expression, we used lentivirus-mediated RNAi (RNA interference) to reduce the expression of CXCR4 in a PCa cell line.
Finally, this study evidences MMP-9 as an essential factor for the activation of the chain of the different MMPs and consequently in the genesis and development of bone metastasis of PCa due to its influence on bone osteoblastic and osteoclastic activity.
Further mechanistic investigations showed that Nur77 inhibited transcription of TGF-β target genes (Snail and MMP9), and thereby inhibits TGF-β-mediated prostate cancer cell invasion following androgen antagonism.
In this study, the therapeutic potential of siRNA-mediated targeting of matrix metalloproteinase-9 (MMP-9), urokinase plasminogen activator receptor (uPAR), and cathepsin B (CB) in prostate cancer was carried out using single and bi-cistronic siRNA-expressing constructs.
Novel regulation of type IV collagenase (matrix metalloproteinase-9 and -2) activities by transforming growth factor-beta1 in human prostate cancer cell lines.
In conclusion, the overexpression of Fn14 may contribute to multiple malignant cellular phenotypes associated with prostate cancer (PCa) progression, in part via MMP-9.
Targeting these newly identified signals via FGF11-siRNA, miRNA-541 inhibitor or MMP9 inhibitor all led to partially reverse the enhanced PCa cell invasion.
Immunohistochemistry and cDNA microarray analyses were used to assess protein and mRNA expression of cyclin A1 and proteins with roles in metastasis, including vascular endothelial growth factor (VEGF), metalloproteinase 2 (MMP2), and MMP9, in human prostate cancer.
FLNA expression decreased in prostate cancer and correlated significantly with T stages, lymph node metastasis, clinic stage, and Gleason score, suggesting that FLNA may play important roles as a negative regulator to prostate cancer PC-3 cell by promoting the degradation of MMP-9.
Consequently, LOX-1 activation by oxLDL promotes actin cytoskeleton restructuration and MMP-2 and MMP-9 activity inducing prostate cancer cell invasion and migration.
These increased ratios support the view of an imbalance between MMP-9 activity and its inhibitory counterparts in cancerous tissue as an important step in the development of prostate carcinoma and implicate the rationale of using synthetic inhibitors of MMPs as potential therapeutic tools.
FLI1 and MMP9 position differently in prostate cancer than in normal tissue and prostate hyperplasia, whereas MMP2 is repositioned in both prostate cancer and hyperplasia.
There were no differences in activities of MMP-2, proMMP-9, and MMP-9/NGAL (neutrophil gelatinase associated lipocalin) complex (gelatin substrate) in men with detected prostate cancer, although the latter two were somewhat diminished.
Importantly, we identified increased MMP9 (Metalloproteinase 9) and PLXNA2 (Plexin A2) expression in TMPRSS2:ERG-positive PCa samples, and their expression levels were significantly correlated with ERG expression in a PCa cohort.
Among these genes, it appears that: PPARG promotes the PPAR signaling pathway via the upregulation of lipoprotein lipase (LPL) expression, but suppresses the cell cycle pathway via downregulation of growth arrest and DNA-damage-inducible, γ (GADD45G) expression; ETV4 stimulates matrix metallopeptidase 9 (MMP9) expression to induce the bladder cancer pathway; FLI upregulates transforming growth factor, β receptor II (TGFBR2) expression to activate TGF-β signaling and upregulates cyclin D3 (CCND3) expression to promote the cell cycle pathway; NFKB1 upregulates interleukin 1, β (IL-1B) expression and initiates the prostate cancer pathway; CEBPB upregulates IL-6 expression and promotes pathways in cancer; and TAL1 promotes kinase insert domain receptor (KDR) expression to promote the TGF-β signaling pathway.
We extended these studies and more recently observed increased expression of genes related to angiogenesis such as vascular endothelial growth factor (VEGF) and those related to metastasis such as matrix metalloproteinases (MMP)-2 and MMP-9 in prostate cancer of TRAMP mice.
Mitogen-activated Protein Kinase 8 (MAPK8), Interleukin 6 (IL6), Vascular Endothelial Growth Factor A (VEGFA), Signal Transducer and Activator of Transcription 3 (STAT3), Jun Proto-Oncogene (JUN), C-X-C Motif Chemokine Ligand 8 (CXCL8), Interleukin-1 Beta (IL1B), Matrix Metalloproteinase-9 (MMP9), C-C Motif Chemokine Ligand 2 (CCL2), RELA Proto-Oncogene (RELA), and CAMP Responsive Element Binding Protein 1 (CREB1) were identified as key targets of HDW in the treatment of PCa.
The higher concentration of MMP-9 as well as the increased ratios of MMP-2 and MMP-9 to TIMP-1 in malignant tissue prove the proteolytic dysbalance in prostate cancer, which does not seem to be associated with the stage and grade of the tumor.
Our data showed that knockdown of SPAG9 in prostate cancer cell lines inhibited cell motility and invasion due to the inactivation of metalloproteinase-2 (MMP‑2)/MMP-9 by upregulation of tissue inhibitor of metalloproteinase-1 (TIMP-1)/TIMP-2.