Disease relevance of MMP11

• Thus, loss of beta-TRCP1 may promote both growth and cell motility of lung cancer cells, possibly through regulation of CDC25A and the MMP11 level [1].
• The matrix metalloproteinase stromelysin-3 (ST3 or MMP11) was initially identified as a breast carcinoma associated protease and has since been shown to be highly expressed in diverse carcinomas and in developmental processes that involve extensive cell death (apoptosis) and tissue remodeling [2].
• Significant factors for survival were tumor stage (P =.0021); weight loss (P =. 013); and high tumor cell expression of MMP-3 (P =.077), MMP-11 (P =. 031), and MMP-14 (P =.019) [3].
• CONCLUSIONS: Among the metalloproteinases examined in this study, only the levels of MMP-11 mRNA were elevated in leiomyoma compared with myometrium [4].
• The increased expression of MMP-11 in uterine leiomyoma compared with myometrium is analagous to previously reported elevations of MMP-11 mRNA in dermatofibromas compared with unaffected skin [4].
• Serum MMP11 levels were also significantly elevated in gastric cancer patients compared with those of the control subjects (P < 0.001), and the positive expression was well correlated with metastasis in gastric cancer patients (P = 0.009) [5].

High impact information on MMP11

• The matrix metalloproteinase (MMP) stromelysin-3 (ST3) was originally discovered as a gene whose expression was associated with human breast cancer carcinomas and with apoptosis during organogenesis and tissue remodeling [6].
• These results indicate that ST3 is required for cell fate determination and cell migration during morphogenesis, most likely through ECM remodeling [6].
• Interestingly, the urokinase and ST3 genes exhibit very similar patterns of expression in breast carcinomas, which suggests that their products may cooperate during cancer progression [7].
• The expression of the stromelysin 3 (ST3) gene, which encodes a putative matrix metalloproteinase, was studied during breast cancer progression [7].
• The ST3 gene is expressed in all invasive breast carcinomas, in a number of their metastases, and in some in situ carcinomas where the probability of detecting ST3 transcripts correlates with the known risk of these carcinomas to become invasive [7].

Chemical compound and disease context of MMP11

• To identify more selective inhibitors of MMP-11, a matrixin overexpressed in breast cancer, a series of phosphinic pseudopeptides bearing a variety of P(1)'-side chains has been synthesized, by parallel diversification of a phosphinic template [8].
• METHODS: Using standard immunohistochemistry, we analysed MMP-11 expression in renal biopsies from 95 patients with primary glomerulonephritis (n = 44) and secondary, either lupus-associated glomerulonephritis (n = 22) or pauci-immune, ANCA-associated glomerulonephritis due to small vessel vasculitis (n = 23) or Wegener's granulomatosis (n = 6) [9].

Biological context of MMP11

• These results provide new insights into the function of MMP11 and suggest that MMP11 may play an important role in the control of cell proliferation and tumor development in GC [10].
• Stable transfection of recombinants into GC cell line BGC823 specifically depleted the mRNA and protein of MMP11 as demonstrated by RT-PCR and Western blotting analysis [10].
• In order to reveal the correlation between expression of MMP11 and biological features of GC cell, we have constructed the recombinant plasmids producing hairpin small interfering RNA (siRNA) to target MMP11 mRNA using a vector-based RNA interference technology [10].
• The levels of MMP-11 mRNA were twofold greater in leiomyoma compared with myometrium throughout the menstrual cycle, and the differences in the levels of MMP-11 were significantly different during the secretory phase [4].
• These findings indicate that the human ST3 gene promoter is characterized by structural and functional features which differ from those previously described in other MMP promoters, and further supports the possibility that ST3 gene expression is controlled by specific factors during tissue remodeling [11].

Anatomical context of MMP11

• MMP-11 was up-regulated in OA chondrocytes and, interestingly, also in the early-stage samples [12].
• Hepatocyte growth factor receptor, matrix metalloproteinase-11, tissue inhibitor of metalloproteinase-1, and fibronectin are up-regulated in papillary thyroid carcinoma: a cDNA and tissue microarray study [13].
• In this study, a significant correlation (p < 0.05, by Mann-Whitney U analysis) between TIMP-2 expression and lymph node involvement was identified, while MMP-11 and TIMP-1 expression patterning also significantly (p < 0.05) differed between those tumours showing calcification and those that did not [14].
• However, the molecular mechanisms leading to ST3 expression in nonmalignant fibroblasts remain unknown [15].
• Although the intracellular function of the beta-ST3 remains to be investigated, these data support the idea that the functions of MMPs are not restricted to the extracellular space [16].

Associations of MMP11 with chemical compounds

• Transient transfection experiments demonstrated that a minimal promotor activity could be modulated by various sequences within the 3.4 kb of 5'-flanking region, and that the ST3 promoter was transactivated by retinoic acid receptors in the presence of retinoic acid [11].
• The addition of batimastat, a broad spectrum MMP inhibitor, reversed the increased cell survival in ST3wt transfectants, confirming that ST3 enzymatic activity was required for this effect [17].
• These reactions also showed that peptides with proline in position 3 were poor substrates for MMP-11 [18].
• The Xenopus laevis ST3 is highly up-regulated by thyroid hormone (T3) during amphibian metamorphosis, and its expression is spatially and temporally correlated with apoptosis in different tissues [19].
• The substrate with a S-para-methoxybenzyl cysteine residue in the P1' position displayed a kcat/Km value of 1.59 10(6) M-1 s-1 and 1.67 10(4) M-1 s-1, when assayed with MT1-MMP and ST3, respectively [20].

Regulatory relationships of MMP11

• In a second approach, TIMP2 overproduction in MCF7 cells expressing hST3 was induced by retroviral infection [21].
• Finally, a tetracycline-inducible expression model allowed us to confirm the central role of these PKC isoforms and the negative regulatory function of c-Src in the control of ST3 expression [15].
• The MIB-1 proliferation index was significantly higher in the meningiomas expressing ST3 (Student t test: P < 0.001) [22].
• Finally, we show that processing of the ST3 proform is inhibited by a furin inhibitor in human MCF7 breast cancer cells stably transfected to constitutively express a full-length human ST3 cDNA [23].
• MEK inhibitor PD98059 and MMP11 antibody (Ab) significantly inhibited in vitro invasive and in vivo metastatic abilities induced by PrPc [24].

Other interactions of MMP11

• This indicates that other degradation pathways might be more important in late stages of cartilage degeneration, involving other enzymes, such as MMP-2 and MMP-11, both of which were up-regulated in late-stage disease [12].
• A cell line immortalized following myc expression was found to up-regulate MMP-7, MMP-11 and MMP-13 [25].
• Kaplan-Meier survival analysis showed that patients with ST-3-positive and TIMP-2-negative carcinoma had a significantly shorter disease-free survival (median disease-free survival time of 4 months) as compared to patients in the other groups (median disease-free survival time of 20 months; p = 0.0016) [26].
• Based on detection of either MMP-9 or MMP-11 mRNAs, we were able to distinguish between malignant and benign disease with a predictive accuracy of 90% with 94% sensitivity and 85% specificity [27].
• The genes TIMP3 and PVALB were assigned to BTA5 and CRYbetaA4 and MMP11 to BTA17 [28].

Analytical, diagnostic and therapeutic context of MMP11

• Endpoint RT-PCR with densitometry gave consistent results with the cDNA array findings for all three genes selected for study (CTSF, MMP11 and MMP12) [29].
• In such conditions, that mimic the in vivo microenvironment, we found a marked decrease in the percentage of cell death when active ST3 was expressed (ST3wt transfectants vs. ST3cat- or vector only transfectants) as assessed by FACS and TUNEL analysis [17].
• The human stromelysin 3 (STMY3) gene, a new member of the matrix metalloproteinase (MMP) gene family, may contribute to breast cancer cell invasion, and has been localized by in situ hybridization to the long arm of chromosome 22 [30].
• Frozen sections of the tumors were immunostained for ST3 and MIB-1 to evaluate the proliferative activity of tumor cells [22].
• Stimulation of MMP-11 (stromelysin-3) expression in mouse fibroblasts by cytokines, collagen and co-culture with human breast cancer cell lines [31].

References