On the other hand, there is evidence that low TIMP-4 levels result in an anti-apoptotic effect [ 15].
These reports, taken together with the data of the present study, may support the importance of low TIMP-4 levels in IBD-related tumorigenesis.
Our finding was of weak statistical significance and failed to be confirmed in multivariate analysis, differing from both Span and colleagues [ 23], who found no prognostic significance for TIMP-3 mRNA levels, and Kotzsch and colleagues [ 24], who showed low TIMP-3 mRNA levels to be an independent poor prognosticator of patient disease-free survival.
We conclude that high MMP-2 and low TIMP-2 expression levels may be linked to the aggressiveness of endometrial cancers.
The presence of increased levels of α2M/MMP complexes shows that TIMP levels are insufficient to inhibit all activated MMPs; thus, the MMP/TIMP imbalance theory is supported by these findings.
Furthermore, low levels of TIMP-1 have been associated with sensitivity to anthracycline- [ 2, 8, 20, 21] and irinotecan-containing therapy [ 41].
Using the ELISA measurements we selected two samples with a low level of TIMP-1 and two with a high level of TIMP-1.
In two breast cancer studies lack of tumour cell TIMP-1 immunoreactivity [ 9] or low levels of TIMP-1 in tumour homogenates [ 34] predicted sensitivity to antracycline-containing therapy but not to cyclophosphamide, methotrexate and 5-fluorouracil in adjuvant treatment.
TIMP-2 inhibits proMMP-2 [ 18, 22], however, TIMP-2 also has a bi-functional effect on MMP-2 since proMMP-2 activation requires low levels of TIMP-2 for activation, whereas a greater concentration of TIMP-2 inhibits MMP-2 [ 23].
Similarly, miR-21 has been previously associated with metastatic tumors and a few mechanistic explanations have been proposed: in hepatocarcinoma it was reported to target the tumor suppressor gene RHOB [ 20], in non-small cell lung cancer it promoted metastasis by targeting PTEN, and in breast cancer miR-21 was associated with low levels of TIMP-3 in metastatic samples [ 21].
