Essay: MMP-2

MMP-2 plays an important role during tumor development and invasiveness in various human malignancies e.g. hepatocellular carcinoma, glioma, colorectal carcinoma. Scarce data are available on the role of MMP-2 in MF especially in the early stage. Sp-1 can mediate the oncogenic effect of MMP-2 through different signaling pathway (Hung et al., 2010; Sze et al., 2011). . Of note, these pathways are usually dysregulated in MF. Sp-1 is also associated with many tumors e.g. breast cancer, colorectal cancer, lung cancer. However, Sp-1 has not been studied in MF before. In the current study, we aimed to detect the expression of MMP-2 and its transcriptional factor Sp-1 in the early stage MF and to compare it with one of its inflammatory mimickers.
We found that the expression of MMP-2 was significantly higher in the MF group. 64% of MF patients showed positive staining of the lymphocytic infiltrate whereas, 16% of control group were positive. Vacca et al. (1997, 2000) reported increased MMP-2 expression in the advanced stage MF. Their study had clarified its role in matrix degradation only in the late stage disease.
However, MMPs not only regulate the matrix disruption in the late invasive stages of the disease but also influence early steps of tumor evolution and possess pro-tumorigenic properties (López-Otín and Bond, 2008; Fanjul-Fernández et al, 2010; Mannello and Medda, 2012). These studies supported our results of the early expression of MMP-2 in MF. Although Rasheed et al. (2010) reported the expression of MMP-9 at early stage disease but no other studies investigated the expression of MMP-2 in early MF patients.
Matrix metalloproteinases can enhance cell proliferation, suppress tumor apoptosis, disrupt epithelial-mesenchymal transition, induce angiogenic switch and evade the host anti-tumor response. These effects are mediated by targeting non-matrix proteins such as chemokines, growth factors and their receptors, adhesion molecules and integrins (Ting et al., 2013).
Thus, proteolytic processing of matrix and non-matrix proteins by MMPs contributes to the formation of a complex microenvironment that promotes malignant transformation in early stages of cancer (Overall and Kleifeld, 2006; Cauwe et al., 2007; López-Otín and Hunter, 2010; Noël et al., 2012).
Furthermore, MF patients showed higher expression of MMP-2 in the stromal cells than controls. This observation suggests a crosstalk between the stromal and neoplastic cells. It is postulated that fibroblast derived MMP-2 is activated by a factor called EMMPRIN , an extracellular matrix metalloproteinase inducer, which is secreted from the cancer cell. The activated MMP-2, in turn, binds to docking sites on the tumor cells. This is followed by internalization of MMP-2 within the cytoplasm. This can highlight the lymphocytic stromal interactions in promoting early carcinogenesis (Leinonen et al., 2008). In addition, MMP-2 binds to heparin and heparan sulfate which may explain the immunoreactivity of the extracellular matrix in some cases of our study (Groth et al., 2009).
Besides stromal and tumor cells, MMP-2 was expressed in keratinocytes. However, no significant difference in the keratinocyte expression of MMP-2 was detected between MF patients and controls. This observation can be explained by Stanciūte et al. (2004) who reported that MMP-2 can normally be produced by keratinocytes. No significant difference was detected when investigating MMP-2 expression as regards the clinical characteristics of MF patients (MF type, sex, age of onset and recurrence).
As regards the Sp-1 expression, we found that there is significant difference between MF cases and the control group of chronic eczema. However, no statistical difference in MF case-case analysis was found as regards type of lesion, sex, age of onset and recurrence.
There are several possible explanations for the increased Sp1 expression in MF lesions. First, the dysregulated signaling pathway in MF (e.g. JNK, Pi3k/Akt, MAPK and STAT3) may lead to Sp1 activation ((Sroka et al., 2007; Wei et al., 2013). Second, Sp1 gene maps to 12q13 which is a target region for CTCL-associated gene aberrations (Hahtola et al., 2006). Moreover, Most of the altered genes in MF (e.g. VEGF, STAT, NF-κB) are actually target genes for Sp1 (Fruchon et al., 2012; Hur and Kim, 2012; Wei et al., 2013; Pileri et al., 2014). Thus, Sp1 may contribute to early development of MF. However, the effect of Sp1 on gene transcription in MF or CTCL cell lines needs to be further investigated.
In addition, both cases and control showed positive staining of the keratinocytes for Sp1 with no statistical significance. Keratinocytes may also show positive staining in normal skin biopsies (Chen et al., 2008). This finding may be attributed to the role of Sp1 in keratinocytes’ biological processes and regulation of keratinization (Bin et al., 2011a).
Furthermore, this study investigated the correlation between Sp1 and MMP-2 immunostaining in the MF group. We found that MMP-2 immunoreactivity was not dependent on Sp1. In addition, we also studied the sensitivity and specificity of MMP-2 and Sp1 in an attempt to find their role in the diagnosis of early MF. The sensitivity and specificity for MMP-2 were 64% and 85% respectively.
On the other hand, Sp1 was more sensitive and less specific showing 80% sensitivity and 50% specificity. The decreased specificity of Sp1 may be ascribed to its role in inflammatory processes as well carcinogenesis (Lee et al., 2005; Bin et al., 2011b). Moreover, both markers together showed higher sensitivity but lower specificity than either marker alone. This low specificity may limit their role in the diagnosis of MF. However, MMP-2 alone was found to be more efficient for distinguishing MF from chronic eczema.
Thus, this study found that patients with early MF may have increased expression of MMP-2 and Sp1 transcription factor. Therefore, these immunohistochemical characteristics may be of help in better understanding of the pathogenesis of early MF as well as improving diagnostic criteria.