Tissue Inhibitor of Matrix Metalloproteinase-2 in Nasopharyngeal Carcinoma

Amr Ahmed El Badry, MD; Amal Abou El-Fadle, MD; Abdel Latif El-Balshy, MD

In This Article


Proteolytic degradation of the extracellular matrix (ECM) is a fundamental aspect of cancer development and a key event in the regulation of tumor proliferation and metastasis. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that are collectively capable of degrading most components of the basement membrane and ECM, facilitating cell migration.[1] Given their ubiquitous presence, MMPs play an important role in tissue breakdown and remodeling during both normal and pathologic conditions.[2] MMPs are secreted as inactive proenzymes and are transformed into active forms after cleavage of a propeptide domain of the molecule.[3] On the basis of their structure, cell localization, and substrate specificity, MMPs are categorized into several groups such as collagenases, gelatinases, stromelysins, and membrane-type MMPs.[4] MMPs are tightly regulated at various levels, including expression level, latent form activation, and the balance between enzyme levels and their inhibitors (TIMPs). TIMPs are the major endogenous regulators of MMPs and consist of 4 homologous members (TIMP 1-4). The balance between MMPs and TIMPs is critical in maintaining the integrity of ECM and its regulatory role in organ development, cell growth and differentiation.[5] Although each TIMP appears capable of inhibiting several MMPs, these proteins exhibit preferential inhibitory capacity (eg, TIMP-1 and -2 selectively inhibit MMP 9 and 2, respectively.[6]

Although early studies have shown TIMPs to have antitumor or antimetastatic effects, more recent reports indicate a dual function, with positive correlation between increased TIMP levels and poor outcome in some human malignancies. The mechanisms supporting the paradoxical positive effect of TIMPs in tumor progression are not completely understood and are the subject of intense investigation. This tumor-promoting activity may be attributable to either excessive proteolytic degradation of ECM, which leads to impairment of tumor cell adhesion and disruption of the cell-matrix interactions required for migration and invasion, or direct influence on cell survival and growth.[7]

The expressions of MMP family members in head and neck squamous cell carcinoma (SCC) tissues are reported widely; however, the correlation of these expressions with clinical features is still controversial.[8,9,10,11,12,13,14,15] Some studies demonstrated that the expressions of MMP family correlated with histologic grade,[9,11,14] tumor invasion,[13] clinical stage,[15] and/or lymph node involvement,[8,9,10,11,12,13,15] although their results were not uniform. Furthermore, a majority of previous studies analyzed these expressions in patients with a wide variety of tumor (T1-4) and node (N0-3) classifications. There is little known about the predictive value of expression of MMP family members for clinical outcomes and prognosis.

In this study, we used Western blot analysis to determine whether there is a correlation between TIMP-2 protein positivity and the incidence of nasopharyngeal carcinoma (NPC), clinical staging, and histopathologic typing. A better understanding of the role of TIMP-2 protein may enable us to design new therapeutic approaches for the management of NPC patients.


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