The Study On Expression Of Matrix Metalloproteinase-12 And Its Tissue Inhibitor-1 In Cutaneous Squamous Cell Carcinoma

Cutaneous squamous cell carcinoma (SCC) is the first most common skin cancer in china. Conventional clinical and pathologic attributes of this neoplasm include an ulcerating papule located in a sun-exposed site with histologic sections showing an infiltrating neoplasm comprised of keratinizing epithelioid cells. Several histologic variants of squamous cell carcinoma with distinctive clinical and pathologic attributes including Bo wen's diseas, keratoacanthoma, acantholytic, spindle cell, desmoplastic, and verrucous and pigmented types. Most cases of primary cutaneous SCC are induced by UV radiation.Chronic sun exposure is the major risk factor, and favored locations include the head and neck and other sun-exposed areas. Moreover, it is important for the clinician to recognize other risk factors associated with this malignancy, including HP infection occupational exposures, various genode-rmatoses, scarring dermatoses, chronic wounds, and burn scars. Most patients who have primary SCC have an excellent prognosis and treatment is usually straight forward. The mortality and morbidity associated with high-risk cutaneous is usually as a consequence of uncontrolled metastatic nodal disease and, to a lesser extent, distant metastases. Squamous-cell carcinoma in situ may progress to invasive disease if not treated completely. The most common forms of squamous-cell carcinoma in situ are Bowen's disease. The typical lesions of Bowen's disease are well defined erythematus patch covered with crusting and erosions. Histological examination showed that atypical cells were seen at all levels of the epidermis. Wide excision of the lesions is the first choice of treatment for Bowen's. If not, it can develop into SCC at the rate of 20% to 30%.Tumor invasion and metastasis require controlled degradaion of extracellular matrix. MMPs play a crucial role in this reakdown of collagen and basement mem brane components MMPs are a family of more than 20 secreted or transmembrane proteins that are capable of digesting extracellular matrix and basement membrane components under physiologic conditions. According to their substrate specificity and structure, MMPs are classified into five subgroups:collagenases (MMP-1, MMP-8, MMP-13), gelatinases(MMP-2, MMP-9), strome-lysins (MMP-3, MMP-10, MM P-11), as well as metalloelastase(MMP-12), the membrane-type MMPs (MMP14, MMP15), and other MMPS (MMP-19, MMP20). Reports have shown correlations between the degradation of the basement membrane by MMPs and the metastatic potential of tumor cells.Tissue inhibitors of metalloproteinases (TIMP) are known to have at least two different functions. They inhibit the catalytic activity of MMPs and they are also able to act as growth factors. Four members of this protein family, TIMP-1 to TIMP-4 have been determined. TIMP-1 plays a role during the activation of MMP-9. It is also able to inactivate the active forms of both MMP-2 and MMP-9. TIMPs have been shown to have the capability to inhibit tumor dissemination animal models.There is discrepancy as to whether TIMP-1 has a role in promoting cancer cell dissemination or whether it inhibits tumor progression and formation of metastases. TIMP-1 has, however, been associated with an unfavorable prognosis in some tumor types, such as lymphomas, lungcancer, colorectal, and gastric carcinoma. Recent reseach shows that the level of MMP and TIMP protein expression correlate with the aggressive behavior of cancers. Higher level of MMP and lower lever of TIMP protein was lower level that may indicate higher level of invasion and metastasis of tumor tissue.MMP-12 was primarily identified as an elastolytic metalloproteinase secreted by inflammatory macrophages. Granulocyte-mcrophage colony stimulating factor (GM-CSF) stimulates tumor infiltrating macrophages to produce Metalloelastase, which cleaves plasminogen into angiostatin. This enzyme has broad substrate specificity, including extracellular matrix proteins such as typeⅠgelactin fibronectin, laminin, vitronectin, proteoglycans, and fibrin and it can also produce angiostatin from plasminogen. Expression of MMP-12 in vivo has previously been described in hepatocellular carcinoma, colorectal carcinoma, vulva carcinoma, renalcell carcinomas, skin cancer, pancreatic cancer, and in esophageal carcinoma. However, the role of MMP-12 in tumor pathogenesis seems to depend on the type of tissue involved. In contrast to our study with SCC, MMP-12 overexpression in hepatocellular as well as in colorectal carcinoma closely correlated with better prognosis, which was explained by the antiangiogenic function of MMP-12 on the basis of the generation of angiostatin from plasminogen. Angiostatin inhibits endothelial cell proliferation, thereby possibly leading to a reduction of metastatic potential.ObjectivesReports have shown correlations between the degradation of the basement membrane by MMPs and the metastatic potential of tumor cells. The clinical relevance of MMPs in Cutaneous squamous cell carcinoma is still under discussion. Several MMPs, especially MMP-2 and MMP-9, seem to correlate with the differe ntiation and lymph node metastasis. For few studies have tried to explore the role of MMP-12 in skin cancers, the aim of the reseach is to investigate the expr ession of matrix metalloproteinase-12 (MMP-12) and its tissue Inhibitor-1 (TIMP-1) in cutaneous squamous cell carcinoma (SCC) and the relationship between the ex pression and tumor differentiation and lymph node metastasis.MethodsImmunohistochemical method by envisionwas used to detect the expression of MMP-12 and TIMP-1 proteins on the paraffin embedded sections of 53 patients with SCC and 32 patients with BD. All statistical analyses were performed using the SPSS software system. The correlations of tumor stage, Tumor-Node-Metastasis classi fication, histological grade, and the primary anatomical site were analyzed separately according to the expression of MMP-12 and TIMP-1 in carcinoma cells. The statis tical significance of these correlations was determined withχ2 Test and the Independ-ent Samples Test, P<0.05.ResultsMMP-12 and TIMP-1 proteins were diffusely expressed in the tumor nets and mesenchymal cells around the nets, while in normal epidermis and BD MMP-12 was negative, and TIMP-1 was weakly positive. The expressive rate of MMP-12 was 84.9 %, and the expression in poorly differentiated tumous or with lymph node metastasis was significantly higher than that in highly differentiated ones (p=0.002) or without lymph node metastasis (p=0.001). The expressive rate of TIMP-1 was 77.4%, and the expression in highly histologic differentiated tumous or without lymph node metastasis was significantly higher than that in poorly histologic differentiated ones (p =0.025) or with lymph node metastasis (p=0.029). The expressive rate of MMP-12 in high histolopathological classification was significantly higher than in low group (p=0.003).There was no significant difference in expressive rate of TIMP-1 between the high histolopathological classification and the low group (p= 0.148)ConclusionThe Expression level of MMP-12 and TIMP-1 protein correlates with the differentiation of carcinoma and lymph node metastasis.The higher expression of MMP-12 and lower expression of TIMP-1 may indicate a higher risk of the tumor invasion and metastasis.