Correlations Between Papillary Thyroid Cancer And Peripheral Blood Levels Of MMP-2、MMP-9、TIMP-1、TIMP-2

Special examinations in the diagnosis of thyroid cancer, mainly relying on ultrasound. The ultrasound is one of the most valuable methods of primary thyroid cancer lesions diagnosis. The American Thyroid Association (ATA) elected underwent ultrasound examination of all thyroid nodules. The use of high-frequency probe sensitivity,2mm diameter tumor can be detected, ultrasound can understand tumor location, number, size, shape, whether coated tumor, substantive or cystic, blood flow, and the presence or absence of calcification regional lymph node abnormalities. The following performance ultrasound to consider a possible thyroid cancer:tumor morphology is irregular, no envelope, no round halo, especially rich in blood flow in the tumor parenchyma with small calcification, central zone or neck area appear abnormal lymph nodes. Course, certain ultrasound misdiagnosis rate, especially combined with other diseases such as nodular goiter, lymphocytic thyroiditis and subacute thyroiditis, and clinicians to understand the special type of thyroid cancer ultrasound performance, such as cystic papillary thyroid carcinoma, diffuse thyroid papillary carcinoma clinical easily with thyroid cyst or lymphocytic thyroiditis confused. Fine-needle aspiration cytology biopsy (FNA) is a relatively precise and cost-effective method of evaluating thyroid nodules. Ultrasound-guided FNA its accuracy can be as high as95%. many medical institutions in Europe and the United States and other countries have sent FNA instead of frozen thyroid surgery, but there are different points of view, a review of the literature, the accuracy of thyroid FNA larger data. Gharib had summarizes the sensitivity, specificity, positive predictive value, false-negative rate and false positive rate and other indicators were65%to98%, from72%to100%, from50%to96%,1%to11%and0～7%. Not only the above indicators exist greater volatility, even researchers that is difficult to accurately calculate the sensitivity and negative predictive value of thyroid FNA. This work is not common, of domestic scholars there are different views, FNA cause misdiagnosis analysis summarized as:①puncture needle is too thin, inadequate cytology specimens.②related to the thyroid tumor size and internal organization of, thyroid tumor volume is smaller, more difficult to locate, fine needle aspiration biopsy diagnosis rate is lower, especially for internal liquefied thyroid tumor, only to puncture needle penetrates the capsule out of the liquid, tissue cells, the diagnosis meaningless.(3) cytologic diagnosis of morphological changes most prominent diseases can play a role, but mainly to organizational structure change lesions difficult. Therefore, even if the the FNA results negative cases can not be completely ruled out the possibility of malignancy, especially for small lesions hidden cancer need more careful investigation, to minimize the probability of missed.In addition to the above checks there any other ways to aid in the diagnosis of thyroid cancer.? In recent years, tumor research in the field of hot spot matrix metalloproteinases, and tissue matrix metalloproteinase inhibitor provides a new idea for us.Matrix metalloproteinase (MMP) is secreted by connective tissue involved in extracellular matrix degradation Zn2+-dependent protease family. The the MMP structures by the signal peptide region, the propeptide region, the catalytic region, the hinge region, the heme-binding protein sample area, which may be mediated by the MMP and extracellular matrix components, or TIMP binding and to determine substrate specificity. MMPs family members have been found in five categories,20kinds of first class collagenase their hydrolysis substrate fiber classes collagen, ie Ⅰ Ⅱ, Ⅲ collagen type the first three enzymes rolein al (Ⅰ) chain Gly775-Ile776and cx2(Ⅰ) chain between Gly775-Leu776peptide bond hydrolysis of the collagen type I fragment into1/4and3/4second type gelatinasetheir main hydrolysis of the substrate is denatured collagen, the main component of the BM collagen type IV and V collagen type, they can act on al (Ⅳ) chain Gly446-Ile447sites and a2(Ⅳ) chain of Gly464-Leu465the sites of the degradation of collagen type IV1/4and3/4fragments. MMP-2can be decomposed glycoprotein component of FN and LN, MMP-9, you can not. third category is the matrix hydrolases, MMP-3and-10hydrolysis substrate, Ⅲ, Ⅳ, Ⅴ type Ⅱ collagen, gelatin, proteoglycans, and glycoproteins such as membrane type-of MMPs, they are the new members of the MMP family, MMP-14,-15,-16,-17cDNA containing3.4,3.53,3.1and1.55kb, respectively582,699,604and518amino acids encoded molecular mass were63,72,64and70ku has found that MMP-14and MMP-16can be activated MMP-2. fifth category for other of MMPs, including MMP-7hydrolyzed substrate also wider, such as:proteoglycans, gelatin, collagen type Ⅳ, FN, LN and entactin etc.. MMP-2, MMP-9specific degradation of the main component of the extracellular matrix and basement membrane type IV collagen, tumor invasion and metastasis is the most direct and most important metalloproteinase. MMP virtually drop discharged polysaccharide other than all the extracellular matrix, an MMP can be directly to the degradation of one or several of the extracellular matrix, can also be the role through the activation of other types of MMP, thus forming the waterfall effect. In addition to MMP in embryonic development, cell migration, angiogenesis, wound healing, the atherosclerosis invasion and metastasis of malignant tumors and other physiological and pathological processes play an important role.Tissue inhibitor of metalloproteinase (TIMP) is a secreted protein family, is a natural inhibitor of an endogenous distribution of a wide range of MMP expression in tumor and stromal tissue. The TIMP is divided into two functional areas, functional areas of the N-terminal cysteine residues and MMP Zn2-active site is formed in a1:1ratio, the C-terminal functional areas in conjunction with the other parts of the MMP, MMP-TIMP composite body, thereby blocking MMP and substrate binding. Can be divided into four kinds of targets of TIMP-1, TIMP-2, TIMP-3, TIMP-4. TIMP can inhibit MMP proteolysis, but the development of tumors, such as cell growth, proliferation, apoptosis, angiogenesis, such as the role of diversity.The mechanisms of TIMP regulating MMP is mainly reflected in the the zymogen activation phase and activation of MMP stage. For example, TIMP-2with MMP-1precursor to form a stable complex and prevent zymogen self-activated MMP-1; TIMP-1or TIMP-2, and activation of MMP binding directly inhibit the catalytic activity of the latter.Waveren that affect the dynamic balance between TIMP-2and MMP-2tumor invasion and metastasis, the unusual significance of the imbalance in the ratio between the two single factor is more significant. In tumor tissue, MMP, TIMP than normal tissue are overexpression of TIMP increased consider feedback regulation caused to the body of the MMP was significantly higher, but its higher below the level of MMP. Body both MMP and TIMP balance was broken, TIMP-relative MMP quantity of reduction, resulting in TIMP inhibiting MMP diminished capacity, and MMP activity is enhanced, accelerated the degradation of the extracellular matrix, promoting tumor cells break through the basement membrane outward diffusion, and even cause hematogenous or lymphatic metastasis.The extracellular matrix (ECM) is the main barrier to tumor metastasis. Break through the basement membrane around into the ECM is the first step in thyroid cancer metastasis and invasion. MMP-9MMP molecular weight enzyme secreted zymogen form, the activated form of collagenase IV, degradation, destruction of the ECM and basement membrane of the surface of the tumor, the cancer cells along the missing basement membrane to the surrounding tissue infiltration. MMP-2can also degradation of type I collagen, activated MMP-9, MMP-13, the joint action of degradation of other ECM components. The TIMP As a natural inhibitor of MMP. Can down-regulate MMP activity has an important role in the maintenance of the ECM. Maintain the relative balance between MMPs and TIMPs in normal tissue state, work together to maintain the ECM degradation or aggregation. But of MMP and TIMP in tumor tissue over-expression, and the expression of MMP than of TIMP, between the balance is broken, resulting in the degradation of the ECM and basement membrane.MMP is a dual role in the formation of new blood vessels in the tumor tissue. One hand, MMP activation without active transforming growth factor beta (TGF-beta) is released by degradation of the matrix component and the matrix component binding of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), by degradation vascular basement membrane and release of membrane-bound tumor necrosis factor-a (TNF-a), the above are to promote angiogenic cytokines. MMP-9can promote endothelial cells or tumor cell VEGF expression, and promote more effective role of VEGF to its receptor, both synergistic release of vascular endothelial cells from the basement membrane and migration, involved in angiogenesis. On the other hand, to promote the release of the angiogenesis inhibitor:Vascular statins cracking plasminogen intrinsic factor (the MMP cleavage III, V basement membrane type X collagen carboxy-terminal fragment), inhibition of angiogenesis. The former plays a dominant role in tumor development. TIMP inhibition of endothelial cell proliferation induced by bFGF, inhibit the migration of endothelial cells of the tubular matrix gel, which inhibits angiogenesis by reducing VEGF production.Apoptosis in tumor cells through the escape be overgrowth and reproduction. MMP-3. MMP-7. MMP-11are involved in tumor cell growth regulation. MMP-3through degradation of laminin protein promoting apoptosis. MMP-7Degradation of the Fas ligand on the cell membrane, shedding it on the cell membrane, thereby inhibiting the Fas-mediated apoptosis mechanism, and promote tumor growth. Lysin3, MMP-11(interstitial) through the decomposition of insulin-like growth factor binding protein, to promote the release of the insulin-like growth factor I (IGFI) reduced spontaneous apoptosis of tumor cells. Division cycle, in particular the S phase, TIMP in the nucleus large gathering, involved in cell growth regulation. TIMP-1and TIMP-2can promote cell mitosis; TIMP-2inhibition of fibroblast growth factor, reducing epithelial cell growth.Closely related to the development and metastasis of thyroid cancer around cancer cells, extracellular matrix and basement membrane degradation. The study showed that in normal thyroid tissue and thyroid adenoma tissue MMP-2. MMP-9mostly negative expression of both a high degree of deteriorationor invasive thyroid carcinoma express a number of strongly positive. Compared with normal tissues, the positive expression of TIMP thyroid cancer also increased. More than that, the one hand, to maintain a balance between the two in order to suppress the increased expression of MMPexpression of TIMP expression increased to inhibit MMP degradation of extracellular matrix and basement membrane, and inhibition of tumor invasion and metastasis; on the other hand the expression of TIMP increased tumor cell growth, proliferation, apoptosis and angiogenesis regulating diverse. Pasieka found in peripheral bloodof MMP-2and TIMP-2concentration and thyroid carcinoma also relevant. The interaction between MMP and TIMP both jointly promote the occurrence and metastasis of thyroid cancer. Peripheral blood MMP and TIMP thyroid cancer is a relationship, whether it can be used as amethod for the diagnosis of thyroid cancer to become the focus of our concern, we want to explore the relationship between them in the subsequent study.In this study, by the enzyme-linked immunosorbent assay (ELISA) and RT-PCR method to detect the peripheral blood of patients with thyroid cancer in MMP-2, MMP-9, TIMP-1and TIMP-2expression. The results found that MMP-2, MMP-9. TIMP-1, of TIMP-2expression in thyroid cancer group were significantly higher than benign thyroid lesions and healthy groups, while no expression in benign thyroid lesions and healthy groups significant difference. Detected in peripheral blood of MMP-2, MMP-9, TIMP-1, TIMP-2, can aid in the diagnosis of papillary thyroid cancer, benign and malignant before surgery to determine thyroid nodules has important reference value.