7076

TIMP1

TIMP metallopeptidase inhibitor 1;TIMP1;TIMP metallopeptidase inhibitor 1

TIMP-1|collagenase inhibitor|erythroid potentiating activity|erythroid-potentiating activity|fibroblast collagenase inhibitor|metalloproteinase inhibitor 1|tissue inhibitor of metalloproteinases 1

Xp11.3-p11.23

protein-coding

Once cancer cells have spread and formed secondary masses, breast cancers are largely incurable even with state-of-the-art medicine. To improve diagnosis and therapy, better markers are needed to distinguish cells which have a high probability for causing clinically relevant, macroscopic metastases. In this review, we summarize the several genes that regulate breast cancer metastasis. Two categories of genes are presented--metastasis activator (ras, MEK1, mta1, proteinases, adhesion molecules, chemoattractants/receptors, autotaxin, PKC, S100A4, RhoC, osteopontin) and metastasis suppressor (Nm23, E-cadherin, TIMPs, KiSS1, Kai1, Maspin, MKK4, BRMS1). While the mechanisms of action for most of these genes are not fully elucidated, some clues are emerging and are presented.

PURPOSE: Only about 50% of metastatic breast cancer patients benefit from cytotoxic chemotherapy. Today, no validated markers exist for prediction of chemotherapy sensitivity/resistance in this patient group. Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been shown to protect against apoptosis, and the purpose of the present study was to test the hypothesis that tumors expressing high levels of TIMP-1 are protected against apoptosis-inducing agents and thus less sensitive to apoptosis-inducing chemotherapeutic drugs. EXPERIMENTAL DESIGN: We investigated the association between primary tumor expression levels of TIMP-1 protein and objective response to first-line chemotherapy in 173 patients with metastatic breast cancer. RESULTS: When analyzed as a continuous log-transformed variable, increasing TIMP-1 levels were significantly associated with lack of response to cyclophosphamide/methotrexate/5-fluorouracil and anthracycline-based chemotherapy (P = 0.01; odds ratio, 2.0; 95% confidence interval, 1.1-3.3). In a multivariate model, including lymph node status, steroid hormone receptor status, menopausal status, dominant metastases site, type of chemotherapy, and disease-free interval, TIMP-1 was significantly associated with resistance to treatment (P = 0.03; odds ratio, 1.7; 95% confidence interval, 1.1-3.3). CONCLUSIONS: In the present exploratory study, we showed that elevated tumor tissue TIMP-1 levels were significantly associated with a poor response to chemotherapy. By using TIMP-1, we identified a group of patients with metastatic breast cancer, which hardly respond to the most frequently used chemotherapy regimes (i.e., cyclophosphamide/methotrexate/5-fluorouracil and anthracyclines).

OBJECTIVE: Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been investigated as a potential tumour marker in breast cancer. Here we investigated the correlation between TIMP-1 in tumour tissue and plasma to evaluate whether TIMP-1 in plasma is actually a surrogate marker for TIMP-1 in primary tumours. Furthermore, we assessed whether increased TIMP-1 levels in plasma could be indicative of tumour progression in patients with advanced breast cancer. METHODS: tumour tissue and preoperatively collected plasma samples from 96 primary breast cancer patients were included together with plasma samples from 46 patients with advanced disease. TIMP-1 levels were measured by ELISA. RESULTS: TIMP-1 levels in plasma (median 81.5 ng/ml, range 41.9-174.9) and tumour tissue (median 25.4 ng/mg of total protein, range 0-110.2) from primary breast cancer patients were not correlated (r = 0.05, p = 0.6). Plasma levels of TIMP-1 in primary breast cancer patients were significantly lower than levels in patients with advanced disease (median 108.7 ng/ml, range 59.7-560.7; p < 0.0001). CONCLUSIONS: Our findings suggest that TIMP-1 release into the blood might be controlled by an active mechanism. They also point to plasma TIMP-1 as a potential marker for predicting tumour progression and for monitoring tumour burden in metastatic breast cancer patients.

In a previous study from our laboratory, high tumor levels of tissue inhibitor of metalloproteinases-1 (TIMP-1) have been associated with an adverse response to chemotherapy in metastatic breast cancer suggesting that TIMP-1, which is known to inhibit apoptosis, may be a new predictive marker in this disease. The purpose of this study was to investigate the association between TIMP-1 and objective response to chemotherapy in an independent patient population consisting of patients with metastatic breast cancer from Sweden and Denmark. TIMP-1 was measured using ELISA in 162 primary tumor extracts from patients who later developed metastatic breast cancer and these levels were related to the objective response to first-line chemotherapy. Increasing levels of TIMP-1 were associated with a decreasing probability of response to treatment, reaching borderline significance (OR = 1.59, 95% CI: 0.97-2.62, P = 0.07). This OR is very similar to the result from our previous study. Increasing levels of TIMP-1 were also associated with a shorter disease-free survival and overall survival, however, not statistically significant. The results from the present study support previous data that TIMP-1 is associated with objective response to chemotherapy for metastatic breast cancer.

AIMS: To investigate the expression of matrix metalloproteases (MMPs) and their inhibitors (TIMPs) in patients who develop local recurrence (LR) after mastectomy. METHODS: We analyzed the expressions of MMP-1, -2, -7, -9, -11, -13, -14, TIMP-1, -2, and -3, using immunohistochemical techniques, in primary tumors from patients without tumoral recurrence (n = 50), patients who developed distant metastasis (n = 50), and from patients who develop LRs (n = 25). LRs of the latter group were also analyzed for MMPs expression. All the patients underwent mastectomy. RESULTS: Score values for all MMPs and TIMPs were significantly higher in primary tumors of patients with distant metastasis. Primary tumors from patients with LR have lower expressions of MMPs and TIMPs compared with those from patients who developed distant metastasis, and with patients without recurrence for some MMPs. Remarkably, however, primary tumors from patients with LR showed significantly higher percentage of TIMP-1 and 2 expression in stromal cells compared to primary tumors from patients with distant metastasis or primary tumors from patients without tumoral progression. Furthermore, LRs had significantly higher MMP-9 expression than their corresponding primary tumors. CONCLUSIONS: Our data indicate differences in MMPs/TIMPs expression between primary tumors of patients with LRs and of those with distant metastasis, both after mastectomy for breast cancer.

INTRODUCTION: Circulating tumor cells (CTCs) reflect aggressive tumor behavior by hematogenous tumor cell dissemination. The tissue inhibitor of metalloproteinase 1 (TIMP-1) plays a role in tissue invasion and is also involved in angiogenesis, abrogation of apoptosis and in chemoresistance. Carbonic anhydrase IX (CAIX) is a metalloenzyme involved in cell adhesion, growth and survival of tumor cells. The aim of the study was to investigate whether serum concentrations of TIMP-1 and CAIX are associated with the detection of CTC in metastatic breast cancer. METHODS: Blood was obtained in a prospective multicenter setting from 253 patients with metastatic breast cancer at the time of disease progression. Serum TIMP-1 and CAIX were determined using commercial ELISA-kits (Oncogene Science). CTC were detected with the CellSearch system (Veridex). RESULTS: Five or more CTCs were detected in 122 patients out of 245 evaluable patients (49.8%). Out of 253 metastatic patients 70 (28%) had serum TIMP-1 levels above 454 ng/mL. Serum CAIX was elevated above 506 ng/mL in 90 (35%) patients. Both serum markers had prognostic significance. Median progression free survival (PFS) was 7.2 months with elevated TIMP-1 vs. 11.4 months with non-elevated levels (p < 0.01). OS was 11.5 vs. 19.1 months (p < 0.01). Median PFS was 7.5 months with elevated CAIX vs. 11.7 months with non-elevated levels (p < 0.01), overall survival (OS) was 13.4 months vs. 19.1 months (p < 0.01). In patients with five or more CTCs, serum levels were above the cut-off for CAIX in 47% vs. 25% in those with less than five CTCs (p = 0.01). For TIMP-1, 37% patients with five or more CTCs had elevated serum levels and 17% of patients with less than five CTCs (p = 0.01). Including TIMP-1, CAIX, CTC and established prognostic factors in the multivariate analysis, the presence of CTCs, the therapy line and elevated CAIX remained independent predictors of OS. CONCLUSIONS: Elevated serum levels of the invasion markers TIMP-1 and CAIX in metastatic breast cancer are prognostic markers and are associated with the presence of CTCs. Whether increased secretion of TIMP-1 and/or CAIX might directly contribute to tumor cell dissemination remains to be elucidated in further investigations. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN59722891.

BACKGROUND & OBJECTIVE: Studies of tumor invasion and metastasis have focused on the degradation of extracellular matrix (ECM). Matrix metalloproteinases (MMPs), which could degrade ECM, were implicated in cancer invasion and metastasis. Activated MMPs were controlled by specific tissue inhibitors of metalloproteinases (TIMPs). This study was designed to investigate the expression of MMP-2, MMP-9 and TIMP-1, TIMP-2 in human squamous cell carcinomas of uterine cervix, and the association with invasion and metastasis of human squamous cell carcinoma of uterine cervix. METHODS: Tissue samples from 40 cases of squamous cell carcinoma of the uterine cervix, 29 cases of cervical intraepithelial neoplasia (CIN), and 16 cases of normal cervices were stained immunohistochemically. RESULTS: Immunohistochemical staining of tumor cells for MMP-2, MMP-9, TIMP-1, and TIMP-2 were noted 82.5%, 70.0%, 62.5%, and 97.5% in carcinomas, 44.8%, 62.1%, 86.21%, and 96.55% in CIN lesions respectively, for MMP-2, MMP-9, TIMP-1 in 25.0% normal cervices, but for TIMP-2 in 56.25% normal cervices. There was significant difference for MMP-2 among carcinomas, normal cervices, and CIN respectively (P < 0.01). There was significant difference for MMP-9 among normal cervices, carcinomas, and CIN, respectively (P < 0.05). The positive rates of TIMP-1 and TIMP-2 in the cervical carcinoma group and CIN group were obviously higher than that in normal cervical group(P < 0.01). The positive rates of MMP-2 and MMP-9 in lymph node metastasis were obviously higher than that in without lymph node metastasis(P < 0.01), but for TIMP-2 was contrary and there was no significant difference for TIMP-1. No significant correlation could be established among the expression of these markers and the tumor diameter, the clinical stage, and pathologic grade. CONCLUSIONS: The over-expression of MMP-2, MMP-9, TIMP-1, and TIMP-2 may play a key role in invasion and lymph-node metastasis of in squamous carcinoma of the cervix.

Here we presented that the expression of RUNX3 was significantly decreased in 75 cases of clear cell renal cell carcinoma (CCRCC) tissues (p<0.05). Enforced RUNX3 expression mediated 786-O cells to exhibit inhibition of growth, G1 cell-cycle arrest and metastasis in vitro, and to lost tumorigenicity in nude mouse model in vivo. RUNX3-induced growth suppression was found partially to regulate various proteins, including inhibition of cyclinD1, cyclinE, cdk2, cdk4 and p-Rb, but increase of p27(Kip1), Rb and TIMP-1. Therefore, RUNX3 had the function of inhibiting the proliferative and metastatic abilities of CCRCC cells by regulating cyclins and TIMP1.

BACKGROUND: We examined expression patterns of matrix metalloproteinase (MMP), tissue inhibitor of metalloproteinase (TIMP), and reversion-inducing cysteine-rich protein with Kazal motifs (RECK) in colorectal cancer tissues to assess their prognostic significance. MATERIALS AND METHODS: mRNA expressions of 17 MMPs, 4 TIMPs, and RECK were measured in 112 colorectal cancerous tissues, 20 normal mucosa tissues, and 11 metastatic liver lesions by real-time reverse-transcriptional-polymerase chain reaction. The protein level expressions were confirmed with immunohistochemistry. RESULTS: cancers and normal mucosa displayed highly significant differences (P < 0.01) in expression of nine genes (MMP-1, -3, -7, -9, -10, -11, -12, -14, and RECK). Primary cancers and metastatic lesions showed highly significant differences (P < 0.01) in MMP-1, -10, -11, and TIMP-1. MMP-12 expression was higher in the primary tumors that were associated without hepatic metastasis than those with metastasis (P < 0.01). High expression of MMP-15 was related to longer disease-free survival (generalized Wilcoxon test, P < 0.0062; Cox hazard model, P < 0.028, hazard ratio, 0.099). CONCLUSIONS: MMP, TIMP, RECK expression patterns may provide an insight into extracellular matrix degrading (which is characteristic of colorectal cancers) and its role in metastasis.

PURPOSE: Tissue inhibitor of metalloproteinase-1 (TIMP-1) is known to protect cells against apoptosis. We raised the hypothesis that elevated tumor tissue levels and thereby plasma levels of TIMP-1 would predict resistance to apoptosis-inducing chemotherapy. EXPERIMENTAL DESIGN: Ninety patients with metastatic colorectal cancer were included in the study. Plasma TIMP-1 and serum carcinoembryonic antigen (CEA) were measured in samples obtained before the first cycle of chemotherapy. RESULTS: Analysis of best objective response (complete or partial response versus stable or progressive disease) showed that patients with low plasma TIMP-1 had higher probability of obtaining an objective response [odds ratio (OR), 3.5; 95% confidence interval (95% CI), 1.4-8.5, P=0.007]. CEA treated as a continuous variable was also a statistically significant predictor of no response (OR, 1.3; 95% CI, 1.0-1.7, P=0.02, area under the curve 0.66) but much less so. Plasma TIMP-1 was the only significant covariate in a multivariable analysis of best objective response (OR, 3.6; 95% CI, 1.4-9.5; P=0.001). Plasma TIMP-1 scored as a continuous variable on the log scale (log(e)) was significantly associated with overall survival [OS; hazard ratio (HR), 3.8; 95% CI, 2.4-5.9; P<0.0001] and with time to progression (TTP; HR, 1.5; 95% CI, 1.0-2.3; P=0.048). Multivariable analysis showed that plasma TIMP-1 was significant for OS when including routine clinical baseline covariates (HR, 3.5; 95% CI, 2.1-5.8; P<0.0001). A multivariable analysis including TTP instead of OS showed that only plasma TIMP-1 was retained in the model (HR, 1.5). CEA was not significantly associated with TTP or OS when TIMP-1 was included in the model. CONCLUSION: This study shows that plasma TIMP-1 levels are significantly and independently associated with objective response, TTP, and OS in patients with metastatic colorectal cancer receiving combination chemotherapy.

BACKGROUND: Matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), have been implicated in invasion and metastasis. The distribution of MMPs and TIMPs in the invasion front of liver metastases from colorectal cancer were investigated in order to understand their potential role in invasiveness. MATERIALS AND METHODS: Freshly frozen material of colorectal metastases of the liver was microdissected into four separate compartments, namely pure liver, liver invasion, tumour invasion and pure tumour. RNA was isolated and analyzed on Affymetrix microarrays. expression of TIMP-1 was confirmed by quantitative polymerase chain reaction in 10 colorectal liver metastases. Cellular localisation of TIMP-1 was examined by immunohistochemistry. RESULTS: Affymetrix microarray data revealed that several MMP and TIMP genes including MMP-2, -3, -7, -9, -11, -12, -14, -15, -16, -19 and -24, and TIMP-1, -2 and -3 were generally up-regulated in both invasion front compartments. Among these genes, TIMP-1 showed the highest expression. The qPCR results indicated an average 15-fold upregulation of TIMP-1 in the liver invasive front and an average 13-fold up-regulation in the tumor invasive front, each compared to normal liver tissue. Immunohistochemistry revealed expression of TIMP-1 in tumour epithelia as well as in host tissue cells, including fibroblastic cells. CONCLUSION: Our data indicate that tumour invasion in colorectal liver metastasis is associated with increased TIMP-1 RNA and protein levels in both tumour and host cells.

BACKGROUND & OBJECTIVE: Matrix metalloproteinase-9 (MMPs) and its tissue inhibitor of metalloproteinase-1 (TIMPs) have the important regulatory roles in the processes during tumor invasion and metastasis. Observing the coexpression of matrix metalloproteinase 9(MMP-9) and tissue inhibitor of metalloproteinase 1(TIMP-1) in gastric carcinomas, this study was designed to investigate the relationship of the expression unbalance of MMP-9 and TIMP-1 to the invasiveness, metastasis, and prognosis in gastric carcinomas. METHODS: By using immunohistochemistry, the expression of MMP-9, TIMP-1, and proliferating cell nuclear antigen Ki-67 was detected in 256 gastric cancers, and the patients were followed-up. RESULTS: The expressive degree of MMP-9 in the tumor invasion beyond musculariis propria(70.13%) was higher than that within lamina propria or submucosa(42.50%, P < 0.05) and its expression in tumor was positively associated with tumor cell proliferation index and lymph node metastasis, and its expression in high TNM stage(75.00%) was higher than those in low TNM stage(46.15%, P < 0.05). The relation of the expression of TIMP-1 to the depth of invasion, lymph node metastasis, and TNM stage was negative(Pearson contingency coefficient were 0.1688, 0.3556, and 0.3004, respectively P < 0.05). There were four groups of the unbalance expression of MMP-9 and TIMP-1 in gastric carcinomas. While the frequency of the serosa invasion and lymph node metastasis in the group of the expression of MMP-9 over TIMP-1 was significantly higher than those in the groups of the expression of TIMP-1 over MMP-9 or the balance expression of MMP-9 and TIMP-1. However, prognosis of the patients with the expression of MMP-9 over TIMP-1 was significantly worse than that with expression of TIMP-1 over MMP-9(P < 0.05). CONCLUSION: The expression of MMP-9 was positively related to the tumor invasiveness and metastasis in gastric cancers, however the association between the positive expression of TIMP-1 and the invasiveness and metastasis was negative. The relationship of MMP-9 and TIMP-1 to the invasiveness and metastasis in gastric carcinomas was that MMP-9 promotes and TIMP-1 inhibits tumor metastasis. The patients with MMP-9 positive expression and TIMP-1 negative expression are poorer prognosis.

AIM: The expressive balance between matrix metalloproteinase-9 (MMP-9) and its tissue inhibitor of metalloproteinase-1 (TIMP-1) plays a critical role in maintaining the degradation and synthesis of extracellular matrix. Loss of such balance is associated with invasion and metastasis of tumors. This study aimed to determine the expression of MMP-9 and TIMP-1 in gastric carcinoma, and the association of the expressive imbalance between MMP-9 and TIMP-1 with the invasion and metastasis and prognosis of gastric carcinoma. METHODS: We used immunohistochemistry to determine the expressions of MMP-9, TIMP-1 and proliferating cell nuclear antigen Ki-67 in the gastric specimens taken from 256 patients with primary gastric carcinoma. The patients were followed-up for up to 96 months. RESULTS: No association between the expression of MMP-9 and TIMP-1 and patients sex and age, tumor size and location of gastric carcinoma was observed. The incidence of the positive expression of MMP-9 in cases with tumors invasion to muscularis propria and visceral peritoneum (70.13 % and 69.09 %, respectively) was significantly higher than that in cases with tumor invasion only to lamina propria or submucosa (42.50 %, P=0.0162). The positive correlation between MMP-9 expression and the depth of tumor invasion was observed (Pearson correlation coefficient=0.2129, P=0.016). Along with the increase of the metastatic station of lymph nodes, the incidence of the MMP-9 expression was increased by degrees; a positive correlation between them was observed (Pearson correlation coefficient=0.2910, P=0.0001). There was also a significant correlation between MMP-9 expression and the TNM stage in gastric carcinoma (Pearson correlation coefficient=0.3027, P<0.0001). The incidence of MMP-9 expression in stage II and III/IV (75.00 % and 76.15 %, respectively) was significantly higher than those in stage I (46.15 %, P<0.0001). A negative correlation between TIMP-1 immunoreactivity and the depth of invasion, status of lymph node metastasis and TNM stage was observed (Pearson correlation coefficient =-0.1688, -0.3556 and -0.3004, P=0.023, <0.0001 and <0.0001, respectively). Four types of co-expression of MMP-9 and TIMP-1 were observed; i.e. MMP-9 positive but TIMP-1 negative (n=115), both positive (n=52), both negative (n=62) and MMP-9 negative but TIMP-1 positive (n=27). The frequency of serosal invasiveness was significant higher in patients with MMP-9 but without TIMP-1 expression than those with other types of the co-expression (P=0.0303). The incidence of lymph node metastasis was highest in patients with MMP-9 but without TIMP-1 expression, and lowest in those with TIMP-1 but without MMP-9 expression (P<0.0001). The survival rate in patients with MMP-9 but without TIMP-1 expression was lower than that in those with TIMP-1 but without MMP-9 expression (P=0.0014). CONCLUSION: Our results in gastric carcinoma demonstrated a significant positive association of MMP-9 over-expression with proliferation of tumor cells, the depth of invasiveness, lymph node metastasis and TNM stage, suggesting MMP-9 can serve as a molecular marker of tumor invasion and metastasis. We also demonstrate a significant negative relationship of TIMP-1 expression with the depth of invasiveness and lymph node metastasis, which provide a new idea in the tumor biological and genetic treatment. The interaction between MMP-9 and TIMP-1 in the processes of tumor invasion and metastasis is that MMP-9 mainly promotes tumor invasion and metastasis and TIMP-1 inhibits functions of MMP-9. The imbalance between MMP-9 and TIMP-1 expression may suggest the occurrence of tumor invasion and metastasis, predict poor prognosis. For patients with imbalanced MMP-9 and TIMP-1 expression, the optimal treatment scheme needs to be selected.

PURPOSE: Tissue inhibitors of metalloproteinases (TIMP) are capable of inhibiting the matrix metalloproteinases, but they also possess other biological functions. Little is known about the role of TIMP-1 in the progression and spreading of cancer cells among patients with head and neck squamous cell carcinoma (HNSCC). In this study, the pretreatment serum levels of TIMP-1 or the overexpression of TIMP-1 immunoreactive protein in the primary tumor was correlated to the clinical course in patients with HNSCC. EXPERIMENTAL DESIGN: The TIMP-1 immunoreactive protein was studied in 74 cases representing HNSCC. The tissue immunoreactive protein was evaluated from paraffin-embedded tumor sections in 68 cases using immunohistologic staining with a specific antibody, and in 68 cases the pretreatment serum levels of TIMP-1 were quantitatively measured by ELISA assay. The results were compared with the clinicopathologic factors of the disease and the patients' outcome. RESULTS: A positive correlation was found between the size of the primary tumor (T) and the circulating TIMP-1 level (P = 0.021) or the positive immunoreaction of TIMP-1 in tumor (P = 0.039). The 5-year cause-specific survival was significantly lower in patients presenting with a high serum TIMP-1 level than in those with a low level of TIMP-1 (38% versus 64%, P = 0.034). They also had an unfavorable 5-year relapse-free survival rate (37% versus 56%, respectively). Similarly, the expression of TIMP-1 in tumor was prognostic for shortened survival, the 5-year cumulative relapse-free survival being 42% in patients with a TIMP-1-positive tumor versus 75% in cases with a negative tumor (P = 0.035). Tissue TIMP-1 positivity also seemed associated to the cause-specific survival (P = 0.075) and to be connected with later lymph node or hematogenic relapses. CONCLUSIONS: This study shows for the first time that both circulating and tissue TIMP-1 immunoreactive protein predicts the clinical course and dissemination in HNSCC, suggesting that TIMP-1 might be related to both tumor growth and metastasis in HNSCC.

Molecular markers can provide additional information to traditional histomorphological evaluation for the assessment of tumor progression and predicting the likelihood of invasion and metastasis in various types of malignancies. We studied the association of E-cadherin, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinase with the progression and metastasis of hepatocellular carcinoma. Tissue microarray including six normal livers, 14 cirrhotic livers, 39 macroregenerative nodules, 16 dysplastic nodules, 22 grade I hepatocellular carcinomas, 43 grade II hepatocellular carcinomas, seven grade III hepatocellular carcinomas, and 10 metastatic hepatocellular carcinomas were stained immunohistochemically with antibodies against MMPs -1, -2, -3, -7, -9, tissue inhibitors of metalloproteinase-1, -2, -3, and E-cadherin. The intensities of staining were scored manually by two pathologists and verified by the Chromavision Automated Cellular Imaging System. Compared with normal liver, cirrhotic liver had significantly lower E-cadherin and tissue inhibitors of metalloproteinase-1 but higher MMP-1 and -7, which suggest a more favorable environment for tumor invasion and metastasis. Grade I and grade II hepatocellular carcinomas demonstrated high E-cadherin and decreased MMP-3 and -9, which may explain the rarity of extrahepatic metastasis in low-grade hepatocellular carcinomas despite the high circulatory volume of the liver. The histological progression from dysplastic nodule to well-differentiated hepatocellular carcinoma and to less differentiated tumors was associated with a gradual decrease in tissue expression of E-cadherin, tissue inhibitors of metalloproteinase-2 and -3. metastatic hepatocellular carcinomas showed significantly lower level of tissue inhibitors of metalloproteinase-1, -2, -3 but higher level of MMP-7. These data suggest that tissue expression of E-cadherin, certain MMPs, and tissue inhibitors of metalloproteinases could be useful markers to predict the progression and metastasis of hepatocellular carcinoma.

We investigated the role of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 in the growth regulation. Primary (PM-WK and KHm-4), recurrent primary (RPM-EP and RPM-MC), lymph node metastatic (MM-AN, MM-BP and MM-RU), and a visceral metastatic (MM-LH) melanoma cell lines were used. Reverse transcriptase-coupled polymerase chain reaction and Western blotting revealed that all expressed and produced TIMP-1 and TIMP-2 except for PM-WK, which neither expressed nor produced TIMP-1. TIMP-1 and TIMP-2 secretion levels were measured by enzyme-linked immunosorbent assay in supernatants of cells. We found that the TIMP-1 production level was correlated with the cell migration rate. Moreover, TIMP-1 enhanced the cell migration of PM-WK. The growth of the primary melanoma cell lines was stimulated by TIMP-1 and inhibited by TIMP-2. In contrast, the growth of the visceral metastatic melanoma cell line was stimulated by TIMP-2.

OBJECTIVE: To investigate the expression and significance of matrix metalloproteinases (MMP-2, MMP-9) and tissue inhibitor of matrix metalloproteinase (TIMP-2, TIMP-1) in non-melanoma skin cancer (NMSC). METHODS: Thirty six patients with squamous cell carcinoma (SCC) and 32 patients with basal cell carcinoma (BCC), confirmed by pathology, were selected, and 30 cases of normal skin were selected as control. The expression of MMP-2, MMP-9, TIMP-1 and TIMP-2 in all samples were examined by immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). The expression rate, expression intensity and expression level of each factor were recorded. The results were compared between the groups. RESULTS: The expression rates of MMP-2 and MMP-9 in the control group were 30.0% and 36.7%, the expression levels of MMP-2 and MMP-9 in the control group were 57.216 +/- 12.785 and 59.318 +/- 13.262, all significantly lower than those in the tumor edge and center of the SCC and BCC groups (P < 0.01). The expression rates of TIMP-1 and TIMP-2 in the control group were 96.7% and 100%, their expression levels were 121.738 +/- 25.516 and 122.612 +/- 25.964, all significantly higher than those in the SCC and BCC groups (P < 0.01). The expression levels of MMP-2 and MMP-9 in the tumor center and edge of SCC group were significantly higher than those in the corresponding parts of the BCC group, while the expression levels of TIMP-1 and TIMP-2 were significantly lower than those in the BCC group (P < 0.01). The expression levels of MMP-2 and MMP-9 in the tumor edge of the SCC and BCC groups were significantly higher than those in the tumor centers (P < 0.01), while the expression levels of TIMP-1and TIMP-2 were significantly lower than those in the tumor centers (P < 0.01). CONCLUSION: MMP-2, MMP-9 and TIMP-2, TIMP-1 may play an important role in the development, progression, invasion and metastasis of non-melanoma skin cancer.

OBJECTIVE: To compare the expression of matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1 of nasopharyngeal carcinoma at Xi'an and Shenzhen area. METHOD: The protein expression of MMP 9 and TIMP 1 were studied by immunohistochemistry staining in 21 cases nasopharyngeal carcinoma of Xi'an and 22 cases of Shenzhen. RESULT: The expression positive rates of MMP-9 in nasopharyngeal carcinoma tissues at Xi'an and Shenzhen were 61.90% and 68.18%. The positive rates of TIMP-1 in nasopharyngeal carcinoma tissues at two regions were 28.57% and 31.82%. The expression between MMP-9 and TIMP-1 were negative relationship either Xi'an or Shenzhen. The expression of MMP-9 was positively correlated to lymph node metastasis, and TIMP-1 was no relationship with lymph node metastasis. The expression of MMP-9 and TIMP-1 was no difference between Xi'an and Shenzhen. CONCLUSION: The expression of MMP-9 and TIMP-1 in nasopharyngeal carcinoma 2 tissues was no difference between Xi'an and Shenzhen. Increase of MMP-9 play an important role in progression and metastasis of nasopharyngeal carcinoma.

Here we presented that the expression of RUNX3 was significantly decreased in 75 cases of clear cell renal cell carcinoma (CCRCC) tissues (p<0.05). Enforced RUNX3 expression mediated 786-O cells to exhibit inhibition of growth, G1 cell-cycle arrest and metastasis in vitro, and to lost tumorigenicity in nude mouse model in vivo. RUNX3-induced growth suppression was found partially to regulate various proteins, including inhibition of cyclinD1, cyclinE, cdk2, cdk4 and p-Rb, but increase of p27(Kip1), Rb and TIMP-1. Therefore, RUNX3 had the function of inhibiting the proliferative and metastatic abilities of CCRCC cells by regulating cyclins and TIMP1.