7077

TIMP2

TIMP metallopeptidase inhibitor 2;TIMP2;TIMP metallopeptidase inhibitor 2

metalloproteinase inhibitor 2|tissue inhibitor of metalloproteinases 2

17q25

protein-coding

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.

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.

BACKGROUND: Hilar cholangiocarcinoma is associated with low resectability and poor survival. The aim of this study was to evaluate the roles of matrix metalloproteinases-2 (MMP-2) and its tissue inhibitor of metalloproteinase-2(TIMP-2) in tumor invasion or as a prognostic factor in patients with human hilar cholangiocarcinoma. METHODS: The expressions of MMP-2 and TIMP-2 were investigated in patients. Paraffinized tissue sections obtained from 50 patients with human hilar cholangiocarcinoma were analysed. The expressions of MMP-2 and TIMP-2 were examined immunohistochemically. Image analysis with image-pro plus analysis software was used to semiquantitatively determine the ratio of MMP-2 to TIMP-2. RESULTS: The expression levels of MMP-2 and TIMP-2 were strongly associated with tumor hepatic invasion in patients with hilar cholangiocarcinoma. Significant differences in the ratio of MMP-2 to TIMP-2 between some pathologic factors were observed in patients with hilar cholangiocarcinoma. CONCLUSIONS: MMP-2 plays an essential role in tumor invasion and metastasis, while TIMP-2 is shown to strongly inhibit cancer invasion and metastasis. The ratio of MMP-2 to TIMP-2 may be a prognostic indicator for patients with hilar cholangiocarcinoma.

tumor metastasis and lack of NKG2D ligand (NKG2DL) expression are associated with poor prognosis in patients with colon cancer. Here, we found that spironolactone (SPIR), an FDA-approved diuretic drug with a long-term safety profile, can up-regulate NKG2DL expression in multiple colon cancer cell lines by activating the ATM-Chk2-mediated checkpoint pathway, which in turn enhances tumor elimination by natural killer cells. SPIR can also up-regulate the expression of metastasis-suppressor genes TIMP2 and TIMP3, thereby reducing tumor cell invasiveness. Although SPIR is an aldosterone antagonist, its antitumor effects are independent of the mineralocorticoid receptor pathway. By screening the human nuclear hormone receptor siRNA library, we identified retinoid X receptor gamma (RXRgamma) instead as being indispensable for the antitumor functions of SPIR. Collectively, our results strongly support the use of SPIR or other RXRgamma agonists with minimal side effects for colon cancer prevention and therapy.

The objective of the study was the assessment of serum levels and tissue expression of matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of matrix metalloproteinases 2 (TIMP-2) in patients with colorectal cancer (CRC). The study included 72 CRC patients and 68 healthy subjects. The serum levels of MMP-2 and TIMP-2 were measured using enzyme-linked immunosorbent assay (ELISA) method, whereas tissue expression of MMP-2 and TIMP-2 in cancer cells, interstitial inflammatory cells, and adjacent normal colorectal mucosa were examined by immunohistochemical staining of tumor samples. The serum levels of MMP-2 and TIMP-2 in cancer patients were significantly lower than those in control group, but the percentage of positive immunoreactivity of these proteins were higher in malignant and inflammatory cells as compared to normal tissue. There was a significant correlation between MMP-2 immunoreactivity in inflammatory cells and the presence of distant metastases and between TIMP-2 expression in inflammatory cells and tumor size, nodal involvement, and distant metastases. Area under receiver operating characteristic (ROC) curve (AUC) for serum MMP-2 was higher than for serum TIMP-2. Moreover, positive tissue expression of MMP-2 was a significant prognostic factor for CRC patients survival. Our findings suggest that MMP-2 and TIMP-2 might play a role in the process of colorectal cancer invasion and metastasis, but the significance of their interactions with tumor stroma and interstitial inflammatory infiltration in colorectal neoplasia require further elucidation.

INTRODUCTION: Factors that emerge as crucial participants in tumour invasion and metastases are matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinase (TIMP) inhibitors and cellular adhesion molecules (CD44 and similar molecules). They play important roles in tumour invasion and metastasis in non-small-cell lung carcinomas (NSCLCs). MATERIALS AND METHODS: The study was performed using the data of 33 patients. MMP-2 from the metalloproteinase family, TIMP-2 from the metalloproteinase inhibitor family and the adhesion molecule CD44v6 expression were investigated immunohistochemically to search their role in the metastasis and the clinical outcome of the patients with NSCLCs. RESULTS: Twenty-three tumours (70%) were squamous cell carcinoma (SCC), 9 (27%) were adenocarcinoma (AC), and 1 (3%) was large cell carcinoma (LCC). MMP-2 and TIMP-2 were expressed in high rates in NSCLC but CD44v6 expression was about 50%. Lymphatic invasion was less frequent in TIMP-2- positive patients and this difference was statistically significant (P = 0.005). There was a statistically significant difference between SCCs and ACs with respect to CD44v6 tumoral expression (P = 0.004). Also, there was a negative correlation between lymphatic invasion and the extent of CD44v6; lymphatic invasion was significantly less in CD44v6-positive cases (P = 0.013). CONCLUSION: We found that TIMP-2 and CD44v6 can decrease the lymphatic invasion in NSCLCs. Also there was observed histiotype-related pattern of CD44v6 variant expression in SCCs.

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 study the expression of tissue inhibitor of matrix metalloproteinase 2 (TIMP2)in the nasopharyngeal carcinoma and to evaluate the relationships between the expression of TIMP2 and biological behavior of NPC. METHOD: The expression of TIMP2 was observed by immunohistochemical technique in 50 cases with nasopharyngeal carcinoma and 15 cases of Inflammation nasopharyngeal tissues. RESULT: The positive rates of TIMP2 are significantly higher in NPC than in Inflammation tissues (P < 0.05). The expression of TIMP2 increase significantly with lymph node metastasis (P < 0.01), but had no relevant to the rise clinical invasion stage (P > 0.05). CONCLUSION: The results indicate that TIMP2 may play a critical role in assisting carcinoma cell to degrade basement membrane to invade surrounding tissues and to form metastatic colonies in lymph node. Especially the unbalance in MMP2/TIMP2 has probably a prognostic value in nasopharyngeal carcinoma.

INTRODUCTION: Factors that emerge as crucial participants in tumour invasion and metastases are matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinase (TIMP) inhibitors and cellular adhesion molecules (CD44 and similar molecules). They play important roles in tumour invasion and metastasis in non-small-cell lung carcinomas (NSCLCs). MATERIALS AND METHODS: The study was performed using the data of 33 patients. MMP-2 from the metalloproteinase family, TIMP-2 from the metalloproteinase inhibitor family and the adhesion molecule CD44v6 expression were investigated immunohistochemically to search their role in the metastasis and the clinical outcome of the patients with NSCLCs. RESULTS: Twenty-three tumours (70%) were squamous cell carcinoma (SCC), 9 (27%) were adenocarcinoma (AC), and 1 (3%) was large cell carcinoma (LCC). MMP-2 and TIMP-2 were expressed in high rates in NSCLC but CD44v6 expression was about 50%. Lymphatic invasion was less frequent in TIMP-2- positive patients and this difference was statistically significant (P = 0.005). There was a statistically significant difference between SCCs and ACs with respect to CD44v6 tumoral expression (P = 0.004). Also, there was a negative correlation between lymphatic invasion and the extent of CD44v6; lymphatic invasion was significantly less in CD44v6-positive cases (P = 0.013). CONCLUSION: We found that TIMP-2 and CD44v6 can decrease the lymphatic invasion in NSCLCs. Also there was observed histiotype-related pattern of CD44v6 variant expression in SCCs.

The aim of this study is to investigate the expression of matrix metalloproteinase 2 (MMP-2) and the tissue inhibitor of metalloproteinase 2 (TIMP-2) in oral squamous cell carcinoma (OSCC) and adjacent normal tissues, and explore the role of MMP-2 and TIMP-2 in carcinoma metastasis and invasion. expression of MMP-2 and TIMP-2 was evaluated in 40 cases with semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemical techniques. The values of MMP-2/beta-actin and TIMP-2/beta-actin in OSCC were significantly higher than those in adjacent normal tissues 2 cm and > or = 5 cm from carcinoma tissues (p<0.05). The results of immunohistochemical analysis show that the positive expression of MMP-2 and TIMP-2 protein in tumor tissues (60.0 and 52.5%) was higher than that in adjacent normal tissues 2 cm (30.0 and 22.5%) and 5 cm (22.5 and 25.0%) from cancer tissues, and the difference was significant p<0.05). The expression of MMP-2 and TIMP-2 was related to the differentiation degree of tumor cells, metastatic lymph node status and stage of carcinoma, but not related to the age and gender of patients, or location of the carcinoma. Therefore, MMP-2 and TIMP-2 may play important roles in the invasion and metastasis of OSCC.

Gene silencing via CpG island methylation in the promoter region is one of the mechanisms by which tumor suppressor genes are inactivated in human cancers. Previous studies have shown that the tissue inhibitors of metalloproteinases (TIMP)-2 gene, which is an endogenous inhibitor of matrix metalloproteinases involved in cell invasion and tumorigenesis, is downregulated or silenced in a variety of human cancer cell lines. Here, we investigated the mechanism underlying TIMP-2 expression in prostate cancer cell lines and primary prostate tumor samples. We observed a strong correlation between promoter hypermethylation and lost expression of TIMP-2 gene, which was supported by other results demonstrating that promoter demethylation by 5-aza-2'-deoxycytidine and trichostatin A reactivated TIMP-2 and restored its expression in TIMP-2-silenced metastatic prostate cell lines. These results were further substantiated by a chromatin immunoprecipitation assay, showing the preferential binding of MeCP2 to methylated CpG island in TIMP-2-silenced metastatic prostate cell lines. In vitro Matrigel invasion assays showed that re-expression of TIMP-2 after a combined treatment with 5-aza and trichostatin-A in metastatic prostate cells resulted in a significant reduction of tumor cell invasion. Furthermore, CpG methylation of TIMP-2 promoter was also shown in primary prostate tumors that expressed decreased TIMP-2 protein levels. These results suggest that the downregulation of the TIMP-2 gene is associated with promoter methylation and that this may play an important role in prostate cancer progression during the invasive and metastatic stages of the disease.