Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that contribute to pathological conditions associated with angiogenesis and tumor invasion. MMP-2 is highly expressed in human astroglioma cells, and contributes to the invasiveness of these cells. The human MMP-2 promoter contains potential cis-acting regulatory elements including cAMP response element-binding protein, AP-1, AP-2, PEA3, C/EBP, and Sp1. Deletion and site-directed mutagenesis analysis of the MMP-2 promoter demonstrates that the Sp1 site at ؊91 to ؊84 base pairs and the AP-2 site at ؊61 to The matrix metalloproteinases (MMPs) 1 are a family of structurally related zinc-dependent endopeptidases capable of degrading extracellular matrix components (for review, see Refs. 1-3). The MMP family includes collagenases, gelatinases, stromelysins, membrane-type metalloproteinases, matrilysin, and metalloelastase. A hallmark of invasive tumors is their ability to degrade the surrounding extracellular matrix, resulting in a compromised matrix organization and disruption of tissue boundaries. A number of in vitro and in vivo studies have documented a direct correlation between high levels of expression of MMP and an increased invasive capacity of tumor cell lines (1, 4 -6). Glioblastoma multiforme is a highly malignant central nervous system tumor that is extremely refractory to therapy due to the rapid growth and local invasive potential of these tumors (for review, see Refs. 7 and 8). This rapid infiltrative growth prevents successful surgical resection of glioblastoma multiformes. The ability of glioma cells to invade the surrounding tissue has been attributed to their secretion of MMPs. In vitro, human glioma cell lines express a variety of MMPs, in particular the type IV collagenases MMP-2 and MMP-9 (9 -15). In vivo studies have also demonstrated the expression of MMP-2 and MMP-9 in human gliomas (11, 12, 16 -18); MMP-2 and MMP-9 expression was the highest in high grade gliomas (glioblastoma multiforme, anaplastic astroglioma) compared with non-invasive low grade astrogliomas and normal brain (11,18,19). Importantly, the invasiveness of glioma cells in vitro correlates with high levels of MMP-2 expression (9,12,14,15,20). A number of strategies have been utilized to modulate MMP-2 expression/activity, then assess subsequent changes in invasive potential. The MMP-2 proenzyme is activated by cell surface-associated membrane-type metalloproteinases (21, 22). Transfection of U251.3 glioma cells with membrane-type metalloproteinases-1 leads to activation of the MMP-2 proenzyme and enhanced invasion as assessed by Matrigel assay (23), as well as remodeling of the extracellular matrix in vitro (24). We have recently demonstrated that two cytokines, tumor necrosis factor-␣ and interferon-␥, inhibit MMP-2 expression in glioma cells, which results in decreased invasiveness of these cells (15). Collectively, these results highlight the important role of MMP-2 in the invasive potential of astroglioma cells.The activity of MMP-2 is regulated by seve...

Human gliomas are highly invasive, and remain to be a major obstacle for any e ective therapeutic remedy. Among many other factors, gliomas express elevated levels of matrix metalloproteinases (MMPs), which have been implicated to play an important role in tumor invasion as well as neovascularization. The tumor suppressor gene mutated in multiple advanced cancers/ phosphatase and tensin homologue (MMAC/PTEN) has been shown to inhibit cell migration, spreading, and focal adhesion. In this study, we determined whether MMAC/ PTEN inhibits tumor invasion by modulating MMP-2 activity. Our results showed that reintroduction of the MMAC/PTEN gene into human glioma U251 and U87 cells modi®ed their phenotype and growth characteristics. The ability of MMAC/PTEN to induce anoikis in U251 cells was accompanied by a signi®cant inhibition of in vitro invasion (70%). Expression of MMAC/PTEN in U251 and U87 cells inhibited MMP-2 enzymatic activity as determined by zymography. Furthermore, MMAC/ PTEN expression strongly decreased MMP-2 mRNA levels, which correlated well with the inhibition of invasion capacity in these cells. Concomitant with MMP-2 expression and activity, MMP-2 promoter activity was also reduced in MMAC/PTEN expressing cells. Our observations suggest that MMAC/PTEN inhibits tumor cell invasion in part by regulating MMP-2 gene transcription and thereby its enzymatic activity. Further characterization of this regulation will facilitate the development of MMAC/PTEN based gene therapy for gliomas. Oncogene (2001) 20, 6669 ± 6678.

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Mutational inactivation of p53, a tumor suppressor gene, is the most common genetic alteration found in human cancer. Most mutated p53s either lose tumor suppressor function or gain oncogenic activity. We recently reported the detection of a heterozygous point mutation of p53 at codon 280 in nasopharyngeal carcinoma (NPC) (1), a high-incidence malignancy in southern China and southeast Asia. Given its heterozygous state, in which both wild-type and mutated p53 gene were expressed, p53-thr280 should function dominantly in the presence of the wild-type form if it is to play a role in nasopharynx carcinogenesis. We tested this dominance hypothesis in the cells of two model systems: 1) human Saos-2 cells lacking endogenous p53, and 2) mouse JB6 tumor promotion-resistant cells (P-) expressing endogenous wild-type p53. The results showed dosage-dependent dominance of p53-thr280 in controlling WT p53-driven transcriptional activity; in governing cell growth; and in progressing P- phenotype to tumor promotion-sensitive (P+) phenotype. This dominant negative effect was seen at a 1:1 (WT:MU) ratio and was more striking at a ratio of 1:3. A model is proposed to explain the dominant negative effect of mutant p53. We conclude from this study that p53-thr280 is likely to be dominant in the heterozygous state found in NPC and that this dominant-negative mutated p53 may contribute to the genesis of NPC or of other carcinomas in which both mutant and wild-type p53 are expressed.

Background As an important nosocomial pathogen, Enterococcus faecium has received increasing attention in recent years. However, a large number of studies have focused on the hospital-associated isolates and ignored isolates originated from the natural environments. Results In this study, comparative genomic analysis was conducted on 161 isolates originated from human, animal, and naturally fermented dairy products. The results showed that the environment played an important role in shaping the genomes of Enterococcus faecium . The isolates from human had the largest average genome size, while the isolates from dairy products had the smallest average genome size and fewest antibiotic resistance genes. A phylogenetic tree was reconstructed based on the genomes of these isolates, which revealed new insights into the phylogenetic relationships among the dairy isolates and those from hospitals, communities, and animals. Furthermore, 202 environment-specific genes were identified, including 136 dairy-specific, 31 human blood-specific, and 35 human gastrointestinal-specific genes. Interestingly, five dairy-specific genes (namely lacF , lacA / B , lacD , lacG , and lacC ) that constituted an integrated lactose metabolism pathway existed in almost all dairy isolates. The pathway conservation demonstrated an active role of the environment in shaping the genomes of Enterococcus faecium . Conclusions This study shows that the Enterococcus faecium species has great genomic plasticity and high versatility to occupy broad ecological roles, dwelling as non-harmful dairy and animal gut commensals as well as significant nosocomial pathogens that disseminate antibiotic resistance genes. Electronic supplementary material The online version of this article (10.1186/s12864-019-5975-8) contains supplementary material, which is available to authorized users.