ADAM12 Is Selectively Overexpressed in Human Glioblastomas and Is Associated with Glioblastoma Cell Proliferation and Shedding of Heparin-Binding Epidermal Growth Factor

Abstract

ADAMs (a disintegrin and metalloproteinases) are multifunctional molecules involved in cell-cell fusion, cell adhesion, membrane protein shedding, and proteolysis. In the present study, we examined the mRNA expression of 13 different ADAM species with putative metalloproteinase activity in human astrocytic tumors, nonneoplastic brain tissues, and other intracranial tumors by reverse transcriptase-polymerase chain reaction, and found that prototype membrane-anchored ADAM12 (ADAM12m) is predominantly expressed in glioblastomas. Real-time quantitative polymerase chain reaction indicated that the expression level of ADAM12m is remarkably at least 5.7-fold higher in glioblastomas (n ‫؍‬ 16) than in nonneoplastic brain tissues (n ‫؍‬ 6), low grade (n ‫؍‬ 7) and anaplastic astrocytic tumors (n ‫؍‬ 9) (P < 0.05 for each group), and intracranial neurinomas (n ‫؍‬ 5) (P < 0.01). In situ hybridization showed that glioblastoma cells are responsible for the gene expression. ADAMs (a disintegrin and metalloproteinases) are a gene family of multidomain membrane-anchored proteins comprising of more than 30 members in various animal species (see http://www.people.virginia.edu/ϳjw7g/Tableof theADAMs.html) and are implicated in pathophysiological conditions, which include neuronal development, 1 cancer development and progression, 2,3 and inflammatory responses 4 through proteolysis, cell adhesion, cell fusion, and cell-matrix interaction. 5,6 They contain several distinct domains with structural homology to the reprolysin/adamalysin family of snake venom metalloproteinases.7 A typical ADAM protein includes an N-terminal signal peptide, and propeptide, metalloproteinase, disintegrin, cysteine-rich, epidermal growth factor-like, transmembrane, and cytoplasmic domains. The metalloproteinase domains of several ADAMs have a catalytic site with the conventional zinc-dependent metalloproteinase sequence (HEXGHXXGXXHD), which is highly homologous to that of the matrix metalloproteinases (MMPs).

Z-DNA-forming silencer in the first exon regulates human ADAM-12 gene expression

“…Because ADAM-12 is synthesized at a high level in several cancers (5,(10)(11)(12)(13)(14)(15), it is tempting to speculate that alteration of Z-DNAmediated transcriptional regulation of ADAM-12 might be responsible, at least in part, for such an increase. Further understanding of the molecular basis of ADAM-12 regulation will have functional implications for suppressing ADAM-12 linked pathologies and ultimately lead to design of new therapeutics.…”

“…9. In many tumor tissues, including breast, liver, gastric, brain, bone, and prostate cancer, ADAM-12 mRNA level is increased (10)(11)(12)(13)(14)(15). ADAM-12 is being considered as a marker of breast cancer progression (5) and prostate tumor progression (15).…”

Expression of ADAMTS-8, a secreted protease with antiangiogenic properties, is downregulated in brain tumours

“…Similarly, angiogenesis (also essential to tumour progression) is reliant on the positive and negative regulation of proteases such as the MMPs, ADAMs and ADAMTS (review by Handsley and Edwards, 2005). Until recently, the ADAMs and ADAMTS genes were relatively understudied in brain tumours (and other cancers), however, recent reports have suggested roles for ADAMTS-4, TS-5 (HeldFeindt et al, 2006;Nakada et al, 2005) and ADAM-12 (Kodama et al, 2004) in GBM, where these proteases are overexpressed. In contrast, we have shown that the expression of ADAMTS-8 is downregulated in brain tumours relative to normal brain.…”

Emerging roles of ADAM and ADAMTS metalloproteinases in cancer

“…The membrane-bound ADAM-12 variant is overexpressed in glioblastomas [123] and a treatment of cultured glioblastoma cells with an ADAM-12 inhibitor decreases the production of mature HB-EGF indicating that ADAM-12-HB-EGF pathway might be of biological significance in those cells.…”