The disintegrin-metalloproteinases ADAM9, ADAM12, and ADAM15 are upregulated in gastric cancer

Carl-McGrath, Stacy; Lendeckel, Uwe; Eder, Matthias; Roessner, Albert; Röcken, Christoph

doi:10.3892/ijo.26.1.17

Cited by 106 publications

(123 citation statements)

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Ray

Dhar

Shakya

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Upregulation of ADAM-12, a novel member of the multifunctional ADAM family of proteins is linked to cancer, arthritis and cardiac hypertrophy. Basal expression of ADAM-12 is very low in adult tissues but rises markedly in response to certain physiological cues, such as during pregnancy in the placenta, during development in neonatal skeletal muscle and bone and in regenerating muscle. Studies on ADAM-12 regulation have identified a highly conserved negative regulatory element (NRE) at the 5′-UTR of human ADAM-12 gene, which acts as a transcriptional repressor. The NRE contains a stretch of dinucleotide-repeat sequence that is able to adopt a Z-DNA conformation both in vitro and in vivo and interacts with hZα ADAR1 , a bona fide Z-DNA-binding protein. Substitution of the dinucleotide-repeat-element with a non-Z-DNA-forming sequence inhibited NRE function. We have detected a NRE DNA-binding protein activity in several tissues where ADAM-12 expression is low while no such activity was seen in the placenta where ADAM-12 expression is high. These observations suggest that interaction of these proteins with ADAM-12 NRE is critical for transcriptional repression of ADAM-12. We also show that the Z-DNA forming transcriptional repressor element, by interacting with these putative Z-DNA-binding proteins, is involved in the maintenance of constitutive low-level expression of human ADAM-12. Together these results provide a foundation for therapeutic down-regulation of ADAM-12 in cancer, arthritis and cardiac hypertrophy.

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Section: Discussionmentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

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

Ray

Dhar

Shakya

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…In vivo, ADAM-10 and -17 are overexpressed in antral mucosa during H. pylori infection and ADAM-9, -10, -12, -15, and -17 are increased in gastric tumours [150,151]. ADAM-10 acts through EGFR ligand shedding leading to gastric cell proliferation [151][152][153].…”

Section: Gastric and Colon Carcinomamentioning

confidence: 99%

Emerging roles of ADAM and ADAMTS metalloproteinases in cancer

et al. 2008

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A disintegrin and metalloproteinases (ADAMs) are a recently discovered family of proteins that share the metalloproteinase domain with matrix metalloproteinases (MMPs). Among this family, structural features distinguish the membrane-anchored ADAMs and the secreted ADAMs with thrombospondin motifs referred to as ADAMTSs. By acting on a large panel of membrane-associated and extracellular substrates, they control several cell functions such as adhesion, fusion, migration and proliferation. The current review addresses the contribution of these proteinases in the positive and negative regulation of cancer progression as mainly mediated by the regulation of growth factor activities and integrin functions.

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“…11). Further, elevated ADAM-15 expression has been reported in cell lines from hematologic malignancies; in ovarian, gastric, breast, prostate, and lung cancers and cell lines; and in brain tumors (21)(22)(23)(24)(25)(26). The ADAM15 gene is localized to chromosome band 1q21.3, a region that is amplified in several types of cancers (27,28).…”

Section: Introductionmentioning

confidence: 99%

Distinct Functions of Natural ADAM-15 Cytoplasmic Domain Variants in Human Mammary Carcinoma

Zhong

Poghosyan

Pennington

et al. 2008

Molecular Cancer Research

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Adamalysins [a disintegrin and metalloproteinase (ADAM)] are a family of cell surface transmembrane proteins that have broad biological functions encompassing proteolysis, adhesion, and cell signal regulation. We previously showed that the cytoplasmic domain of ADAM-15 interacts with Src family protein tyrosine kinases and the adaptor protein growth factor receptor binding protein 2 (Grb2). In the present study, we have cloned and characterized four alternatively spliced forms of ADAM-15, which differ only in their cytoplasmic domains. We show that the four ADAM-15 variants were differentially expressed in human mammary carcinoma tissues compared with normal breast. The expression of the individual isoforms did not correlate with age, menopausal status, tumor size or grade, nodal status, Nottingham Prognostic Index, or steroid hormone receptor status. However, higher levels of two isoforms (ADAM-15A and ADAM-5B) were associated with poorer relapse-free survival in node-negative patients, whereas elevated ADAM-15C correlated with better relapse-free survival in node-positive, but not in node-negative, patients. The expression of ADAM-15A and ADAM-15B variants in MDA-MB-435 cells had differential effects on cell morphology, with adhesion, migration, and invasion enhanced by expression of ADAM-15A, whereas ADAM-15B led to reduced adhesion. Using glutathione S-transferase pull-down assays, we showed that the cytoplasmic domains of ADAM-15A, ADAM-15B, and ADAM-15C show equivalent abilities to interact with extracellular signal-regulated kinase and the adaptor molecules Grb2 and Tks5/Fish, but associate in an isoform-specific fashion with Nck and the Src and Brk tyrosine kinases. These data indicate that selective expression of ADAM-15 variants in breast cancers could play an important role in determining tumor aggressiveness by interplay with intracellular signaling pathways. (Mol Cancer Res 2008;6(3):383 -94)

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The disintegrin-metalloproteinases ADAM9, ADAM12, and ADAM15 are upregulated in gastric cancer

Cited by 106 publications

References 0 publications

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

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

Emerging roles of ADAM and ADAMTS metalloproteinases in cancer

Distinct Functions of Natural ADAM-15 Cytoplasmic Domain Variants in Human Mammary Carcinoma

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