A disintegrin and metalloprotease 12 (ADAM12) is a prognostic factor in resected pathological stage I lung adenocarcinoma

Mino, Nobuya; Miyahara, Ryoji; Nakayama, Eiichiro; Takahashi, Tsuyoshi; Takahashi, Ayuko; Iwakiri, Shotaro; Sonobe, Makoto; Okubo, Kan; Hirata, Toshiki; Sehara, Atsuko; Date, Hiroshi

doi:10.1002/jso.21313

Cited by 38 publications

(24 citation statements)

References 41 publications

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“…MMP-9 has also been reported to induce the angiogenic switch in a carcinogenic model of pancreatic islets, which is a critical requirement for the acquisition of the angiogenic phenotype in early cancer development (52). Also worth noting is the fact that the mRNA of ADAM12 has been previously detected in cancer tissues of early-stage lung cancer (31). On the basis of these previous reports and our current results, ADAM12 and MMP-9/NGAL complex appear to be promising sentinels of the presence of gastric cancer.…”

Section: Discussionmentioning

confidence: 98%

Urinary ADAM12 and MMP-9/NGAL Complex Detect the Presence of Gastric Cancer

Shimura

Dagher

Sachdev

et al. 2015

Cancer Prevention Research

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Although the early diagnosis of gastric cancer provides the opportunity for curative endoscopic resection, comprehensive screening endoscopy would be invasive and expensive. To date, there is a complete absence of clinically useful gastric cancer biomarkers. With the goal of discovering noninvasive biomarkers for the early diagnosis of gastric cancer, we have conducted a case-control study using urine samples from individuals with gastric cancer versus healthy control samples. Of the enrolled 106 patients from September, 2012 to April, 2013, a cohort of 70 patients composed of 35 patients with gastric cancer and 35 age-and sex-matched healthy controls was analyzed. The gastric cancer group was composed of stage IA of 62.9% (22/35). The urinary levels of MMP-9/NGAL complex (uMMP-9/NGAL) and ADAM12 (uADAM12) were significantly higher in the gastric cancer group compared with the healthy control group as determined by monospecific ELISAs (uMMP-9/NGAL: median, 85 pg/mL vs. 0 pg/mL; P ¼ 0.020; uADAM12: median, 3.35 ng/mL vs. 1.44 ng/mL; P < 0.001). Multivariate analysis demonstrated that both uMMP-9/NGAL and uADAM12 were significant, independent diagnostic biomarkers for gastric cancer. Moreover, MMP-9/NGAL activity was significantly elevated as determined by gelatin zymography. The combination of uMMP-9/NGAL with uADAM12 distinguished between control samples and gastric cancer samples with an AUC of 0.825 (P < 0.001) in an ROC analysis. Significantly, immunohistochemical analyses demonstrated a high coexpression of MMP-9 and NGAL (P < 0.001) and high expression of ADAM12 (P < 0.001) in gastric cancer tissues compared with adjacent normal tissues (N ¼ 35). In summary, uMMP-9/NGAL and uADAM12 are potential noninvasive biomarkers for gastric cancer, including early-stage disease. Cancer Prev Res; 8(3); 240-8. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 98%

Urinary ADAM12 and MMP-9/NGAL Complex Detect the Presence of Gastric Cancer

Shimura

Dagher

Sachdev

et al. 2015

Cancer Prevention Research

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“…An understanding of the mechanisms that promote tumor angiogenesis could help us target tumors more efficiently and effectively. ADAM12 ( a d isintegrin a nd m etalloprotease) is upregulated in breast (1–5), prostate (6), ovarian (7), skin (8), stomach (9), lung (10) and brain cancers (11), however, a role for ADAM12 in either developmental or pathological angiogenesis has not yet been described. Human ADAM12 can be expressed as two alternately spliced variants: the membrane-associated ADAM12-L, and the shorter secreted ADAM12-S (12).…”

Section: Introductionmentioning

confidence: 99%

ADAM12 Is a Novel Regulator of Tumor Angiogenesis via STAT3 Signaling

Roy

Dagher

Butterfield

et al. 2017

Molecular Cancer Research

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ADAM12, (A Disintegrin and metalloproteinase domain-containing protein 12), is upregulated in epithelial cancers and contributes to increased tumor proliferation, metastasis and endocrine resistance. However, its role in tumor angiogenesis is unknown. Here we report that ADAM12 is upregulated in the vessels of aggressive breast tumors and exerts key regulatory functions. ADAM12 significantly increases bFGF-mediated angiogenesis in vivo and ADAM12 levels are upregulated in tumors that have undergone a switch to the angiogenic phenotype. Importantly, ADAM12-overexpressing breast tumors display a higher microvessel density (MVD). Our aim was to identify the mechanisms by which tumor-associated ADAM12 promotes angiogenesis. ADAM12 expression in breast tumor cells correlated with a significant upregulation of proangiogenic factors such as VEGF and MMP-9 and downregulation of antiangiogenic factors such as Thrombospondin-1 (THBS1/TSP1) and Tissue inhibitor of metalloproteinases-2 (TIMP-2). Co-culture with ADAM12-expressing tumor cells promoted endothelial cell (EC) recruitment and capillary tube formation. Conversely, downregulation of endogenous ADAM12 in breast cancer cell lines resulted in reduction of pro-angiogenic factors and EC recruitment. These ADAM12-mediated effects are driven by the activation of EGFR, STAT3 and Akt signaling. Blockade of EGFR/STAT3 or silencing of ADAM12 reversed the proangiogenic tumor phenotype, significantly downregulated pro-angiogenic mitogens and reduced EC recruitment. In human breast cancer tissues, ADAM12 expression was significantly positively correlated with pro-angiogenic factors including VEGF and MMP-9 but negatively associated with TSP1.

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“…For example, ADAM12 expression levels are 20 -30-fold higher in human breast tumors than in normal mammary epithelium (7)(8)(9)(10)(11)(12). ADAM12 expression is also markedly up-regulated in cancers of the liver, lung, stomach, colon, prostate, bladder, and in glioblastoma (13)(14)(15)(16)(17)(18). Increased ADAM12 expression levels are found in the cardiac tissue of patients with hypertrophic obstructive cardiomyopathy (19) and in mice with angiotensin II-induced hypertension and cardiac hypertrophy (20,21).…”

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confidence: 99%

The Role of SnoN in Transforming Growth Factor β1-induced Expression of Metalloprotease-Disintegrin ADAM12

Solomon

Muggy

et al. 2010

Journal of Biological Chemistry

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Increased expression of metalloprotease-disintegrin ADAM12 is a hallmark of several pathological conditions, including cancer, cardiovascular disease, and certain inflammatory diseases of the central nervous system or the muscoskeletal system. We show that transforming growth factor ␤1 (TGF␤1) is a potent inducer of ADAM12 mRNA and protein in mouse fibroblasts and in mouse and human mammary epithelial cells. Induction of ADAM12 is detected within 2 h of treatment with TGF␤1, is Smad2/Smad3-dependent, and is a result of derepression of the ADAM12, a member of the metalloprotease-disintegrin family of proteins, has been implicated in the progression of cancer, cardiovascular disease, osteoarthritis, and neurological disorders (1). The ADAM12 gene is frequently mutated in human breast cancers (2, 3), and cancer-associated mutations cause mislocalization of the ADAM12 protein in cells and alter its function (4). Missense single nuclear polymorphism in the ADAM12 gene shows strong association with osteoarthritis (5, 6). In addition to changes in its amino acid sequence, expression levels of ADAM12 are significantly increased in many pathological states. For example, ADAM12 expression levels are 20 -30-fold higher in human breast tumors than in normal mammary epithelium (7-12). ADAM12 expression is also markedly up-regulated in cancers of the liver, lung, stomach, colon, prostate, bladder, and in glioblastoma (13-18). Increased ADAM12 expression levels are found in the cardiac tissue of patients with hypertrophic obstructive cardiomyopathy (19) and in mice with angiotensin II-induced hypertension and cardiac hypertrophy (20,21). During inflammatory responses and aseptic osteolysis associated with loosened hip replacement implants, ADAM12 is up-regulated in the interface tissue around loosening implants (22). In experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, ADAM12 level is markedly increased in the T cells that infiltrate spinal cords (23).The mechanisms regulating ADAM12 expression, in particular those that may be responsible for altered levels of ADAM12 in various pathological states, are poorly understood. Previous studies employing hepatic stellate cells, a mesenchymal cell type in hepatic parenchyma, have indicated that ADAM12 expression is induced by transforming growth factor ␤ (TGF␤) 2 (13, 24). The TGF␤ signaling pathway is initiated when one of the family members, e.g. TGF␤1, -␤2, or -␤3, binds to a complex of TGF␤ type I and type II serine/threonine kinase receptors (T␤RI and T␤RII, respectively) and induces phosphorylation and activation of T␤RI by T␤RII. T␤RI then phosphorylates receptor Smads (R-Smads), Smad2 and Smad3. Phosphorylated Smad2/3 associate with the common partner Smad4 and translocate to the nucleus, where they regulate transcription of target genes (25,26). In addition, receptor activation in certain cell types leads to Smad-independent responses via the activation of mitogen-activated protein kinases (MAPKs), phosphoinositide 3-kinase, and Rho family memb...

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A disintegrin and metalloprotease 12 (ADAM12) is a prognostic factor in resected pathological stage I lung adenocarcinoma

Abstract: ADAM12-L mRNA expression is an independent prognostic factor in resected p-stage I lung adenocarcinoma, and is significantly correlated with tumor differentiation stage and postoperative cancer recurrence.

Cited by 38 publications

References 41 publications

Urinary ADAM12 and MMP-9/NGAL Complex Detect the Presence of Gastric Cancer

Urinary ADAM12 and MMP-9/NGAL Complex Detect the Presence of Gastric Cancer

ADAM12 Is a Novel Regulator of Tumor Angiogenesis via STAT3 Signaling

The Role of SnoN in Transforming Growth Factor β1-induced Expression of Metalloprotease-Disintegrin ADAM12

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