A Disintegrin And Metalloprotease 12 Research Articles

Amplifying T cell-mediated antitumor immune responsesin nonsmall cell lung cancer through photodynamic therapy and anti-PD1.

Photodynamic therapy (PDT)is nowadays widely employed in cancer treatment. We sought to assess the efficacy of combining PDT with anti-programmed cell death protein 1 (PD1)and to investigate the associated mechanisms in nonsmall cell lung cancer (NSCLC).We established a xenograft tumor model in C57BL/6J mice using Lewis lung carcinoma (LLC)cells, recorded tumor growth, and quantified reactive oxygen species (ROS)levels using a ROS detection kit. Pathological changes were assessed through H&E staining, while immunofluorescence (IF)was used to determine the expression of CD8 and Foxp3. Transcriptomic analysis was conducted, analyzing differential expressed genes (DEGs)among control, PDT, and PDT combined with anti-PD1(PDT+anti-PD1)groups. Functional enrichment analysis via Gene Ontology (GO)and Kyoto Encyclopedia of Genes and Genomes (KEGG)was performed. The Cancer Genome Atlas (TCGA)database was utilized to analyze the expression of aminolevulinate synthase gene (ALAS2),integrin alpha10 (ITGA10),ATP1A2, a disintegrin and metalloprotease 12 (ADAM12),and Lox1 in lung adenocarcinoma and adjacent tissues, with concurrent immune infiltration analysis. Quantitative real-time polymerase chain reaction and western blot were employed to measure mRNA and protein expression levels. Treatment with PDT combined with anti-PD1significantly inhibited tumor growth and increased the number of CD8+ cells while decreasing Foxp3+ cells. Immune infiltration results presented ALAS2, ADAM12, and ITGA10 were associated with various types of T cells or macrophages. Additionally, the expression levels of EGFR, ERK, and PI3K/Akt were suppressed after PDT with anti-PD1treatment. Our findings collectively suggest that PDT combined with anti-PD1 treatment could enhance the infiltration of CD8+ T cells, suppressing tumor growth, and this effect was associated with ALAS2, ITGA10, and ADAM12. The underlying mechanism might be linked to EGFR, ERK, and PI3K/Akt signaling. Overall, this study provides valuable insights into the application of PDT combined with anti-PD1 treatment in NSCLC.

A disintegrin and metalloprotease 12 contributes to colorectal cancer metastasis by regulating epithelial‑mesenchymal transition.

A disintegrin and metalloprotease 12 (ADAM12) and epithelial‑mesenchymal transition (EMT) are linked in the metastasis of various types of cancer. The present study aimed to assess the ability of ADAM12 to induce EMT and its potential as a therapeutic target for colorectal cancer (CRC). ADAM12 expression in CRC cell lines, CRC tissues and a mouse model of peritoneal metastasis was assessed. The effect of ADAM12 on CRC EMT and metastasis was investigated using ADAM12‑pcDNA6‑myc and ADAM12‑pGFP‑C‑shLenti constructs. ADAM12 overexpression enhanced the proliferation, migration, invasion and EMT of CRC cells. The phosphorylation levels of factors associated with the PI3K/Akt pathway were also increased by ADAM12 overexpression. The knockdown of ADAM12 reversed these effects. ADAM12 expression and the loss of E‑cadherin expression were significantly associated with poorer survival compared with other expression statuses of both proteins. In a mouse model of peritoneal metastasis, overexpression of ADAM12 induced increased tumor weight and peritoneal carcinomatosis index compared with that in the negative control group. Conversely, knockdown of ADAM12 reversed these effects. Furthermore, E‑cadherin expression was significantly decreased by overexpression of ADAM12 compared with in the negative control group. By contrast, E‑cadherin expression was increased by knockdown of ADAM12 compared with in the negative control group. ADAM12 overexpression contributed to CRC metastasis by regulating EMT. In addition, in the mouse model of peritoneal metastasis, ADAM12 knockdown exhibited strong anti‑metastatic action. Consequently, ADAM12 may be considered a therapeutic target for CRC metastasis.

Validation of a multiple marker test for early pregnancy outcome prediction.

To validate the use of a multiple biomarker test panel for predicting first trimester pregnancy outcome in a multi-center cohort. A case-control study of women presenting with pain and bleeding in early pregnancy at 5-10 weeks gestational age was performed at three academic centers. Sera from women with ectopic pregnancy (EP), viable intrauterine pregnancy (IUP), and miscarriage (SAB) were analyzed via immunoassay for Activin A (AA), Progesterone (P4), A Disintegrin And Metalloprotease-12 (ADAM12), pregnancy-associated plasma protein A (PAPP-A), glycodelin (Glyc), and human chorionic gonadotropin (hCG). Biomarkers were assessed for reproducibility using medians, ranges, standard deviations, and area under receiver-operating characteristic curve (AUC) and accuracy in early pregnancy outcome classification compared to a previous derivation population. In 192 pregnancies, the biomarkers demonstrated good reproducibility with similar medians, ranges, and AUCs when compared to the derivation population except glycodelin. Pregnancy location was conclusively classified in 53% (n = 94) of the whole study sample with 78% accuracy. Pregnancy viability was conclusively classified in 58% (n = 112) of the new sample with 89% accuracy. Results were similar with subsequent model revisions where glycodelin was excluded and in the subgroups of subjects with a hCG below 2000 mIU/mL and a gestational age less than 6 weeks. The use of a panel of biomarkers to maximize test accuracy of a prediction of pregnancy location and prediction of pregnancy viability was reproducible and validated in an external population from which it was derived, but clinical utility is limited based on the test characteristics obtained.

ADAM12 promotes gemcitabine resistance by activating EGFR signaling pathway and induces EMT in bladder cancer.

Gemcitabine (GEM)-based chemotherapy regimens is widely used in bladder cancer (BC) patients. However, GEM resistance may occur and result in treatment failure and disease progression. A disintegrin and metalloprotease 12 (ADAM12) plays a critical role in many cancers. However, the role of ADAM12 in GEM resistance of BC remains unclear. We analyzed the relationship between ADAM12 expression and tumor characteristics using the data downloaded from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database. Then, we established GEM resistant BC cell lines and used quantitative real-time PCR, western blot, cell counting kit-8, immunohistochemistry, and xenograft mouse model to investigate the role of ADAM12 in GEM resistance. In general, ADAM12 was found to be upregulated in GEM resistant BC cells. ADAM12 knockdown increased the chemosensitivity of BC cells. We further proved that ADAM12 could promote GEM resistance by activating the epidermal growth factor receptor (EGFR) signaling pathway in BC. Furthermore, the epithelial-mesenchymal transition (EMT) phenotype was observed in GEM resistant BC cells. ADAM12 induced EMT process and promotes tumor progression in BC. Our findings suggested that ADAM12 was a key gene for GEM resistance and positively correlated with malignancy of BC. It might serve as a novel and valuable therapeutic target for BC.

Proteomics and Biochemical Analyses of Secreted Proteins Revealed a Novel Mechanism by Which ADAM12S Regulates the Migration of Gastric Cancer Cells.

Gastric cancer is one of the cancers with the highest morbidity and mortality. Although several therapeutic approaches have been developed to treat this disease, the overall survival rate is still very low due to metastasis, drug resistance, and so forth. Therefore, it is necessary to discover new regulatory molecules and signaling pathways that modulate the metastasis of gastric cancer cells. A Disintegrin And Metalloprotease 12 (ADAM12) was highly expressed in gastric cancer tissues and presented in the patient urine. However, it is unclear whether and how ADAM12 regulates the migration of gastric cancer cells. In this work, we used the secretome protein enrichment with click sugars (SPECS) method to purify the secreted glycosylated proteins and performed quantitative proteomics to identify the secreted proteins that were differentially regulated by ADAM12S, the short and secreted form of ADAM12. Our proteomic and biochemical analyses revealed that ADAM12S upregulated the cell surface glycoprotein CD146, a cell adhesion molecule and melanoma marker, which was dependent on the catalytic residue of ADAM12S. Furthermore, we discovered that the ADAM12S-enhanced migration of gastric cancer cells was, at least partially, mediated by CD146. This work may help to evaluate whether ADAM12 could be a potential therapeutic target for the treatment of gastric cancer patients.

Serum-based measurements of stromal activation through ADAM12 associate with poor prognosis in colorectal cancer

BackgroundRecently it has been recognized that stromal markers could be used as a clinically relevant biomarker for therapy response and prognosis. Here, we report on a serum marker for stromal activation, A Disintegrin and Metalloprotease 12 (ADAM12) in colorectal cancer (CRC).MethodsUsing gene expression databases we investigated ADAM12 expression in CRC and delineated the source of ADAM12 expression. The clinical value of ADAM12 was retrospectively assessed in the CAIRO2 trial in metastatic CRC with 235 patients (31% of total cohort), and an independent rectal cancer cohort (n = 20).ResultsADAM12 is expressed by activated CRC associated fibroblasts. In the CAIRO2 trial cohort, ADAM12 serum levels were prognostic (ADAM12 low versus ADAM12 high; median OS 25.3 vs. 17.1 months, HR 1.48 [95% CI 1.11–1.96], P = 0.007). The prognostic potential was specifically high for metastatic rectal cancer (HR 1.78 [95% CI 1.06–3.00], P = 0.030) and mesenchymal subtype tumors (HR 2.12 [95% CI 1.25–3.60], P = 0.004). ADAM12 also showed potential for predicting recurrence in an exploratory analysis of non-metastatic rectal cancers.ConclusionsHere we describe a non-invasive marker for activated stroma in CRC which associates with poor outcome, especially for primary cancers located in the rectum.

Elevation of ADAM12 facilitates tumor progression by enhancing metastasis and immune infiltration in gastric cancer.

A disintegrin and metalloprotease 12 (ADAM12), an essential transmembrane protein with metalloprotease, cell binding and intracellular signal-regulating capabilities, has been reported to play a crucial role in various types of cancers. However, the biological function of ADAM12 in gastric cancer (GC) remains unclear. Bioinformatic and experimental analyses were used to determine the expression level and prognostic value of ADAM12 in GC. The level of DNA methylation and the competing endogenous RNA (ceRNA) network was identified using MethSurv, Starbase3.0, miRNet2.0 and experimental analyses. Then, the co-expression profiles of ADAM12 were determined and subjected to enrichment analysis using the LinkedOmics database. The protein-protein interaction network and the docking model of ADAM12 were constructed using the GeneMANIA, STRING, and HDOCK webservers. The role of ADAM12 in tumor metastasis and immune infiltration was investigated using in vitro assays and TIMER database exploration. It was found that ADAM12 was overexpressed and was correlated with a poor prognosis of GC patients. In addition, the aberrant DNA methylation status and ceRNA regulation may contribute to the upregulation of ADAM12 in GC. Moreover, the enrichment analysis revealed that ADAM12 is involved in multiple vital biological functions and pathways, such as 'macrophage activation', 'extracellular matrix binding' and 'ECM-receptor interaction'. Subsequently, the protein-protein interaction network and molecular docking model demonstrated that follistatin like 3 (FSTL3) is a potential binding partner of ADAM12. Finally, it was demonstrated that ADAM12 promotes tumor metastasis, immune infiltration and M2 macrophage polarization in GC. In summary, these results highlight the potential of ADAM12 to be used as a therapeutic target for GC.

Tetra-primers ARMS-PCR Based Association Analyses of Synonymous and Intronic Variants in the ADAM12 Gene with Susceptibility to Knee Osteoarthritis: A Case-Control Study.

Genetic variations in a disintegrin and metalloprotease 12 (ADAM12) gene may contribute to develop Osteoarthritis (OA) that is characterized by cartilage matrix degradation and osteophytes formation. Therefore, the aim of present study was to analyze the association between the ADAM12 gene variants and knee OA predisposition. Tetra-primers ARMS-PCR was employed, to genotype the ADAM12 gene polymorphisms (rs1044122 and rs1871054) in 400 knee OA patients and equal number of age-matched controls. The association between ADAM12 gene variants and OA susceptibility was estimated using the Chi-square, logistic regression, haplotypes and linkage analyses. A significant association of rs1044122 (genotype: χ2 = 18.94; P < 0.001, allele: χ2 = 19.10; P < 0.001) and rs1871054 (genotype: χ2 = 10.04; P = 0.007, allele: χ2 = 10.57; P = 0.001) was observed with increased OA susceptibility. The variant genotype of rs1044122 increased OA risk more than twice [odds ratio (OR) 2.20; P = 0.001] and the risk was higher in females (OR 2.43; P = 0.001). The variant genotype of rs1871054 was perceived to almost double the risk in females (OR 1.97; P = 0.003). Moreover, a significant association of rs1044122 and rs1871054 under the additive genetic model (P < 0.001 and P = 0.002, respectively) was observed. The targeted ADAM12 gene polymorphisms, showed significant association with knee OA susceptibility. Females harboring the polymorphisms might be at risk. Besides, the haplotype CC of rs1044122 and rs1871054 in the ADAM12 gene may double knee OA risk. These findings may help in determining the etiology of OA and recognizing the people at risk of developing knee OA.

FOXC2/ADAM12-dependent radiosensitivity of head and neck squamous cell carcinoma cells.

Radiotherapy greatly benefits patients with tumors, but not all patients show favorable treatment response. This study investigated the impact of forkhead box protein C2 (FOXC2)-mediated a disintegrin and metalloprotease 12 (ADAM12) on the radiosensitivity of head and neck squamous cell carcinoma (HNSCC). After transfection and ionizing radiation, the biological activities of HNSCC cells were assessed. The relationship between ADAM12 and FOXC2 was verified. A xenograft model was used to evaluate the effect of FOXC2 knockdown on HNSCC growth in the context of radiation therapy. FOXC2 and ADAM12 were upregulated in irradiated CAL-27 and HN4 cells. Knockdown of FOXC2 suppressed the malignant behaviors of CAL-27 and HN4 cells and inhibited the growth of transplanted tumors in nude mice. FOXC2 could bind ADAM12 promoter. Overexpression of ADAM12 reversed the promotion of FOXC2 silencing on the radiosensitivity of HNSCC cells. FOXC2 regulates the radiosensitivity of HNSCC by targeting ADAM12.

Preoperative serum ADAM12 levels as a stromal marker for overall survival and benefit of adjuvant therapy in patients with resected pancreatic and periampullary cancer.

We evaluated the stroma marker A Disintegrin And Metalloprotease 12 (ADAM12) as a preoperative prognostic and treatment-predictive marker for overall survival (OS) in pancreatic ductal adenocarcinoma (PDAC) and periampullary cancers. Materials were derived from the prospective nationwide Dutch Pancreas Biobank (2015-2017). We included patients who underwent resection because of PDAC/periampullary cancer or non-invasive IPMN (control group) and had a preoperative serum sample available. ADAM12 levels were dichotomized using a pre-defined cut-off (316pg/mL). Univariable and multivariable Cox regression analyses (backward selection) were performed. Median ADAM12 levels were 161 (IQR 79-352) pg/mL in 215 PDAC and periampullary adenocarcinomas. High ADAM12 levels (>316pg/mL) predicted poor OS in the total group of pancreatic and periampullary adenocarcinomas (P=0.04), but not after adjustment. In distal cholangiocarcinoma (n=33), high ADAM12 levels predicted poor OS in univariable analysis (P=0.02), but not in PDAC (P=0.63). PDAC patients (n=135) with high ADAM12 levels benefited from adjuvant treatment (median OS 27 vs 14 months, P=0.02), whereas those with low levels did not (21 vs 21 months, P=0.87). High circulating ADAM12 levels, as a proxy for activated stroma, predict survival benefit from adjuvant chemotherapy in PDAC, requiring validation in future studies.

Hypoxia-inducible factor-dependent ADAM12 expression mediates breast cancer invasion and metastasis

Breast cancer patients with increased expression of hypoxia-inducible factors (HIFs) in primary tumor biopsies are at increased risk of metastasis, which is the major cause of breast cancer-related mortality. The mechanisms by which intratumoral hypoxia and HIFs regulate metastasis are not fully elucidated. In this paper, we report that exposure of human breast cancer cells to hypoxia activates epidermal growth factor receptor (EGFR) signaling that is mediated by the HIF-dependent expression of a disintegrin and metalloprotease 12 (ADAM12), which mediates increased ectodomain shedding of heparin-binding EGF-like growth factor, an EGFR ligand, leading to EGFR-dependent phosphorylation of focal adhesion kinase. Inhibition of ADAM12 expression or activity decreased hypoxia-induced breast cancer cell migration and invasion in vitro, and dramatically impaired lung metastasis after orthotopic implantation of MDA-MB-231 human breast cancer cells into the mammary fat pad of immunodeficient mice.

A Disintegrin and Metalloprotease 12 Promotes Tumor Progression by Inhibiting Apoptosis in Human Colorectal Cancer.

Simple SummaryA disintegrin and metalloprotease 12 (ADAM12) has been associated with tumor development and progression. The aim of the current study was to evaluate the impact of ADAM12 on cancer progression, prognosis, and therapeutic targets in colorectal cancer (CRC). Our results show that ADAM12 overexpression enhanced proliferation, inhibited apoptosis, and acted as a positive regulator of cell cycle progression in CRC cells. Phosphorylation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was decreased and that of Akt was increased by ADAM12 overexpression. These results were reversed upon ADAM12 knockdown. ADAM12 overexpression was significantly associated with the cancer stage, depth of invasion, lymph node metastasis, distant metastasis, and poor survival in CRC patients. In a mouse xenograft model, tumor area, volume, and weight were significantly greater for the ADAM12 overexpression group and significantly lower for the ADAM12 knockdown group. In conclusion, ADAM12 may serve as a promising biomarker and/or therapeutic target in CRC.A disintegrin and metalloprotease 12 (ADAM12) has been implicated in cell growth, tumor formation, and metastasis. Therefore, we evaluated the role of ADAM12 in colorectal cancer (CRC) progression and prognosis, and elucidated whether targeted downregulation of ADAM12 could lead to therapeutic sensitization. The effect of ADAM12 on tumor cell behavior was assessed in CRC cell lines, CRC tissues, and a mouse xenograft model. ADAM12 overexpression enhanced proliferation, inhibited apoptosis, and acted as positive regulator of cell cycle progression in CRC cells. Phosphorylation of PTEN was decreased and that of Akt was increased by ADAM12 overexpression. These results were reversed upon ADAM12 knockdown. ADAM12 overexpression was significantly associated with the cancer stage, depth of invasion, lymph node metastasis, distant metastasis, and poor survival in CRC patients. In a mouse xenograft model, tumor area, volume, and weight were significantly greater for the ADAM12-pcDNA6-myc-transfected group than for the empty-pcDNA6-myc-transfected group, and significantly lower for the ADAM12-pGFP-C-shLenti-transfected group than for the scrambled pGFP-C-shLenti-transfected group. In conclusion, ADAM12 overexpression is essential for the growth and progression of CRC. Furthermore, ADAM12 knockdown reveals potent anti-tumor activity in a mouse xenograft model. Thus, ADAM12 may serve as a promising biomarker and/or therapeutic target in CRC.

First-trimester prediction of preterm labor using disintegrin and metalloprotease 12, uterine artery Doppler, and maternal characteristics

Background A disintegrin and metalloprotease 12 (ADAM12) is a complex placenta-derived protein with proteolytic activity that may serve as a marker of placental dysfunction for the identification of preterm birth. This has benefits of an early intervention and increased antenatal surveillance. In addition, uterine artery Doppler studies are noninvasive measurements of placental vascular flow with increased resistance reflecting impaired trophoblastic invasion. Objectives The objective of this study is to estimate the efficiency of first-trimester maternal serum ADAM12, uterine artery Doppler, and maternal characteristics in the early prediction of preterm birth. Patients and methods This cohort study was conducted on 90 pregnant women in their first trimesters with selection criteria. All patients were investigated for ADAM12 protein level, uterine artery Doppler, and maternal characteristics. They were followed up for screening of preterm birth (before 37 weeks). Results Uterine artery Doppler pulsatility index and maternal serum ADAM12 level either individually or combined are not statistically significant predictors of spontaneous preterm birth. The combination of maternal ADAM12 and BMI with cutoff levels of 162 pg/ml and 32 kg/m2, respectively, was a highly significant effective predictor of preterm birth. Advancing maternal age, increasing parity, increased BMI, and hypertension were maternal characteristics that correlated significantly with preterm birth. Conclusion Uterine artery Doppler pulsatility index and maternal serum ADAM12 level are not statistically significant predictors of spontaneous preterm birth, but ‘combined’ ADAM12 and BMI can do it significantly.

Triptolide inhibits pituitary adenoma cell viability, migration and invasion via ADAM12/EGFR signaling pathway

AimTriptolide, an effective component derived from Tripterygium wilfordii, has been well recognized to process a broad-spectrum antitumor activities in various tumor types. However, the potential role of triptolide in pituitary adenomas remains unknown. The aim of this study was to investigate the precise role of triptolide and underlying mechanism in regulating pituitary adenoma cell viability, migration and invasion. Main methodsWe use mouse pituitary adenoma cells (TtT/GF and AtT20 cells) as the experiment model and treated them with varying concentrations of triptolide. The corresponding inhibitory effects on cell viability, migration, invasion and apoptosis were examined respectively, and the underlying mechanism was determined by investigating ADAM12 (a disintegrin and metalloprotease 12)/EGFR signaling. Key findingsTriptolide significantly inhibited cell viability, migration and invasion in TtT/GF and AtT20 cells in a dose-dependent manner. Mechanistically, triptolide significantly reduced ADAM12 expression at protein levels and attenuated ADAM12/EGFR signaling. Meanwhile, triptolide treatment combined with ADAM12 silencing enhanced the suppression effects on cell viability, migration and invasion, and those effects were restored following ADAM12-rescued. Moreover, triptolide suppressed the tumorigenesis of TtT/GF and AtT20 cells in vivo. SignificanceOur research provides evidence that triptolide inhibits pituitary adenoma cell viability, migration and invasion via ADAM12/EGFR signaling pathway. These findings suggest a potential role for triptolide in treating pituitary adenomas.

ADAM12 induces EMT and promotes cell migration, invasion and proliferation in pituitary adenomas via EGFR/ERK signaling pathway

Pituitary adenomas are the second most common primary brain tumor with invasive properties. We have previously identified that ADAM12 (a disintegrin and metalloprotease 12) overexpression is associated with the tumor invasion of pituitary adenomas, however, the underlying mechanism remains unknown. This study aims to elucidate the mechanistic role of ADAM12 in regulating the tumor invasion of pituitary adenomas. In this study, we first showed that ADAM12 expression was concomitant with epithelial to mesenchymal transition (EMT) process in clinical specimens of human pituitary adenomas. Further functional studies showed that ADAM12 silencing in pituitary adenoma cells significantly inhibited the EMT process and suppressed cell migration, invasion and proliferation without influencing cell apoptosis. Mechanistically, ADAM12 silencing significantly reduced ectodomain shedding of epidermal growth factor receptor (EGFR) ligands and attenuated the EGFR/ERK signaling pathway. Blocking of EGFR signaling resulted in EMT suppression similar to silencing of ADAM12 and reduced cell migration, invasion and proliferation, while EGFR activation abolished the suppression on EMT, proliferation, migration and invasion induced by ADAM12 silencing. Moreover, ADAM12 silencing significantly impaired tumorigenesis and EMT of pituitary adenoma cells in vivo. Taken together, our study provide crucial evidence that ADAM12 induces EMT and promotes cell migration, invasion and proliferation in pituitary adenomas via EGFR/ERK signaling pathway. These finds strongly suggest that ADAM12 might serve as a novel valuable therapeutic target for pituitary adenomas.

Association of ADAM12 gene polymorphisms with knee osteoarthritis susceptibility.

Previous studies that evaluated the association between a disintegrin and metalloprotease 12 (ADAM12) gene polymorphisms and knee osteoarthritis (KOA) have given controversial and indefinite results. Therefore, we performed a meta-analysis to confirm this correlation. We searched the PubMed, Embase, and SinoMed databases for all papers published up to April 11, 2017. Overall, five different studies, totaling 2,353 cases and 3,668 controls, were retrieved on the basis of the search criteria for KOA susceptibility related to four polymorphisms (rs3740199, rs1278279, rs1871054, and rs1044122) in the ADAM12 gene. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of this association. Publication bias was assessed using Egger's and Begg's tests. The rs3740199 G/C polymorphism was found to be associated with increased KOA risk in men (e.g., CG versus GG: OR = 1.44, 95% CI = 1.02–2.04, P = 0.040), but not in the overall analysis and in analyses of other subgroups. Significantly increased associations were also found for the rs1871054 polymorphism (e.g., C versus T allele: OR = 1.85, 95% CI = 1.49–2.30, P < 0.001). However, there were no associations for the rs1278279 and rs1044122 polymorphisms. Furthermore, no obvious evidence of publication bias was detected. Our study indicated that the rs1871054 polymorphism of ADAM12 was significantly associated with increased KOA risk.

Performance of first trimester biochemical markers and mean arterial pressure in prediction of early-onset pre-eclampsia

ObjectiveTo develop a predictive risk model for early-onset pre-eclampsia (EO-PE) using maternal characteristics, combined screening markers, previously reported biomarkers for PE and mean arterial pressure (MAP). MethodsThis retrospective study was conducted at Oulu University hospital between 2006 and 2010. Maternal serum from first trimester combined screening was further analyzed for alpha fetoprotein (AFP), placental growth factor (PlGF), soluble tumor necrosis factor receptor-1 (sTNFR1), retinol binding protein-4 (RBP4), a disintegrin and metalloprotease-12 (ADAM12), soluble P-selectin (sP-selectin), follistatin like-3 (FSTL3), adiponectin, angiopoietin-2 (Ang-2) and sex hormone binding globulin (SHBG). First, the training sample set with 29 cases of EO-PE and 652 controls was developed to study whether these biomarkers separately or in combination with prior risk (maternal characteristics, first trimester pregnancy associated plasma protein-A (PAPP-A) and free beta human chorionic gonadotrophin (fβ-hCG)) could be used to predict the development of EO-PE. Second, the developed risk models were validated with a test sample set of 42 EO-PE and 141 control subjects. For the test set MAP data was also available. ResultsSingle marker statistically significant (ANOVA p<0.05) changes between control and EO-PE pregnancies were observed with AFP, RBP4 and sTNFR1 with both training and test sample sets. Based on the test sample set performances, the best detection rate, 47% for a 10% false positive rate, was achieved with PlGF and sTNFR1 added with prior risk and MAP. ConclusionBased on our results, the best first trimester biomarkers to predict the subsequent EO-PE were AFP, PlGF, RBP4 and sTNFR1. The risk models that performed best for the prediction of EO-PE included prior risk, MAP, sTNFR1 and AFP or PlGF or RBP4.

First trimester maternal serum analytes and second trimester uterine artery Doppler in the prediction of preeclampsia and fetal growth restriction

ObjectiveThis study aimed to determine whether pregnancy-associated plasma protein-A (PAPP-A), free β-human chorionic gonadotropin (β-hCG), a disintegrin and metalloprotease 12 (ADAM12), and placenta protein 13 (PP13) in the first trimester, and uterine artery Doppler (UAD) in the second trimester, predict preeclampsia and fetal growth restriction (FGR). Materials and methodsMaternal serum levels of PAPP-A, free β-hCG, ADAM12, and PP13 at 11–13+6 weeks of gestation and bilateral uterine artery pulsatility index (PI) at 22–24 weeks of gestation were measured in a nested case–control study within a prospective cohort. The serum analytes and Doppler measurements were compared for uncomplicated pregnancies and pregnancies complicated by preeclampsia and FGR. The efficacy of biochemical and Doppler measurements for the prediction of preelampsia and FGR was investigated. ResultsCompared with gestational age-matched controls (n = 200), the mean PAPP-A and ADAM12 were lower (P < 0.001, P < 0.05) in pregnancies complicated by preeclampsia (n = 462) and FGR (n = 350). The median uterine artery mean PI was higher (P < 0.001) in preeclampsia and FGR groups. However, the median free β-hCG and PP13 were not significantly different from normal (P > 0.05). In screening for preeclampsia and FGR, assuming a fixed false positive rate (FPR) of 10%, the detection rates were 72% and 68% for a combination of PAPP-A, ADAM12, and UAD, respectively. ConclusionFirst trimester PAPP-A and ADAM12 levels and second trimester uterine artery PI are associated with adverse pregnancy outcomes. The combination of biochemical markers and UAD improves the screening efficiency for the prediction of preeclampsia and FGR.

ADAM12 induction by Twist1 promotes tumor invasion and metastasis via regulation of invadopodia and focal adhesions.

The Twist1 transcription factor promotes tumor invasion and metastasis by inducing epithelial-mesenchymal transition (EMT) and invadopodia-mediated extracellular matrix (ECM) degradation. The critical transcription targets of Twist1 for mediating these events remain to be uncovered. Here, we report that Twist1 strongly induces expression of a disintegrin and metalloproteinase 12 (ADAM12). We observed that the expression levels of Twist1 mRNA and ADAM12 mRNA are tightly correlated in human breast tumors. Knocking down ADAM12 blocked cell invasion in a 3D mammary organoid culture. Suppression of ADAM12 also inhibited Twist1-induced tumor invasion and metastasis in human breast tumor xenografts, without affecting primary tumor formation. Mechanistically, knockdown of ADAM12 in breast cancer cells significantly reduced invadopodia formation and matrix degradation, and simultaneously increased overall cell adhesion to the ECM. Live-imaging analysis showed that knockdown of ADAM12 significantly inhibited focal adhesion turnover. Mechanistically, both the disintegrin and metalloproteinase domains of ADAM12 are required for its function at invadopodia, whereas the metalloproteinase domain is dispensable for its function at focal adhesions. Taken together, these data suggest that ADAM12 plays a crucial role in tumor invasion and metastasis by regulating both invadopodia and focal adhesions.

Abstract A53: ADAM12 contributes to the malignant potential of pancreatic cancer and may serve as a non-invasive biomarker for its detection

Abstract Pancreatic malignancies are the fourth leading cause of all cancer-related deaths of both men and women in the United States. A majority of patients with pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumors (pNET) present with advanced disease due to a lack of specific symptoms. The high mortality rate associated with pancreatic cancer can be attributed to both a lack of clinical diagnostic tests for early detection as well as an inadequate understanding of the underlying molecular mechanisms of its aggressive pathogenesis. We have recently become interested in the role that ADAM12 (a disintegrin and metalloprotease 12), a member of the disintegrin metalloprotease family, may play in the development and progression of pancreatic cancer. We have found that ADAM12 protein levels are significantly upregulated in human pancreatic cancer and in mouse models of PDAC and correlate with disease progression. ADAM12 levels were also upregulated in precursor PanIN lesions in a transgenic mouse model. ADAM12 transcript and protein expression is higher in poorly differentiated/quasi-mesenchymal pancreatic cancer cell lines such as Panc1 and MiaPaca2 compared to well-differentiated/classical cell lines such as AspC1 and BxPC3. Downregulation of ADAM12 in pancreatic tumor cells resulted in reduced cell migration, invasion and proliferation whereas apoptotic rates were significantly higher. In agreement with these findings, activation of common signaling pathways including pEGFR, pSTAT3 and pErk were also downregulated in response to ADAM12 silencing in these cells. We have also determined whether ADAM12 could be detected in the urine of patients with pancreatic malignancies and whether ADAM12 levels might serve as an independent predictor of disease status. Retrospective analyses of urine samples (n=130) from PDAC and pNET patients as well as age- and sex-matched controls were conducted. Urinary ADAM12 levels were determined using a monospecific ELISA system. Multivariable logistic regression analyses indicated that, when controlling for age and sex, urinary ADAM12 could serve as significant independent predictor for distinguishing PDAC (P&amp;lt;0.001) and pNET (P&amp;lt;0.008) patients from healthy controls. Kaplan-Meier analysis of estimated patient survival stratified by urinary ADAM12 levels indicated a significantly shorter patient survival time for PDAC patients with high ADAM12 levels (P=0.015) compared to patients with lower urinary ADAM12. Taken together, our results indicate that ADAM12 is aberrantly upregulated in PDAC tumors and contributes to the malignant properties of pancreatic tumor cells. These data also support the conclusion that the measurement of ADAM12 levels may have diagnostic value in detection and/or clinical monitoring of disease status in patients with pancreatic malignancies. [Supported by: The Advanced Medical Research Foundation] Citation Format: Roopali Roy, Adelle Dagher, David Zurakowski, Matthew Kulke, Marsha A. Moses.{Authors}. ADAM12 contributes to the malignant potential of pancreatic cancer and may serve as a non-invasive biomarker for its detection. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A53.