Gene Summary

Gene:ADAM12; ADAM metallopeptidase domain 12
Aliases: MCMP, MLTN, CAR10, MLTNA, MCMPMltna, ADAM12-OT1
Summary:This gene encodes a member of a family of proteins that are structurally related to snake venom disintegrins and have been implicated in a variety of biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. Expression of this gene has been used as a maternal serum marker for pre-natal development. Alternative splicing results in multiple transcript variants encoding different isoforms. Shorter isoforms are secreted, while longer isoforms are membrane-bound form. [provided by RefSeq, Jan 2014]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:disintegrin and metalloproteinase domain-containing protein 12
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (15)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Models, Genetic
  • Breast Cancer
  • Disease Progression
  • Metalloendopeptidases
  • Cell Proliferation
  • Messenger RNA
  • Apoptosis
  • MAP Kinase Signaling System
  • Neoplasm Proteins
  • Disintegrins
  • Biomarkers, Tumor
  • Drug Resistance
  • Gene Expression
  • RT-PCR
  • Cancer Gene Expression Regulation
  • Lung Cancer
  • Cell Movement
  • Molecular Sequence Data
  • Base Sequence
  • RNA Interference
  • Cluster Analysis
  • ErbB Receptors
  • Immunohistochemistry
  • Membrane Proteins
  • Phenotype
  • Neoplasm Invasiveness
  • MicroRNAs
  • Chromosome 10
  • Squamous Cell Carcinoma
  • Western Blotting
  • ADAM12 Protein
  • Staging
  • Gene Expression Profiling
  • Oligonucleotide Array Sequence Analysis
  • Mutation
  • Adenocarcinoma
  • Phosphorylation
  • ADAM Proteins
  • Tumor Burden
  • Signal Transduction
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: ADAM12 (cancer-related)

Yang H, Wu J, Zhang J, et al.
Integrated bioinformatics analysis of key genes involved in progress of colon cancer.
Mol Genet Genomic Med. 2019; 7(4):e00588 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Colon cancer is one of most malignant cancers around worldwide. Nearly 20% patients were diagnosed at colon cancer with metastasis. However, the lack of understanding regarding its pathogenesis brings difficulties to study it.
METHODS: In this study, we acquired high-sequence data from GEO dataset, and performed integrated bioinformatic analysis including differently expressed genes, gene ontology and Kyoto Encyclopedia of Genes and Genomes pathways analysis, protein-protein analysis, survival analysis to analyze the development of colon cancer.
RESULTS: By comparing the colon cancer tissues with normal colon tissues, 109 genes were dysregulated; among them, 83 genes were downregulated and 26 genes were upregulated. Two clusters were founded based on the STRING database and MCODE plugin of cytoscape software. Then, six genes with prognostic value were filtered out in UALCAN website.
CONCLUSION: We found that SPP1, VIP, COL11A1, CA2, ADAM12, INHBA could provide great significant prognostic value for colon cancer.

Ebbing EA, van der Zalm AP, Steins A, et al.
Stromal-derived interleukin 6 drives epithelial-to-mesenchymal transition and therapy resistance in esophageal adenocarcinoma.
Proc Natl Acad Sci U S A. 2019; 116(6):2237-2242 [PubMed] Free Access to Full Article Related Publications
Esophageal adenocarcinoma (EAC) has a dismal prognosis, and survival benefits of recent multimodality treatments remain small. Cancer-associated fibroblasts (CAFs) are known to contribute to poor outcome by conferring therapy resistance to various cancer types, but this has not been explored in EAC. Importantly, a targeted strategy to circumvent CAF-induced resistance has yet to be identified. By using EAC patient-derived CAFs, organoid cultures, and xenograft models we identified IL-6 as the stromal driver of therapy resistance in EAC. IL-6 activated epithelial-to-mesenchymal transition in cancer cells, which was accompanied by enhanced treatment resistance, migratory capacity, and clonogenicity. Inhibition of IL-6 restored drug sensitivity in patient-derived organoid cultures and cell lines. Analysis of patient gene expression profiles identified ADAM12 as a noninflammation-related serum-borne marker for IL-6-producing CAFs, and serum levels of this marker predicted unfavorable responses to neoadjuvant chemoradiation in EAC patients. These results demonstrate a stromal contribution to therapy resistance in EAC. This signaling can be targeted to resensitize EAC to therapy, and its activity can be measured using serum-borne markers.

Ge X, Li GY, Jiang L, et al.
Long noncoding RNA CAR10 promotes lung adenocarcinoma metastasis via miR-203/30/SNAI axis.
Oncogene. 2019; 38(16):3061-3076 [PubMed] Free Access to Full Article Related Publications
Long noncoding RNAs (lncRNAs) play an important role in lung adenocarcinoma (LUAD) metastasis. Here, we found that lncRNA chromatin-associated RNA 10 (CAR10) was upregulated in the tumor tissue of patients with LUAD and enhanced tumor metastasis in vitro and in vivo. Mechanistically, CAR10 induced epithelial-to-mesenchymal transition (EMT) by directly binding with miR-30 and miR-203 and then regulating the expression of SNAI1 and SNAI2. CAR10 overexpression was positively correlated with a poor prognosis in LUAD patients, whereas overexpression of both CAR10 and SNAI was correlated with even worse clinical outcomes. In conclusion, the CAR10/miR-30/203/SNAI axis is a novel and potential therapeutic target for LUAD.

Lu H, Han N, Xu W, et al.
Screening and bioinformatics analysis of mRNA, long non-coding RNA and circular RNA expression profiles in mucoepidermoid carcinoma of salivary gland.
Biochem Biophys Res Commun. 2019; 508(1):66-71 [PubMed] Related Publications
Mucoepidermoid carcinoma (MEC) of salivary gland is a disease characterized by high rate of diatant metastasis, and associated with poor outcomes. However, the molecular mechanisms underlying the MEC remain poorly understand. Here, we simultaneously detected, for the first time, the expression profiles of mRNAs, lncRNAs, and circRNAs in four pairs of MEC and matched non-carcinoma tissues by microarrays. A total of 3612 mRNA, 3091 lncRNAs, and 284 circRNAs were altered during the pathogenesis of MEC. The functions of these differentially expressed RNAs were predicted by Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Co-expression networks of lncRNA-mRNA and circRNA-miRNA were conducted to uncovered the hidden ceRNA mechanisms. Moreover, NONHSAT154433.1 that associated with ADAM12 and hsa_circ_0012342 were further screened and confirmed using qRT-PCR analysis. In conclusion, this study provides a systematic perspective on the potential function of non-coding RNAs (ncRNAs) in the molecular mechanisms of MEC. Among these, NONHSAT154433.1 and hsa_circ_0012342 might be served as potential prognostic biomarkers and therapeutic target of MEC.

Luo ML, Zhou Z, Sun L, et al.
An ADAM12 and FAK positive feedback loop amplifies the interaction signal of tumor cells with extracellular matrix to promote esophageal cancer metastasis.
Cancer Lett. 2018; 422:118-128 [PubMed] Related Publications
Esophageal squamous cell carcinomas (ESCCs) have a poor prognosis mostly due to early metastasis. To explore the early event of metastasis in ESCC, we established an in vitro selection model to mimic the interaction of tumor cells with extracellular matrix, through which a sub-line of ESCC cells with high invasive ability was generated. By comparing the gene expression profile of the highly invasive sub-line to that of the parental cells, ADAM12-L was identified as a candidate gene promoting ESCC cell invasion. Immunohistochemistry revealed that the ADAM12-L was overexpressed in human ESCC tissues, especially at cancer invasive edge, and ADAM12-L overexpression tightly correlated with increased metastasis and poor outcome of ESCC patients. Indeed, ADAM12-L knockdown reduced the invasion and metastasis of ESCC cells both in vitro and in vivo. Furthermore, we demonstrated that ADAM12-L participated in focal adhesion turnover and promoted the activation of focal adhesion kinase (FAK), which in turn increased ADAM12-L transcription through FAK/JNK/c-Jun axis. Therefore, a loop initiated from the cancer cell upon the engagement with extracellular matrix through FAK and c-Jun to enhance ADAM12-L expression is established, leading to the positive feedback of further FAK activation and prompting metastasis. Our study indicates that overexpression of ADAM12-L can serve as a precision marker to determine the activation of this loop. Targeting ADAM12-L to disrupt this positive feedback loop represents a promising strategy to treat the metastasis of esophageal cancers.

Cesarini V, Silvestris DA, Tassinari V, et al.
ADAR2/miR-589-3p axis controls glioblastoma cell migration/invasion.
Nucleic Acids Res. 2018; 46(4):2045-2059 [PubMed] Free Access to Full Article Related Publications
Recent studies have reported the emerging role of microRNAs (miRNAs) in human cancers. We systematically characterized miRNA expression and editing in the human brain, which displays the highest number of A-to-I RNA editing sites among human tissues, and in de novo glioblastoma brain cancer. We identified 299 miRNAs altered in their expression and 24 miRNAs differently edited in human brain compared to glioblastoma tissues. We focused on the editing site within the miR-589-3p seed. MiR-589-3p is a unique miRNA almost fully edited (∼100%) in normal brain and with a consistent editing decrease in glioblastoma. The edited version of miR-589-3p inhibits glioblastoma cell proliferation, migration and invasion, while the unedited version boosts cell proliferation and motility/invasion, thus being a potential cancer-promoting factor. We demonstrated that the editing of this miRNA is mediated by ADAR2, and retargets miR-589-3p from the tumor-suppressor PCDH9 to ADAM12, which codes for the metalloproteinase 12 promoting glioblastoma invasion. Overall, our study dissects the role of a unique brain-specific editing site within miR-589-3p, with important anticancer features, and highlights the importance of RNA editing as an essential player not only for diversifying the genomic message but also for correcting not-tolerable/critical genomic coding sites.

Walkiewicz K, Nowakowska-Zajdel E, Strzelczyk J, et al.
Serum levels of ADAM10, ADAM12, ADAM17 AND ADAM28 in colorectal cancer patients.
J Biol Regul Homeost Agents. 2017 Oct-Dec; 31(4):929-934 [PubMed] Related Publications
Colorectal cancer is the third most common cancer in the world. Our study analyzed the potential significance of serum levels of selected adamalysines (ADAM10, ADAM12, ADAM17, ADAM28) in colorectal cancer patients. The study was performed on a group of 85 colorectal cancer patients (48 men, 37 women). Serum protein concentrations were measured by ELISA. The ADAMs serum level changes were analyzed according to selected clinical parameters (BMI, sex, age, clinical stage of disease). The following ranges of concentration of analyzed proteins were obtained: ADAM10 min=1.7, max=321.8 [ng/ml]; ADAM12 min=0.6, max=26.7 [ng/ml]; ADAM17 min=0.4, max=9.8 [ng/ml]; ADAM28 min=17.1, max=1545.8 [ng/ml]. In addition, it was stated that there is a relationship between the serum level of ADAM28 and the degree of the clinical stage (p less than 0.04). The obtained results could be the starting point for further research into the role of adamalysines in the development of colorectal cancer, as well as the potential predictive and prognostic value of these proteins.

Wang J, Zhang Z, Li R, et al.
ADAM12 induces EMT and promotes cell migration, invasion and proliferation in pituitary adenomas via EGFR/ERK signaling pathway.
Biomed Pharmacother. 2018; 97:1066-1077 [PubMed] Related Publications
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.

Wang X, Wang Y, Gu J, et al.
ADAM12-L confers acquired 5-fluorouracil resistance in breast cancer cells.
Sci Rep. 2017; 7(1):9687 [PubMed] Free Access to Full Article Related Publications
5-FU-based combinatory chemotherapeutic regimens have been routinely used for many years for the treatment of breast cancer patients. Recurrence and chemotherapeutic drug resistance are two of the most prominent factors that underpin the high mortality rates associated with most breast cancers (BC). Increasing evidence indicates that overexpression of ADAMs could correlate with cancer progression. However, the role of ADAMs in the chemoresistance of cancer cells has rarely been reported. In this study, we observed that 5-FU induces expression of the ADAM12 isoform ADAM12-L but not ADAM12-S in BC cells and in recurrent BC tissues. The overexpression of ADAM12-L in BC cells following 5-FU treatment results in the acquisition of resistance to 5-FU. ADAM12-L overexoression also resulted in increased levels of p-Akt but not p-ERK. These alterations enhanced BC cell growth and invasive abilities. Conversely, ADAM12 knockdown attenuated the levels of p-Akt and restored 5-FU sensitivity in 5-FU-resistant BC cells. ADAM12 knockdown also reduced BC cell survival and invasive abilities. These findings suggest that ADAM12-L mediates chemoresistance to 5-FU and 5-FU-induced recurrence of BC by enhancing PI3K/Akt signaling. The results of this study suggest that specific ADAM12-L inhibition could optimize 5-FU-based chemotherapy of BC, thereby preventing BC recurrence in patients.

Roy R, Dagher A, Butterfield C, Moses MA
ADAM12 Is a Novel Regulator of Tumor Angiogenesis via STAT3 Signaling.
Mol Cancer Res. 2017; 15(11):1608-1622 [PubMed] Free Access to Full Article Related Publications
ADAM12, (

Honnemyr M, Bruserud Ø, Brenner AK
The constitutive protease release by primary human acute myeloid leukemia cells.
J Cancer Res Clin Oncol. 2017; 143(10):1985-1998 [PubMed] Related Publications
INTRODUCTION: Acute myeloid leukemia (AML) cells show constitutive release of matrix metalloproteases and their inhibitors. We now investigated this constitutive release of protease/protease regulators associated with carcinogenesis (ADAM12, uPA, cystatin B), angiogenesis (serpin E1, uPA, CD147), cancer cell migration (uPA, cystatin C), coagulation (ADAM TS13, serpin C1), inflammation (fetuin A, caspase 1, cystatin C), monocytic differentiation (CFD) or regulation of hematopoiesis (neutrophil elastase).
METHODS: AML blasts from 79 consecutive patients were cultured in serum-free medium and mediator levels determined in culture supernatants.
RESULTS: Detectable release of serpin C1 and E1, cystatin B and C, CD147 and uPA was seen for most patients. These mediators together with fetuin A, caspase 1, and CFD were included in a hierarchical clustering analysis and three patient subsets were identified (high, intermediate, and low release). High levels were associated with monocytic differentiation. Global gene expression analyses showed increased levels of several zinc finger proteins for low-release patients and high expression of several cell surface molecules, ATPases, and calcium-binding proteins for high-release patients. Constitutive release of several mediators was also seen for normal hematopoietic cells and mesenchymal stem cells. In cocultures of the latter and AML blasts, the release level for most mediators was altered to resemble the levels of the mesenchymal cells cultured alone.
CONCLUSION: Differences in constitutive release of protease/protease regulators are a part of the disease heterogeneity in AML.

Eckert MA, Santiago-Medina M, Lwin TM, et al.
ADAM12 induction by Twist1 promotes tumor invasion and metastasis via regulation of invadopodia and focal adhesions.
J Cell Sci. 2017; 130(12):2036-2048 [PubMed] Free Access to Full Article Related Publications
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

Yin H, Zhong F, Ouyang Y, et al.
Upregulation of ADAM12 contributes to accelerated cell proliferation and cell adhesion-mediated drug resistance (CAM-DR) in Non-Hodgkin's Lymphoma.
Hematology. 2017; 22(9):527-535 [PubMed] Related Publications
OBJECTIVE: ADAM12 is a member of a disintegrin and metalloproteinase family and has been reported to participate in the development of variety of tumors. However, the role of ADAM12 in Non-Hodgkin Lymphoma (NHL) has not been investigated. The present study was undertaken to determine the expression and biologic function of ADAM12 in human NHL.
METHODS: First, we constructed a model of cell adhesion in NHL, the mRNA, and protein level of ADAM12 in suspension and the adhesion model was analyzed by RT-PCR and western blot. Then, flow cytometry assay and western blot were used to investigate the mechanism of ADAM12 in the proliferation of NHL cells. In vitro, after using siRNA interfering ADAM12 expression, we performed adhesion assay and cell viability assay to determine the effect of ADAM12 on adhesive rate and drug sensitivity.
RESULTS: ADAM12 was lowly expressed in suspended cells and highly expressed in adherent NHL cells. In addition, ADAM12 was positively correlated with the proliferation and apoptosis of NHL cells by regulating the expression of p-AKT and p-GSK-3β. Furthermore, ADAM12 promoted cell adhesion-mediated drug resistance (CAM-DR) in DLBCL via AKT signaling pathway.
CONCLUSION AND DISCUSSION: Our data support a role for ADAM12 in NHL cell proliferation, adhesion, and drug resistance, and it may pave the way for a novel therapeutic approach for CAM-DR in NHL.

Duhachek-Muggy S, Qi Y, Wise R, et al.
Metalloprotease-disintegrin ADAM12 actively promotes the stem cell-like phenotype in claudin-low breast cancer.
Mol Cancer. 2017; 16(1):32 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: ADAM12 is upregulated in human breast cancers and is a predictor of chemoresistance in estrogen receptor-negative tumors. ADAM12 is induced during epithelial-to-mesenchymal transition, a feature associated with claudin-low breast tumors, which are enriched in cancer stem cell (CSC) markers. It is currently unknown whether ADAM12 plays an active role in promoting the CSC phenotype in breast cancer cells.
METHODS: ADAM12 expression was downregulated in representative claudin-low breast cancer cell lines, SUM159PT and Hs578T, using siRNA transfection or inducible shRNA expression. Cell characteristics commonly associated with the CSC phenotype in vitro (cell migration, invasion, anoikis resistance, mammosphere formation, ALDH activity, and expression of the CD44 and CD24 cell surface markers) and in vivo (tumor formation in mice using limiting dilution transplantation assays) were evaluated. RNA sequencing was performed to identify global gene expression changes after ADAM12 knockdown.
RESULTS: We found that sorted SUM159PT cell populations with high ADAM12 levels had elevated expression of CSC markers and an increased ability to form mammospheres. ADAM12 knockdown reduced cell migration and invasion, decreased anoikis resistance, and compromised mammosphere formation. ADAM12 knockdown also diminished ALDEFLUOR
CONCLUSIONS: These results indicate that ADAM12 actively supports the CSC phenotype in claudin-low breast cancer cells via modulation of the EGFR pathway.

Fang T, Lin J, Wang Y, et al.
Tetraspanin-8 promotes hepatocellular carcinoma metastasis by increasing ADAM12m expression.
Oncotarget. 2016; 7(26):40630-40643 [PubMed] Free Access to Full Article Related Publications
Recent evidence indicates that tetraspanin-8 (TSPAN8) promotes tumor progression and metastasis. In this study, we explored the effects of TSPAN8 and the molecular mechanisms underlying hepatocellular carcinoma (HCC) metastasis using various HCC cell lines, tissues from 149 HCC patients, and animal models of HCC progression. We showed that elevated expression of TSPAN8 promoted HCC invasion in vitro and metastasis in vivo, but did not influence HCC cell proliferation in vitro. Increased TSPAN8 expression in human HCC was predictive of poor survival, and multivariate analyses indicated TSPAN8 expression to be an independent predictor for both postoperative overall survival and relapse-free survival. Importantly, TSPAN8 enhanced HCC invasion and metastasis by increasing ADAM12m expression. We therefore conclude that TSPAN8 and ADAM12m may be useful therapeutic targets for the prevention of HCC progression and metastasis.

Xu Y, Wang Y, Liu H, et al.
Genetic variants of genes in the Notch signaling pathway predict overall survival of non-small cell lung cancer patients in the PLCO study.
Oncotarget. 2016; 7(38):61716-61727 [PubMed] Free Access to Full Article Related Publications
The Notch signaling pathway has been shown to have biological significance and therapeutic application in non-small cell lung cancer (NSCLC). We hypothesize that genetic variants of genes in the Notch signaling pathway are associated with overall survival (OS) of NSCLC patients. To test this hypothesis, we performed multivariate Cox proportional hazards regression analysis to evaluate associations of 19,571 single nucleotide polymorphisms (SNPs) in 132 Notch pathway genes with OS of 1,185 NSCLC patients available from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. We found that five potentially functional tagSNPs in four genes (i.e., ADAM12 rs10794069 A > G, DTX1 rs1732793 G > A, TLE1 rs199731120 C > CA, TLE1 rs35970494 T > TC and E2F3 rs3806116 G > T) were associated with a poor OS, with a variant-allele attributed hazards ratio (HR) of 1.27 [95% confidence interval (95% CI) = 1.13-1.42, P = 3.62E-05], 1.30 (1.14-1.49, 8.16E-05), 1.40 (1.16-1.68, 3.47E-04), 1.27 (1.11-1.44, 3.38E-04), and 1.21 (1.09-1.33, 2.56E-04), respectively. Combined analysis of these five risk genotypes revealed that the genetic score 0-5 was associated with the adjusted HR in a dose-response manner (Ptrend = 3.44E-13); individuals with 2-5 risk genotypes had an adjusted HR of 1.56 (1.34-1.82, 1.46E-08), compared with those with 0-1 risk genotypes. Larger studies are needed to validate our findings.

Micocci KC, Moritz MN, Lino RL, et al.
ADAM9 silencing inhibits breast tumor cells transmigration through blood and lymphatic endothelial cells.
Biochimie. 2016 Sep-Oct; 128-129:174-82 [PubMed] Related Publications
ADAMs are transmembrane multifunctional proteins that contain disintegrin and metalloprotease domains. ADAMs act in a diverse set of biological processes, including fertilization, inflammatory responses, myogenesis, cell migration, cell proliferation and ectodomain cleavage of membrane proteins. These proteins also have additional functions in pathological processes as cancer and metastasis development. ADAM9 is a member of ADAM protein family that is overexpressed in several types of human carcinomas. The aim of this study was to investigate the role of ADAM9 in hematogenous and lymphatic tumor cell dissemination assisting the development of new therapeutic tools. The role of ADAM9 in the interaction of breast tumor cells (MDA-MB-231) and endothelial cells was studied through RNA silencing. ADAM9 silencing in MDA-MB-231 cells had no influence in expression of several genes related to the metastatic process such as ADAM10, ADAM12, ADAM17, cMYC, MMP9, VEGF-A, VEGF-C, osteopontin and collagen XVII. However, there was a minor decrease in ADAM15 expression but an increase in that of MMP2. Moreover, ADAM9 silencing had no effect in the adhesion of MDA-MB-231 cells to vascular (HMEC-1 and HUVEC) and lymphatic cells (HMVEC-dLyNeo) under flow condition. Nevertheless, siADAM9 in MDA-MB-231 decreased transendothelial cell migration in vitro through HUVEC, HMEC-1 and HMVEC-dLyNeo (50%, 40% and 32% respectively). These results suggest a role for ADAM9 on the extravasation step of the metastatic cascade through both blood and lymph vessels.

Zhou Y, Xiong L, Zhang Y, et al.
Quantitative proteomics identifies myoferlin as a novel regulator of A Disintegrin and Metalloproteinase 12 in HeLa cells.
J Proteomics. 2016; 148:94-104 [PubMed] Related Publications
UNLABELLED: A Disintegrin and Metalloproteinase 12 (ADAM12) is expressed significantly higher in multiple tumors than in normal tissues and has been used as a prognostic marker for the evaluation of cancer progression. Although several ADAM12 substrates have been identified biochemically and its proteolytic function has been explored, the upstream regulators and the interacting proteins have not been systematically investigated. Here, we use immunoprecipitation and mass spectrometry (MS)-based quantitative proteomic approaches to identify 28 interacting partners for the long form of ADAM12 (ADAM12-L) in HeLa cells. Proteins that regulate cell proliferation, invasion, and epithelial to mesenchymal transition are among the identified ADAM12-interacting proteins. Further biochemical experiments discover that the protein level and the stability of ADAM12 are upregulated by one of its interacting proteins, myoferlin. In addition, myoferlin also increases the proteolytic activity of ADAM12, leading to the reduction of an ADAM12 substrate, E-cadherin. This result implies that ADAM12 and its interacting proteins might converge to certain signaling pathways in the regulation of cancer cell progression. The information obtained here might be useful in the development of new strategies for modulating cell proliferation and invasion involved in the regulation between ADAM12 and its interacting partners. MS data are available via ProteomeXchange with identifier PXD003560.
BIOLOGICAL SIGNIFICANCE: Regulation of the proliferation and invasion of cancer cells is important in cancer treatment. ADAM12 has been found to play important roles in regulating these processes and identification of its interacting partners will improve our understanding of its biological functions and provide basis for functional modulation. Through mass spectrometry-based quantitative proteomic approaches, we identify the interacting partners for ADAM12 in a human cancer cell line and find many proteins that are involved in the proliferation and invasion of cancer cells. A novel regulator, myoferlin, of ADAM12 is discovered and this protein increases ADAM12 expression level, stability, and its enzymatic activity, leading to the reduction of its substrate, E-cadherin, which plays important roles in the regulation of cell adhesion and tumor metastasis. This result provides a connection for two highly expressed proteins in cancer cells and may shed light on the regulation of their biological functions in cancer progression.

Wei MM, Zhou YC, Wen ZS, et al.
Long non-coding RNA stabilizes the Y-box-binding protein 1 and regulates the epidermal growth factor receptor to promote lung carcinogenesis.
Oncotarget. 2016; 7(37):59556-59571 [PubMed] Free Access to Full Article Related Publications
Indoor and outdoor air pollution has been classified as group I carcinogen in humans, but the underlying tumorigenesis remains unclear. Here, we screened for abnormal long noncoding RNAs (lncRNAs) in lung cancers from patients living in Xuanwei city which has the highest lung cancer incidence in China due to smoky coal combustion-generated air pollution. We reported that Xuanwei patients had much more dysregulated lncRNAs than patients from control regions where smoky coal was not used. The lncRNA CAR intergenic 10 (CAR10) was up-regulated in 39/62 (62.9%) of the Xuanwei patients, which was much higher than in patients from control regions (32/86, 37.2%; p=0.002). A multivariate regression analysis showed an association between CAR10 overexpression and air pollution, and a smoky coal combustion-generated carcinogen dibenz[a,h]anthracene up-regulated CAR10 by increasing transcription factor FoxF2 expression. CAR10 bound and stabilized transcription factor Y-box-binding protein 1 (YB-1), leading to up-regulation of the epidermal growth factor receptor (EGFR) and proliferation of lung cancer cells. Knockdown of CAR10 inhibited cell growth in vitro and tumor growth in vivo. These results demonstrate the role of lncRNAs in environmental lung carcinogenesis, and CAR10-YB-1 represents a potential therapeutic target.

Wang J, Voellger B, Benzel J, et al.
Metalloproteinases ADAM12 and MMP-14 are associated with cavernous sinus invasion in pituitary adenomas.
Int J Cancer. 2016; 139(6):1327-39 [PubMed] Related Publications
Invasion of tumor cells critically depends on cell-cell or cell-extracellular matrix interactions. Enzymes capable of modulating these interactions belong to the proteinase families of ADAM (a disintegrin and metalloprotease) and MMP (matrix metalloprotease) proteins. Our objective is to examine their expression levels and evaluate the relationship between expression levels and cavernous sinus invasion in pituitary adenomas. Tissue samples from 35 patients with pituitary adenomas were analyzed. Quantitative real-time polymerase chain reaction (qPCR) was employed to assess mRNA expression levels for ADAM and MMP genes. Protein levels were examined using immunohistochemistry and Western Blot. Correlation analyses between expression levels and clinical parameters were performed. By silencing ADAM12 and MMP-14 with siRNA in a mouse pituitary adenoma cell line (TtT/GF), their cellular effects were investigated. In our study, nine women and 26 men were included, with a mean age of 53.1 years (range 15-84 years) at the time of surgery. There were 19 cases with cavernous sinus invasion. The proteins ADAM12 and MMP-14 were significantly up-regulated in invasive adenomas compared to noninvasive adenomas. Both human isoforms of ADAM12 (ADAM12L and ADAM12s) were involved in tumor invasion; moreover, ADAM12L was found to correlate positively with Ki-67 proliferation index in pituitary adenomas. In TtT/GF pituitary adenoma cells, silencing of ADAM12 and MMP-14 significantly inhibited cell invasion and migration, respectively, whereas only silencing of ADAM12 suppressed cell proliferation. We conclude that ADAM12 and MMP-14 are associated with cavernous sinus invasion in pituitary adenomas, which qualifies these proteins in diagnosis and therapy.

Ma B, Ma Q, Jin C, et al.
ADAM12 expression predicts clinical outcome in estrogen receptor-positive breast cancer.
Int J Clin Exp Pathol. 2015; 8(10):13279-83 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: Our study was aimed to make sure whether ADAM12 could serve as a prognostic biomarker of estrogen receptor (ER) -positive breast cancer.
METHODS: 127 patients with ER-positive breast cancer were included in the present study. The level of ADAM12 was assayed through real-time quantitative PCR (RT-qPCR). Levels of ADAM12 in tumor tissues and adjacent normal tissues were compared with paired t-test. The association of ADAM12 expression with clinical characteristics was analyzed via χ(2) test. Kaplan-Meier survival curve was used to evaluate the role of ADAM12 expression in overall survival (OS) of patients. Cox-regression analysis was performed to judge if ADAM12 could serve as a prognostic marker in breast cancer.
RESULTS: The level of ADAM12 was upregulated in tumor tissues of breast cancer compared to that of adjacent normal tissues (P < 0.05). The expression of ADAM12 was closely related to the Ki-67 and HER2 status (P < 0.05 for both). The results of Kaplan-Meier survival curve showed that patients with higher level of ADAM12 exhibited shorter survival time compared to that of low level of ADAM12 (P < 0.001). Cox regression analysis showed that ADAM12 might be a biomarker in predicting prognosis of patients with ER-positive breast cancer (HR = 7.116, 95% CI = 3.329-15.212).
CONCLUSION: ADAM12 appears to be a prognostic marker in ER-positive breast cancer.

Li Z, Wang Y, Kong L, et al.
Expression of ADAM12 is regulated by E2F1 in small cell lung cancer.
Oncol Rep. 2015; 34(6):3231-7 [PubMed] Related Publications
Our previous study reported that ADAM12 was highly expressed in small cell lung cancer (SCLC) and could be an effective marker for diagnosis and prognosis. Yet, the reason for the high expression of ADAM12 in SCLC requires further elucidation. Transcription factor E2F1 has been receiving increasing attention due to the complexity and diversity of its function in cancer. In the present study, the expression of ADAM12 was significantly decreased following silencing of E2F1 expression by siRNA, thus indicating that E2F1 may regulate the expression of ADAM12 at the level of transcription. Chromatin immunoprecipitation-to-sequence analysis identified three binding sites for E2F1 in the locus for ADAM12. They were Chr10: 128010444-128011026, located in the intron of ADAM12, named seq0; Chr10: 128076927‑128078127, located in the promoter of ADAM12, named seq1; and Chr10: 128086195‑128086876, located in the upstream 20 kb from the transcription start site of ADAM12, named: seq2. Dual‑luciferase reporter experiments revealed that seq1 not seq0 and seq2 was able to promote the expression of luciferase. Notably, co-transfection of E2F1 significantly increased the activity of seq1 not seq0 and seq2, but quantitative polymerase chain reaction results showed that seq0, seq1 and seq2 could recruit E2F1, indicating that the influence of E2F1 in regulating the expression of ADAM12 was complex. Sequence analysis clarified that seq1 was a part of the ADAM12 promoter, yet the functions of seq0 and seq2 were unknown. Fusion fragments containing seq0-seq1 or seq2-seq1 were analyzed in luciferase constructs. Compared with seq1 alone, the activities of these fusion fragments were non-significantly reduced. The activities of fusion fragments were significantly decreased following co-transfection with E2F1. Thus, the present findings support the conclusion that the E2F1 transcription factor regulates the expression of ADAM12 by binding differential cis-acting elements.

Lulli V, Buccarelli M, Martini M, et al.
miR-135b suppresses tumorigenesis in glioblastoma stem-like cells impairing proliferation, migration and self-renewal.
Oncotarget. 2015; 6(35):37241-56 [PubMed] Free Access to Full Article Related Publications
Glioblastoma multiforme (GBM) is the most common and fatal malignant adult primary brain tumor. Currently, the overall prognosis for GBM patients remains poor despite advances in neurosurgery and adjuvant treatments. MicroRNAs (miRNAs) contribute to the pathogenesis of various types of tumor, including GBM. In this study we analyzed the expression of a panel of miRNAs, which are known to be differentially expressed by the brain and GBM tumor, in a collection of patient-derived GBM stem-like cells (GSCs). Notably, the average expression level of miR-135b, was the most downregulated compared to its normal counterpart, suggesting a potential role as anti-oncogene.Restoration of miR-135b in GSCs significantly decreased proliferation, migration and clonogenic abilities. More importantly, miR-135b restoration was able to significantly reduce brain infiltration in mouse models of GBM obtained by intracerebral injection of GSC lines. We identified ADAM12 and confirmed SMAD5 and GSK3β as miR-135b targets and potential mediators of its effects. The whole transcriptome analysis ascertained that the expression of miR-135b downmodulated additional genes driving key pathways in GBM survival and infiltration capabilities.Our results identify a critical role of miR-135b in the regulation of GBM development, suggesting that miR-135b might act as a tumor-suppressor factor and thus providing a potential candidate for the treatment of GBM patients.

Chiu YC, Wu CT, Hsiao TH, et al.
Co-modulation analysis of gene regulation in breast cancer reveals complex interplay between ESR1 and ERBB2 genes.
BMC Genomics. 2015; 16 Suppl 7:S19 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gene regulation is dynamic across cellular conditions and disease subtypes. From the aspect of regulation under modulation, regulation strength between a pair of genes can be modulated by (dependent on) expression abundance of another gene (modulator gene). Previous studies have demonstrated the involvement of genes modulated by single modulator genes in cancers, including breast cancer. However, analysis of multi-modulator co-modulation that can further delineate the landscape of complex gene regulation is, to our knowledge, unexplored previously. In the present study we aim to explore the joint effects of multiple modulator genes in modulating global gene regulation and dissect the biological functions in breast cancer.
RESULTS: To carry out the analysis, we proposed the Covariability-based Multiple Regression (CoMRe) method. The method is mainly built on a multiple regression model that takes expression levels of multiple modulators as inputs and regulation strength between genes as output. Pairs of genes were divided into groups based on their co-modulation patterns. Analyzing gene expression profiles from 286 breast cancer patients, CoMRe investigated ten candidate modulator genes that interacted and jointly determined global gene regulation. Among the candidate modulators, ESR1, ERBB2, and ADAM12 were found modulating the most numbers of gene pairs. The largest group of gene pairs was composed of ones that were modulated by merely ESR1. Functional annotation revealed that the group was significantly related to tumorigenesis and estrogen signaling in breast cancer. ESR1-ERBB2 co-modulation was the largest group modulated by more than one modulators. Similarly, the group was functionally associated with hormone stimulus, suggesting that functions of the two modulators are performed, at least partially, through modulation. The findings were validated in majorities of patients (> 99%) of two independent breast cancer datasets.
CONCLUSIONS: We have showed CoMRe is a robust method to discover critical modulators in gene regulatory networks, and it is capable of achieving reproducible and biologically meaningful results. Our data reveal that gene regulatory networks modulated by single modulator or co-modulated by multiple modulators play important roles in breast cancer. Findings of this report illuminate complex and dynamic gene regulation under modulation and its involvement in breast cancer.

Cheon DJ, Li AJ, Beach JA, et al.
ADAM12 is a prognostic factor associated with an aggressive molecular subtype of high-grade serous ovarian carcinoma.
Carcinogenesis. 2015; 36(7):739-47 [PubMed] Related Publications
ADAM metallopeptidase domain 12 (ADAM12) is a promising biomarker because of its low expression in normal tissues and high expression in a variety of human cancers. However, ADAM12 levels in ovarian cancer have not been well characterized. We previously identified ADAM12 as one of the signature genes associated with poor survival in high-grade serous ovarian carcinoma (HGSOC). Here, we sought to determine if high levels of the ADAM12 protein and/or messenger RNA (mRNA) are associated with clinical variables in HGSOC. We show that high protein levels of ADAM12 in banked preoperative sera are associated with shorter progression-free and overall survival. Tumor levels of ADAM12 mRNA were also associated with shorter progression-free and overall survival as well as with lymphatic and vascular invasion, and residual tumor volume following cytoreductive surgery. The majority of genes co-expressed with ADAM12 in HGSOC were transforming growth factor (TGF)β signaling targets that function in collagen remodeling and cell-matrix adhesion. In tumor sections, the ADAM12 protein and mRNA were expressed in epithelial cancer cells and surrounding stromal cells. In vitro data showed that ADAM12 mRNA levels can be increased by TGFβ signaling and direct contact between epithelial and stromal cells. High tumor levels of ADAM12 mRNA were characteristic of the mesenchymal/desmoplastic molecular subtype of HGSOC, which is known to have the poorest prognosis. Thus, ADAM12 may be a useful biomarker of aggressive ovarian cancer for which standard treatment is not effective.

Duhachek-Muggy S, Zolkiewska A
ADAM12-L is a direct target of the miR-29 and miR-200 families in breast cancer.
BMC Cancer. 2015; 15:93 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: ADAM12-L and ADAM12-S represent two major splice variants of human metalloproteinase-disintegrin 12 mRNA, which differ in their 3'-untranslated regions (3'UTRs). ADAM12-L, but not ADAM12-S, has prognostic and chemopredictive values in breast cancer. Expression levels of the two ADAM12 splice variants in clinical samples are highly discordant, suggesting post-transcriptional regulation of the ADAM12 gene. The miR-29, miR-30, and miR-200 families have potential target sites in the ADAM12-L 3'UTR and they may negatively regulate ADAM12-L expression.
METHODS: miR-29b/c, miR-30b/d, miR-200b/c, or control miRNA mimics were transfected into SUM159PT, BT549, SUM1315MO2, or Hs578T breast cancer cells. ADAM12-L and ADAM12-S mRNA levels were measured by qRT-PCR, and ADAM12-L protein was detected by Western blotting. Direct targeting of the ADAM12-L 3'UTR by miRNAs was tested using an ADAM12-L 3'UTR luciferase reporter. The rate of ADAM12-L translation was evaluated by metabolic labeling of cells with (35)S cysteine/methionine. The roles of endogenous miR-29b and miR-200c were tested by transfecting cells with miRNA hairpin inhibitors.
RESULTS: Transfection of miR-29b/c mimics strongly decreased ADAM12-L mRNA levels in SUM159PT and BT549 cells, whereas ADAM12-S levels were not changed. ADAM12-L, but not ADAM12-S, levels were also significantly diminished by miR-200b/c in SUM1315MO2 cells. In Hs578T cells, miR-200b/c mimics impeded translation of ADAM12-L mRNA. Importantly, both miR-29b/c and miR-200b/c strongly decreased steady state levels of ADAM12-L protein in all breast cancer cell lines tested. miR-29b/c and miR-200b/c also significantly decreased the activity of an ADAM12-L 3'UTR reporter, and this effect was abolished when miR-29b/c and miR-200b/c target sequences were mutated. In contrast, miR-30b/d did not elicit consistent and significant effects on ADAM12-L expression. Analysis of a publicly available gene expression dataset for 100 breast tumors revealed a statistically significant negative correlation between ADAM12-L and both miR-29b and miR-200c. Inhibition of endogenous miR-29b and miR-200c in SUM149PT and SUM102PT cells led to increased ADAM12-L expression.
CONCLUSIONS: The ADAM12-L 3'UTR is a direct target of miR-29 and miR-200 family members. Since the miR-29 and miR-200 families play important roles in breast cancer progression, these results may help explain the different prognostic and chemopredictive values of ADAM12-L and ADAM12-S in breast cancer.

Guo H, Zhang X, Dong R, et al.
Integrated analysis of long noncoding RNAs and mRNAs reveals their potential roles in the pathogenesis of uterine leiomyomas.
Oncotarget. 2014; 5(18):8625-36 [PubMed] Free Access to Full Article Related Publications
Global expression profiling studies showed that miRNAs are aberrantly expressed in uterine leiomyomas (ULMs) and are involved in ULM pathogenesis. Long noncoding RNAs (lncRNAs) are another group of regulatory RNA whose expression and roles in ULMs have not been explored. In this study, we examined the global expressions of lncRNAs and mRNAs in ULMs using microarray and interrogated their interrelationship through co-expression analysis. We found that lncRNAs and mRNAs were dysregulated in ULMs and the degree of dysregulation was positively correlated with tumor size. Further analysis showed that lncRNAs correlate to their cis mRNAs in expression levels depending on genomic locations and orientations. Moreover, we identified several dysregulated pathways that were correlated to dysregulated lncRNAs. We validated several aberrantly expressed lncRNAs in extended samples and confirmed that AK023096 was down-regulated and chromatin-associated RNA (CAR) Intergenic 10 was up-regulated in the majority of leiomyomas. Knockdown of Intergenic 10 inhibited the proliferation of leiomyoma cells in vitro, indicating its functional importance in ULM pathogenesis. The neighboring protein-coding gene ADAM12 was also downregulated in Intergenic 10 knockdown leiomyoma cells. We showed for the first time that lncRNAs were dysregulated in uterine leiomyomas. Aberrantly expressed lncRNAs may contribute to the pathogenesis of uterine leiomyomas.

Rao VH, Vogel K, Yanagida JK, et al.
Erbb2 up-regulation of ADAM12 expression accelerates skin cancer progression.
Mol Carcinog. 2015; 54(10):1026-36 [PubMed] Related Publications
Solar ultraviolet (UV) radiation can cause severe damage to the skin and is the primary cause of most skin cancer. UV radiation causes DNA damage leading to mutations and also activates the Erbb2/HER2 receptor through indirect mechanisms involving reactive oxygen species. We hypothesized that Erbb2 activation accelerates the malignant progression of UV-induced skin cancer. Following the induction of benign squamous papillomas by UV exposure of v-ras(Ha) transgenic Tg.AC mice, mice were treated topically with the Erbb2 inhibitor AG825 and tumor progression monitored. AG825 treatment reduced tumor volume, increased tumor regression, and delayed the development of malignant squamous cell carcinoma (SCC). Progression to malignancy was associated with increased Erbb2 and ADAM12 (A Disintegin And Metalloproteinase 12) transcripts and protein, while inhibition of Erbb2 blocked the increase in ADAM12 message upon malignant progression. Similarly, human SCC and SCC cell lines had increased ADAM12 protein and transcripts when compared to normal controls. To determine whether Erbb2 up-regulation of ADAM12 contributed to malignant progression of skin cancer, Erbb2 expression was modulated in cultured SCC cells using forced over-expression or siRNA targeting, demonstrating up-regulation of ADAM12 by Erbb2. Furthermore, ADAM12 transfection or siRNA targeting revealed that ADAM12 increased both the migration and invasion of cutaneous SCC cells. Collectively, these results suggest Erbb2 up-regulation of ADAM12 as a novel mechanism contributing to the malignant progression of UV-induced skin cancer. Inhibition of Erbb2/HER2 reduced tumor burden, increased tumor regression, and delayed the progression of benign skin tumors to malignant SCC in UV-exposed mice. Inhibition of Erbb2 suppressed the increase in metalloproteinase ADAM12 expression in skin tumors, which in turn increased migration and tumor cell invasiveness.

Qi Y, Duhachek-Muggy S, Li H, Zolkiewska A
Phenotypic diversity of breast cancer-related mutations in metalloproteinase-disintegrin ADAM12.
PLoS One. 2014; 9(3):e92536 [PubMed] Free Access to Full Article Related Publications
Six different somatic missense mutations in the human ADAM12 gene have been identified so far in breast cancer. Five of these mutations involve highly conserved residues in the extracellular domain of the transmembrane ADAM12-L protein. Two of these extracellular mutations, D301H and G479E, have been previously characterized in the context of mouse ADAM12. Three other mutations, T596A, R612Q, and G668A, have been reported more recently, and their effects on ADAM12-L protein structure/function are not known. Here, we show that ADAM12-L bearing the G668A mutation is largely retained in the endoplasmic reticulum in its nascent, full-length form, with an intact N-terminal pro-domain. The T596A and R612Q mutants are efficiently trafficked to the cell surface and proteolytically processed to remove their pro-domains. However, the T596A mutant shows decreased catalytic activity at the cell surface, while the R612Q mutant is fully active and comparable to the wild-type ADAM12-L. The D301H and G479E mutants, consistent with the corresponding D299H and G477E mutants of mouse ADAM12 described earlier, are not proteolytically processed and do not exhibit catalytic activity at the cell surface. Among all six breast cancer-associated mutations in ADAM12-L, mutations that preserve the activity--R612Q and L792F--occur in triple-negative breast cancers, while loss-of-function mutations--D301H, G479E, T596A, and G668A--are found in non-triple negative cancers. This apparent association between the catalytic activity of the mutants and the type of breast cancer supports a previously postulated role of an active ADAM12-L in the triple negative breast cancer disease.

Misemer BS, Skubitz AP, Carlos Manivel J, et al.
Expression of FAP, ADAM12, WISP1, and SOX11 is heterogeneous in aggressive fibromatosis and spatially relates to the histologic features of tumor activity.
Cancer Med. 2014; 3(1):81-90 [PubMed] Free Access to Full Article Related Publications
Aggressive fibromatosis (AF) represents a group of tumors with a variable and unpredictable clinical course, characterized by a monoclonal proliferation of myofibroblastic cells. The optimal treatment for AF remains unclear. Identification and validation of genes whose expression patterns are associated with AF may elucidate biological mechanisms in AF, and aid treatment selection. This study was designed to examine the protein expression by immunohistochemistry (IHC) of four genes, ADAM12, FAP, SOX11, and WISP1, that were found in an earlier study to be uniquely overexpressed in AF compared with normal tissues. Digital image analysis was performed to evaluate inter- and intratumor heterogeneity, and correlate protein expression with histologic features, including a histopathologic assessment of tumor activity, defined by nuclear chromatin density ratio (CDR). AF tumors exhibited marked inter- and intratumor histologic heterogeneity. Pathologic assessment of tumor activity and digital assessment of average nuclear size and CDR were all significantly correlated. IHC revealed protein expression of all four genes. IHC staining for ADAM12, FAP, and WISP1 correlated with CDR and was higher, whereas SOX11 staining was lower in tumors with earlier recurrence following excision. All four proteins were expressed, and the regional variation in tumor activity within and among AF cases was demonstrated. A spatial correlation between protein expression and nuclear morphology was observed. IHC also correlated with the probability of recurrence following excision. These proteins may be involved in AF pathogenesis and the corresponding pathways could serve as potential targets of therapy.

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