Research IndicatorsGraph generated 14 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 14 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (2)
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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: ADAM12 (cancer-related)
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
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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.
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
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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.
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.
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
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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.
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.
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
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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.
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
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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.
Zhou Z, Darwal MA, Cheng EA, et al.Cellular reprogramming into a brown adipose tissue-like phenotype by co-expression of HB-EGF and ADAM 12S.
Growth Factors. 2013; 31(6):185-98 [PubMed
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Abnormal adipogenesis leads to excessive fat accumulation and several health disorders. Mouse fibroblasts (MLC) transfected with ADAM 12S and HB-EGF promoted lipid accumulation. Addition of KBR-7785, an ADAM 12S inhibitor, to HB-EGF/ADAM 12S expressing cells suppressed adipogenesis. BrdU incorporation was attenuated and enhanced mitotracker staining was observed in HB-EGF/ADAM 12S cells. Quantitative real time RT-PCR resulted in elevated levels of expression of three brown adipose tissue (BAT) genes (PRDM16, PGC-1α, and UCP-1), while expression levels of the three white adipose tissue (WAT) genes (PPARγ, C/EBPα, and AKT-1) were unaltered in HB-EGF/ADAM 12S cells. Amino- or carboxy-terminal deletions of HB-EGF (HB-EGFΔN and HB-EGFΔC) co-expressed with ADAM 12S stimulated lipid accumulation. Human epidermoid carcinoma cells (A431) also exhibited lipid accumulation by HB-EGF/ADAM 12S co-expression. These studies suggest ADAM 12S and HB-EGF are involved in cellular plasticity resulting in the production of BAT-like cells and offers insight into novel therapeutic approaches for fighting obesity.
Members of the ADAM family of proteases have been associated with mammary tumorigenesis. Gene profiling of human breast tumors identified several intrinsic subtypes of breast cancer, which differ in terms of their basic biology, response to chemotherapy/radiation, preferential sites of metastasis, and overall patient survival. Whether or not the expression of individual ADAM proteases is linked to a particular subtype of breast cancer and whether the functions of these ADAMs are relevant to the cancer subtype have not been investigated. We analyzed several transcriptomic datasets and found that ADAM12L is specifically up-regulated in claudin-low tumors. These tumors are poorly differentiated, exhibit aggressive characteristics, have molecular signatures of epithelial-to-mesenchymal transition (EMT), and are rich in markers of breast tumor-initiating cells (BTICs). Consistently, we find that ADAM12L, but not the alternative splice variant ADAM12S, is a part of stromal, mammosphere, and EMT gene signatures, which are all associated with BTICs. In patients with estrogen receptor-negative tumors, high expression of ADAM12L, but not ADAM12S, is predictive of resistance to neoadjuvant chemotherapy. Using MCF10DCIS.com breast cancer cells, which express the endogenous ADAM12L and efficiently form mammospheres when plated at the density of single cell per well, we show that ADAM12L plays an important role in supporting mammosphere growth. We postulate that ADAM12L may serve as a novel marker and/or a novel therapeutic target in BTICs.
Cireap N, Narita DMolecular profiling of ADAM12 and ADAM17 genes in human malignant melanoma.
Pathol Oncol Res. 2013; 19(4):755-62 [PubMed
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ADAM12 and ADAM17 proteins belong to a family of transmembrane disintegrin-containing metalloproteinases (ADAMs) involved in the proteins ectodomain shedding and cell-cell and cell-matrix interactions. However, the specific biological functions of ADAMs are still unclear and, until now, these proteins were not investigated yet in melanoma. The aim of this study was to analyze the splicing variants of ADAM12 (L and S) and ADAM17 gene expression in melanoma at transcriptional and translational level in comparison with control (non-tumor) tissues. Taking in account that ADAM17 sheddase is involved in the modulation of TNF-α (tumor necrosis factor alpha), we analyzed also this cytokine in the plasma of the same patients before any treatment, and we compared the results with healthy controls. Quantitative-RT-PCR and immunohistochemistry were used to analyze ADAM12 and ADAM17 genes expression and the analysis of TNF-α expression was carried out in the plasma using ELISA. We demonstrated that ADAM12L splicing variant together with ADAM17 gene are strongly overexpressed in melanomas, whereas ADAM12S, although up-regulated when compared with the non-tumor controls, the difference was not statistically significant. When we compared the levels of expression for the ADAMs genes according to the tumor stage, we observed that all three investigated genes were significantly overexpressed in advanced stage in comparison with early stage melanomas. In the plasma of the same patients, the expression of TNF-α was up-regulated and significantly correlated with the expression of ADAM17 and respectively, with the advanced tumor stage.
Kogure M, Takawa M, Cho HS, et al.Deregulation of the histone demethylase JMJD2A is involved in human carcinogenesis through regulation of the G(1)/S transition.
Cancer Lett. 2013; 336(1):76-84 [PubMed
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Although a number of JmjC-containing histone demethylases have been identified and biochemically characterized, pathological roles of their dysfunction in human disease such as cancer have not been well elucidated. Here, we report the Jumonji domain containing 2A (JMJD2A) is integral to proliferation of cancer cells. Quantitative real-time PCR analysis revealed higher expression of JMJD2A in clinical bladder cancer tissues than in corresponding non-neoplastic tissues (P<0.0001). Immunohistochemical analysis also showed positive staining for JMJD2A in 288 out of 403 lung cancer cases, whereas no staining was observed in lung normal tissues. Suppression of JMJD2A expression in lung and bladder cancer cells overexpressing this gene, using specific siRNAs, inhibited incorporation of BrdU and resulted in significant suppression of cell growth. Furthermore, JMJD2A appears to directly transactivate the expression of some tumor associated proteins including ADAM12 through the regulation of histone H3K9 methylation. As expression levels of JMJD2A are low in normal tissues, it may be feasible to develop specific inhibitors targeting the enzyme as anti-tumor agents which should have a minimal risk of adverse reaction.
Georges S, Chesneau J, Hervouet S, et al.A Disintegrin And Metalloproteinase 12 produced by tumour cells accelerates osteosarcoma tumour progression and associated osteolysis.
Eur J Cancer. 2013; 49(9):2253-63 [PubMed
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BACKGROUND: Osteosarcoma is the most common primary malignant bone tumour in children and adolescents for whom the prognosis remains unfavourable despite treatment protocols that combine chemotherapy and surgery. Metalloproteinases decisively contribute to cancer development and promotion by regulating cell growth, angiogenesis or inflammation. However, their role in osteosarcoma remains still unknown.
METHODS: A screening of a large panel of metalloproteinases and their inhibitors, carried out in osteolytic (K7M2 and POS-1) or osteoblastic (MOS-J) mouse osteosarcoma models, shows that a member of a family of cell surface metallopeptidases, A Disintegrin And Metalloproteinase 12 (ADAM12), is highly expressed in the K7M2 and POS-1 cell lines and weakly expressed in the MOS-J cell line. To investigate whether ADAM12, involved in several pathologic conditions characterised by abnormal cell growth, plays a role in osteosarcoma tumour growth, ADAM12 was overexpressed in MOS-J and downregulated in K7M2 cells.
RESULTS: In vivo experiments demonstrated that ADAM12 favours tumour growth, leading to a significant modification in animal survival. In vitro assays showed that ADAM12 knockdown in K7M2 cells slows cell proliferation. In addition, the study of microarchitectural parameters, assessed by micro-computed tomography (CT) analysis, showed that ADAM12 favours bone osteolysis, as demonstrated both in an ADAM12 overexpressing (MOS-J) and a knockdown (K7M2) model. Histological analysis showed that ADAM12 inhibited osteoblast activity and therefore enhanced bone resorption.
CONCLUSIONS: Our study demonstrates that ADAM12 expression not only favours tumour growth but also associates enhanced osteolysis with a significant reduction in animal survival, suggesting that ADAM12 could be a new therapeutic target in osteosarcoma.
Fröhlich C, Klitgaard M, Noer JB, et al.ADAM12 is expressed in the tumour vasculature and mediates ectodomain shedding of several membrane-anchored endothelial proteins.
Biochem J. 2013; 452(1):97-109 [PubMed
] Related Publications
ADAM (a disintegrin and metalloproteinase) 12 is a metalloprotease implicated in cancer progression. ADAM12 can activate membrane-anchored proteins, such as sonic hedgehog, Delta-like 1 and certain epidermal growth factor receptor ligands, through a process called ectodomain shedding. We screened several membrane-anchored proteins to further dissect the substrate profile of ADAM12-mediated ectodomain shedding, and found shedding of five previously unreported substrates [Kitl1, VE-cadherin (vascular endothelial cadherin), Flk-1 (fetal liver kinase 1), Tie-2, and VCAM-1 (vascular cell adhesion molecule 1)], of which the latter four are specifically expressed by endothelial cells. We also observed that ADAM12 expression was increased in the tumour vasculature of infiltrating ductal carcinoma of the human breast as compared with little to no expression in normal breast tissue vasculature, suggesting a role for ADAM12 in tumour vessels. These results prompted us to further evaluate ADAM12-mediated shedding of two endothelial cell proteins, VE-cadherin and Tie-2. Endogenous ADAM12 expression was very low in cultured endothelial cells, but was significantly increased by cytokine stimulation. In parallel, the shed form of VE-cadherin was elevated in such cytokine-stimulated endothelial cells, and ADAM12 siRNA (small interfering RNA) knockdown reduced cytokine-induced shedding of VE-cadherin. In conclusion, the results of the present study demonstrate a role for ADAM12 in ectodomain shedding of several membrane-anchored endothelial proteins. We speculate that this process may have importance in tumour neovascularization or/and tumour cell extravasation.
Ray BK, Dhar S, Henry C, et al.Epigenetic regulation by Z-DNA silencer function controls cancer-associated ADAM-12 expression in breast cancer: cross-talk between MeCP2 and NF1 transcription factor family.
Cancer Res. 2013; 73(2):736-44 [PubMed
] Related Publications
A disintegrin and metalloprotease domain-containing protein 12 (ADAM-12) is upregulated in many human cancers and promotes cancer metastasis. Increased urinary level of ADAM-12 in breast and bladder cancers correlates with disease progression. However, the mechanism of its induction in cancer remains less understood. Previously, we reported a Z-DNA-forming negative regulatory element (NRE) in ADAM-12 that functions as a transcriptional suppressor to maintain a low-level expression of ADAM-12 in most normal cells. We now report here that overexpression of ADAM-12 in triple-negative MDA-MB-231 breast cancer cells and breast cancer tumors is likely due to a marked loss of this Z-DNA-mediated transcriptional suppression function. We show that Z-DNA suppressor operates by interaction with methyl-CpG-binding protein, MeCP2, a prominent epigenetic regulator, and two members of the nuclear factor 1 family of transcription factors, NF1C and NF1X. While this tripartite interaction is highly prevalent in normal breast epithelial cells, both in vitro and in vivo, it is significantly lower in breast cancer cells. Western blot analysis has revealed significant differences in the levels of these 3 proteins between normal mammary epithelial and breast cancer cells. Furthermore, we show, by NRE mutation analysis, that interaction of these proteins with the NRE is necessary for effective suppressor function. Our findings unveil a new epigenetic regulatory process in which Z-DNA/MeCP2/NF1 interaction leads to transcriptional suppression, loss of which results in ADAM-12 overexpression in breast cancer cells.
PURPOSE: Cancer associated stromal fibroblasts (CAFs) undergo transcriptional and phenotypic changes that contribute to tumor progression, but the mechanisms responsible for these changes are not well understood. Aberrant DNA methylation is an important cause of transcriptional alterations in cancer cells but it is not known how important DNA methylation alterations are to CAF behavior.
EXPERIMENTAL DESIGN: We used Affymetrix exon arrays to compare genes induced by the DNA methylation inhibitor 5-aza-dC in cultured pancreatic cancer associated fibroblasts, pancreatic control fibroblasts and pancreatic cancer cell lines.
RESULTS: We found that pancreatic CAFs and control pancreatic fibroblasts were less responsive to 5-aza-dC-mediated gene reactivation than pancreatic cancer cells (mean+/-SD of genes induced ≥ 5-fold was 9 ± 10 genes in 10 pancreatic CAF cultures, 17 ± 14 genes in 3 control pancreatic fibroblast cultures, and 134 ± 85 genes in 4 pancreatic cancer cell lines). We examined differentially expressed genes between CAFs and control fibroblasts for candidate methylated genes and identified the disintegrin and metalloprotease, ADAM12 as hypomethylated and overexpressed in pancreatic CAF lines and overexpressed in fibroblasts adjacent to primary pancreatic adenocarcinomas.
CONCLUSIONS: Compared to pancreatic cancer cells, few genes are reactivated by DNMT1 inhibition in pancreatic CAFs suggesting these cells do not harbor many functionally important alterations in DNA methylation. CAFs may also not be very responsive to therapeutic targeting with DNA methylation inhibitors.
In the absence of HER2 overexpression, triple-negative breast cancers (TNBCs) rely on signaling by epidermal growth factor receptor (EGFR/ErbB1/HER1) to convey growth signals and stimulate cell proliferation. Soluble EGF-like ligands are derived from their transmembrane precursors by ADAM proteases, but the identity of the ADAM that is primarily responsible for ligand release and activation of EGFR in TNBCs is not clear. Using publicly available gene expression data for patients with lymph node-negative breast tumors who did not receive systemic treatment, we show that ADAM12L is the only ADAM with an expression level significantly associated with decreased distant metastasis-free survival times. Similar effect was not observed for patients with ER-negative non-TNBCs. There was a positive correlation between ADAM12L and HB-EGF and EGFR in TNBCs, but not in ER-negative non-TNBCs. We further demonstrate that ectopic expression of ADAM12L increased EGFR phosphorylation in a mouse intraductal xenograft model of early breast cancer. Finally, we detect strong correlation between the level of anti-ADAM12L and anti-phospho-EGFR immunostaining in human breast tumors using tissue microarrays. These studies suggest that ADAM12L is the primary protease responsible for the activation of EGFR in early stage, lymph node-negative TNBCs. Thus, our results may provide novel insight into the biology of TNBC.
Do EK, Kim YM, Heo SC, et al.Lysophosphatidic acid-induced ADAM12 expression mediates human adipose tissue-derived mesenchymal stem cell-stimulated tumor growth.
Int J Biochem Cell Biol. 2012; 44(11):2069-76 [PubMed
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Lysophosphatidic acid (LPA) is involved in mesenchymal stem cell-stimulated tumor growth in vivo. However, the molecular mechanism by which mesenchymal stem cells promote tumorigenesis remains elusive. In the present study, we demonstrate that conditioned medium from A549 human lung adenocarcinoma cells (A549 CM) induced the expression of ADAM12, a disintegrin and metalloproteases family member, in human adipose tissue-derived mesenchymal stem cells (hASCs). A549 CM-stimulated ADAM12 expression was abrogated by pretreatment of hASCs with the LPA receptor 1 inhibitor Ki16425 or by small interfering RNA-mediated silencing of LPA receptor 1, suggesting a key role for the LPA-LPA receptor 1 signaling axis in A549 CM-stimulated ADAM12 expression. Silencing of ADAM12 expression using small interfering RNA or short hairpin RNA abrogated LPA-induced expression of both α-smooth muscle actin, a marker of carcinoma-associated fibroblasts, and ADAM12 in hASCs. Using a xenograft transplantation model of A549 cells, we demonstrated that silencing of ADAM12 inhibited the hASC-stimulated in vivo growth of A549 xenograft tumors and the differentiation of transplanted hASCs to α-smooth muscle actin-positive carcinoma-associated fibroblasts. LPA-conditioned medium from hASCs induced the adhesion of A549 cells and silencing of ADAM12 inhibited LPA-induced expression of extracellular matrix proteins, periostin and βig-h3, in hASCs and LPA-conditioned medium-stimulated adhesion of A549 cells. These results suggest a pivotal role for LPA-stimulated ADAM12 expression in tumor growth and the differentiation of hASCs to carcinoma-associated fibroblasts expressing α-smooth muscle actin, periostin, and βig-h3.
Sedic M, Pavelic SK, Hock KUsing functional genomics to identify drug targets: a Dupuytren's disease example.
Methods Mol Biol. 2012; 910:15-31 [PubMed
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Research into the molecular mechanism of Dupuytren's disease (DD) illustrates all the problems common to drug discovery in orphan diseases, but also in more commonly investigated ailments. Current findings characterize DD as a disease with complex molecular pathology, with changes in expression of multiple genes and proteins as well as many contributing risk factors. Some of the observed changes include genes and proteins that have been identified in a number of other pathological processes, such as TGF-β, some which may be more specific to DD, such as ADAM12, and undoubtedly also some that have yet to be discovered in future studies. When all these results are taken into consideration, it can be deduced that DD is an end result of several pathological processes that can have many points of origin, and probably involves several subtypes that give rise to sufficiently similar clinical symptoms to be unified under a single medical term. Such breadth of view has become possible with the advent of functional genomics methods and system-wide overview of the molecular processes, which highlight molecular players and processes that might not be intuitively obvious from symptoms, as is the case with the observed parallels with wound-healing processes. As functional genomics methods allow researchers to compile a more complete image of the molecular mechanisms involved in DD pathogenesis, they also help to propose new drug targets that can be employed to develop an effective pharmacological treatment for DD. Identification of key molecular players in DD has already benefited from the integration of functional genomics and biocomputational methods, and such approach may reveal new ways how we can interfere with the emergence of the DD phenotype.
BACKGROUND: Degradation of the extracellular matrix is fundamental to tumour development, invasion and metastasis. Several protease families have been implicated in the development of a broad range of tumour types, including oesophago-gastric (OG) adenocarcinoma. The aim of this study was to analyse the expression levels of all core members of the cancer degradome in OG adenocarcinoma and to investigate the relationship between expression levels and tumour/patient variables associated with poor prognosis.
METHODS: Comprehensive expression profiling of the protease families (matrix metalloproteinases (MMPs), members of the ADAM metalloproteinase-disintegrin family (ADAMs)), their inhibitors (tissue inhibitors of metalloproteinase), and molecules involved in the c-Met signalling pathway, was performed using quantitative real-time reverse transcription polymerase chain reaction in a cohort of matched malignant and benign peri-tumoural OG tissue (n=25 patients). Data were analysed with respect to clinico-pathological variables (tumour stage and grade, age, sex and pre-operative plasma C-reactive protein level).
RESULTS: Gene expression of MMP1, 3, 7, 9, 10, 11, 12, 16 and 24 was upregulated by factors >4-fold in OG adenocarcinoma samples compared with matched benign tissue (P<0.01). Expression of ADAM8 and ADAM15 correlated significantly with tumour stage (P=0.048 and P=0.044), and ADAM12 expression correlated with tumour grade (P=0.011).
CONCLUSION: This study represents the first comprehensive quantitative analysis of the expression of proteases and their inhibitors in human OG adenocarcinoma. These findings implicate elevated ADAM8, 12 and 15 mRNA expression as potential prognostic molecular markers.
A recently identified breast cancer-associated mutation in the metalloprotease ADAM12 alters a potential dileucine trafficking signal, which could affect protein processing and cellular localization. ADAM12 belongs to the group of A Disintegrin And Metalloproteases (ADAMs), which are typically membrane-associated proteins involved in ectodomain shedding, cell-adhesion, and signaling. ADAM12 as well as several members of the ADAM family are over-expressed in various cancers, correlating with disease stage. Three breast cancer-associated somatic mutations were previously identified in ADAM12, and two of these, one in the metalloprotease domain and another in the disintegrin domain, were investigated and found to result in protein misfolding, retention in the secretory pathway, and failure of zymogen maturation. The third mutation, p.L792F in the ADAM12 cytoplasmic tail, was not investigated, but is potentially significant given its location within a di-leucine motif, which is recognized as a potential cellular trafficking signal. The present study was motivated both by the potential relevance of this documented mutation to cancer, as well as for determining the role of the di-leucine motif in ADAM12 trafficking. Expression of ADAM12 p.L792F in mammalian cells demonstrated quantitatively similar expression levels and zymogen maturation as wild-type (WT) ADAM12, as well as comparable cellular localizations. A cell surface biotinylation assay demonstrated that cell surface levels of ADAM12 WT and ADAM12 p.L792F were similar and that internalization of the mutant occurred at the same rate and extent as for ADAM12 WT. Moreover, functional analysis revealed no differences in cell proliferation or ectodomain shedding of epidermal growth factor (EGF), a known ADAM12 substrate between WT and mutant ADAM12. These data suggest that the ADAM12 p.L792F mutation is unlikely to be a driver (cancer causing)-mutation in breast cancer.
Exome sequencing of human breast cancers has revealed a substantial number of candidate cancer genes with recurring but infrequent somatic mutations. To determine more accurately their mutation prevalence, we performed a mutation analysis of 36 novel candidate cancer genes in 96 human breast cancers. Somatic mutations with potential impact on protein function were observed in the genes ADAM12, CENTB1, CENTG1, DIP2C, GLI1, GRIN2D, HDLBP, IKBKB, KPNA5, NFKB1, NOTCH1, and OTOF. These findings strengthen the evidence for involvement of the Notch, Hedgehog, NF-KB, and PIK3CA pathways in breast cancer development, and point to novel processes that likely are involved.
Uehara E, Shiiba M, Shinozuka K, et al.Upregulated expression of ADAM12 is associated with progression of oral squamous cell carcinoma.
Int J Oncol. 2012; 40(5):1414-22 [PubMed
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ADAMs are a disintegrin and metalloproteinase family of membrane-associated metalloproteinases characterized by their multidomain structure, and have been reported to be associated with various malignant tumors. The aim of this study was to identify crucial members of the ADAM family in oral squamous cell carcinoma (OSCC), and to reveal their biological function and clinical significance. To clarify whether ADAM family genes are involved in OSCC, changes in the expression profile were investigated by real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) analysis and immunohistochemical analysis. Functional analysis was performed by comparing cellular proliferation of siADAM-transfected cell lines and parental cell lines. Real-time qRT-PCR analysis identified significantly upregulated expression of ADAM12 in OSCC-derived cell lines. This was validated in OSCC samples using real-time qRT-PCR and immuno-histochemical staining. ADAM12 expression was correlated with TNM classification; significantly greater expression of ADAM12 was observed in tumors with higher T classification and more advanced stages. Moreover, siADAM12-transfected cells showed both a suppressed proliferation rate and increased transforming growth factor (TGF)-β3 expression. Our data indicate that ADAM12 is overexpressed in OSCC and might accelerate cellular proliferation. Its function may be associated with TGF-β signaling. This study suggests that controlling the expression or activity of ADAM12 could be a useful strategy in the development of an effective cure for OSCC.
Seubwai W, Kraiklang R, Wongkham C, Wongkham SHypoxia enhances aggressiveness of cholangiocarcinoma cells.
Asian Pac J Cancer Prev. 2012; 13 Suppl:53-8 [PubMed
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Hypoxia, a common feature of solid tumors, plays a significant role in determining tumor phenotype and tumor progression. In this study, using an in-house PCR-array, we investigated phenotypic changes and differentially expressed hypoxia related genes in the KKU-M213 CCA cell line, cultured under hypoxic (1% O2) condition. Trefoil factor-1 (TFF1), a disintegrin, and metalloprotease 12 (ADAM12), integrin-alpha 5 (ITGA5) and baculoviral IAP repeat-containing 5 (BIRC5/survivin), proteins involved with cell proliferation, metastasis and apoptosis resistance, were up-regulated whereas uridine 5'-monophosphate synthase (UMPS) and S100 calcium binding protein P (S100P), involved with chemosensitivity and cell adhesion, were down-regulated. Growth arrest, apoptosis resistance to UV-irradiation and chemotherapeutic drugs (5- flourouracil, cisplatin, doxorubicin) as well as cell adhesion were thus significantly enhanced upon exposure to hypoxic condition. These findings emphasize the significance of a hypoxic state in the induction of an aggressive phenotype and suggest the potential of targeting hypoxia regulated genes to enhance the sensitivity of chemotherapeutic drug against CCA.
Colombo C, Creighton CJ, Ghadimi MP, et al.Increased midkine expression correlates with desmoid tumour recurrence: a potential biomarker and therapeutic target.
J Pathol. 2011; 225(4):574-82 [PubMed
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Desmoid tumours (DTs) are soft tissue monoclonal neoplasms exhibiting a unique phenotype, consisting of aggressive local invasiveness without metastatic capacity. While DTs can infrequently occur as part of familial adenomatosis polyposis, most cases arise sporadically. Sporadic DTs harbour a high prevalence of CTNNB1 mutations and hence increased β-catenin signalling. However, β-catenin downstream transcriptional targets and other molecular deregulations operative in DT inception and progression are currently not well defined, contributing to the lack of sensitive molecular prognosticators and efficacious targeted therapeutic strategies. We compared the gene expression profiles of 14 sporadic DTs to those of five corresponding normal tissues and six solitary fibrous tumour specimens. A DT expression signature consisting of 636 up- and 119 down-regulated genes highly enriched for extracellular matrix, cell adhesion and wound healing-related proteins was generated. Furthermore, 98 (15%) of the over-expressed genes were demonstrated to contain a TCF/LEF consensus binding site in their promoters, possibly heralding direct β-catenin downstream targets relevant to DT. The protein products of three of the up-regulated DT genes: ADAM12, MMP2 and midkine, were found to be commonly expressed in a large cohort of human DT samples assembled on a tissue microarray. Interestingly, enhanced midkine expression significantly correlated with a higher propensity and decreased time for primary DT recurrence (log-rank p = 0.0025). Finally, midkine was found to enhance the migration and invasion of primary DT cell cultures. Taken together, these studies provide insights into potential DT molecular aberrations and novel β-catenin transcriptional targets. Further studies to confirm the utility of midkine as a clinical DT molecular prognosticator and a potential therapeutic target are therefore warranted. Raw gene array data can be found at: http://smd.stanford.edu/
The molecular phenotype of tumor vasculature is different from normal vasculature, offering new opportunities for diagnosis and therapy of cancer, but the identification of tumor-restricted targets remains a challenge. We investigated 13 tumor vascular markers (TVMs) from 50 candidates identified through expression profiling of ovarian cancer vascular cells and selected to be either transmembrane or secreted, and to be either absent or expressed at low levels in normal tissues while overexpressed in tumors, based on analysis of 1,110 normal and tumor tissues from publicly available Affymetrix microarray data. Tumor-specific expression of each TVM was confirmed at the protein level in tumor tissue and/or in serum. Among the 13 TVMs, 11 were expressed on tumor vascular endothelium; the remaining 2 TVMs were expressed by tumor leukocytes. Our results demonstrate that certain transmembrane TVMs such as ADAM12 and CDCP1 are selectively expressed in tumor vasculature and represent promising targets for vascular imaging or anti-vascular therapy of epithelial ovarian cancer, while secreted or shed molecules such as TNFRSF21/DR6 can function as serum biomarkers. We have identified novel tumor-specific vasculature markers which appear promising for cancer serum diagnostics, molecular imaging and/or therapeutic targeting applications and warrant further clinical development.
Narita D, Seclaman E, Ursoniu S, Anghel AIncreased expression of ADAM12 and ADAM17 genes in laser-capture microdissected breast cancers and correlations with clinical and pathological characteristics.
Acta Histochem. 2012; 114(2):131-9 [PubMed
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ADAMs (a desintegrin and metalloprotease) are transmembrane glycoproteins involved in cell growth, differentiation, motility, and respectively, tumor growth and progression. Our aim was to evaluate ADAM12 spliced variants (ADAM12L - long membrane-bound and ADAM12S - secreted-short variant) and ADAM17 genes expression in breast cancers and to correlate their level of expression with clinical and pathological characteristics. Expression of ADAMs was analyzed using quantitative reverse-transcription polymerase chain reaction in laser-capture microdissected specimens of breast cancers and corresponding non-neoplastic breast tissues from 92 patients. The proteins' expression was confirmed by immunohistochemistry. Significantly elevated amounts of ADAM12L, ADAM12S and ADAM17 transcripts were found in malignant breast cells compared with normal breast tissue and both ADAMs proteins showed moderate to strong immunoexpression in tumor cells and peritumoral fibroblasts. ADAM12L and ADAM12S expressions were correlated with age, younger patients having higher expression of ADAM12L and ADAM12S; ductal cancers had higher expression of ADAM12L compared with lobular types, whereas ADAM12S was higher expressed in lobular cancers; higher expressions were found for both ADAM12 and ADAM17 in HER2/neu positive and highly proliferative cancers. High-grade cancers showed significantly increased expression of ADAM17. Our study on laser-capture microdissected specimens confers motivation for future work on development of ADAM-selective inhibitors for treatment of breast cancers.