Gene Summary

Gene:ADAM9; ADAM metallopeptidase domain 9
Aliases: MCMP, MDC9, CORD9, Mltng
Summary:This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this family are membrane-anchored proteins 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. The protein encoded by this gene interacts with SH3 domain-containing proteins, binds mitotic arrest deficient 2 beta protein, and is also involved in TPA-induced ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor. Several alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Jul 2010]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:disintegrin and metalloproteinase domain-containing protein 9
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

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

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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: ADAM9 (cancer-related)

Li W, Wang D, Sun X, et al.
ADAM17 promotes lymph node metastasis in gastric cancer via activation of the Notch and Wnt signaling pathways.
Int J Mol Med. 2019; 43(2):914-926 [PubMed] Free Access to Full Article Related Publications
Disintegrin and metalloproteinase domain-containing proteins (ADAMs) have been implicated in cell adhesion, signaling and migration. The aim of the present study was to identify key members of the ADAM protein family associated with the metastasis of gastric cancer and to evaluate their clinical significance. A total of 193 patients with gastric cancer and positive lymph node metastasis were enrolled. Key members of the ADAM family associated with lymph node metastasis were identified. The correlations between survival times and the clinicopathological features of patients were investigated. Furthermore, ADAM17 expression in gastric cancer cells with different metastatic potentials was determined. ADAM17 was overexpressed in BGC‑823 cells and suppressed in SGC‑7901 cells to further investigate its effects on cell viability and migration. The key pathways associated with ADAM17 were identified by gene set enrichment analysis (GSEA). It was found that ADAM9 and ADAM17 were significantly upregulated in gastric cancer and positive metastatic lymph node tissues. Further, there was a strong correlation between the survival times of patients and ADAM17 expression. ADAM17 was upregulated in gastric cancer cells with high metastatic potential. The viability of BGC‑823 cells significantly increased following ADAM17 overexpression, whereas the viability and migration of SGC‑7901 cells decreased following ADAM17 suppression. GSEA and western blot analysis revealed a positive correlation between the Notch and Wnt signaling pathways with ADAM17 expression. In conclusion, the increased expression of ADAM17 promoted the progression of gastric cancer, potentially via Notch and/or Wnt signaling pathway activation, and ADAM17 may serve as a useful prognostic marker.

Liu Q, Jiang J, Fu Y, et al.
MiR-129-5p functions as a tumor suppressor in gastric cancer progression through targeting ADAM9.
Biomed Pharmacother. 2018; 105:420-427 [PubMed] Related Publications
MicroRNAs (miRNAs) are identified as key regulators in cancer initiation, progression and metastasis including gastric cancer (GC). The aim of the study is to explore clinical significance and potential mechanism of miR-129-5p in GC development. In the study, our results found that miR-129-5p expression was significantly downregulated in GC tissues, compared with adjacent normal tissues using qRT-PCR analyses. Furthermore, lower miR-129-5p expression closely associated with tumor size and lymph node invasion and poor prognosis of GC patients. Using CCK8 assay, cell colony formation, transwell invasion assay, we demonstrated that miR-129-5p overexpression reduced cell proliferation, cell colony formation and cell invasion capacity in MKN45 (higher miR-129-5p expression) and SGC-7901 (lower miR-129-5p expression). However, downregulation of miR-129-5p had reverse effects on cell proliferation and invasion. Targeting association analysis, dual luciferase assay, qRT-PCR and western blot analysis results verified that miR-129-5p could target the 3'UTR of ADAM9 mRNA and regulated its protein expression. Furthermore, we confirmed that miR-129-5p suppressed cell proliferation and invasion ability through regulating ADAM9. In vivo, upregulation of miR-129-5p also inhibited tumor growth. Therefore, these results indicated that miR-129-5p functioned as a tumor suppressor in GC and may be a potential target of GC treatment.

Mygind KJ, Störiko T, Freiberg ML, et al.
Sorting nexin 9 (SNX9) regulates levels of the transmembrane ADAM9 at the cell surface.
J Biol Chem. 2018; 293(21):8077-8088 [PubMed] Free Access to Full Article Related Publications
ADAM9 is an active member of the family of transmembrane ADAMs (a disintegrin and metalloproteases). It plays a role in processes such as bone formation and retinal neovascularization, and importantly, its expression in human cancers correlates with disease stage and poor prognosis. Functionally, ADAM9 can cleave several transmembrane proteins, thereby shedding their ectodomains from the cell surface. Moreover, ADAM9 regulates cell behavior by binding cell-surface receptors such as integrin and membrane-type matrix metalloproteases. Because these functions are mainly restricted to the cell surface, understanding the mechanisms regulating ADAM9 localization and activity at this site is highly important. To this end, we here investigated how intracellular trafficking regulates ADAM9 availability at the cell surface. We found that ADAM9 undergoes constitutive clathrin-dependent internalization and subsequent degradation or recycling to the plasma membrane. We confirmed previous findings of an interaction between ADAM9 and the intracellular sorting protein, sorting nexin 9 (SNX9), as well as its close homolog SNX18. Knockdown of either SNX9 or SNX18 had no apparent effects on ADAM9 internalization or recycling. However, double knockdown of SNX9 and SNX18 decreased ADAM9 internalization significantly, demonstrating a redundant role in this process. Moreover, SNX9 knockdown revealed a nonredundant effect on overall ADAM9 protein levels, resulting in increased ADAM9 levels at the cell surface, and a corresponding increase in the shedding of Ephrin receptor B4, a well-known ADAM9 substrate. Together, our findings demonstrate that intracellular SNX9-mediated trafficking constitutes an important ADAM9 regulatory pathway.

Oria VO, Lopatta P, Schilling O
The pleiotropic roles of ADAM9 in the biology of solid tumors.
Cell Mol Life Sci. 2018; 75(13):2291-2301 [PubMed] Related Publications
A disintegrin and a metalloprotease (ADAM) 9 is a metzincin cell-surface protease involved in several biological processes such as myogenesis, fertilization, cell migration, inflammatory response, proliferation, and cell-cell interactions. ADAM9 has been found over-expressed in several solid tumors entities such as glioma, melanoma, prostate cancer, pancreatic ductal adenocarcinoma, gastric, breast, lung, and liver cancers. Immunohistochemical analyses highlight ADAM9 expression by actual cancer cells and associate its abundant presence with clinicopathological features such as shortened overall survival, poor tumor grade, de-differentiation, therapy resistance, and metastasis formation. In each of these tumors, ADAM9 may contribute to tumor biology via proteolytic or non-proteolytic mechanisms. For example, in liver cancer, ADAM9 has been found to shed MHC class I polypeptide-related sequence A, contributing towards the evasion of tumor immunity. ADAM9 may also contribute to tumor biology in non-proteolytic ways probably through interaction with different integrins. For example, in melanoma, the interaction between ADAM9 and β1 integrins facilitates tumor stroma cross talks, which then promotes invasion and metastasis via the activation of MMP1 and MMP2. In breast cancer, the interaction between β1 integrins on endothelial cells and ADAM9 on tumor cells facilitate tumor cell extravasation and invasion to distant sites. This review summarizes the present knowledge on ADAM9 in solid cancers, and the different mechanisms which it employ to drive tumor progression.

Ueno M, Shiomi T, Mochizuki S, et al.
ADAM9 is over-expressed in human ovarian clear cell carcinomas and suppresses cisplatin-induced cell death.
Cancer Sci. 2018; 109(2):471-482 [PubMed] Free Access to Full Article Related Publications
ADAMs (a disintegrin and metalloproteinases) are involved in various biological events such as cell adhesion, migration and invasion, membrane protein shedding and proteolysis. However, there have been no systematic studies on the expression of ADAMs in human ovarian carcinomas. We therefore examined mRNA expression of all the proteolytic ADAM species including ADAM8, 9, 10, 12, 15, 17, 19, 20, 21, 28, 30, 33 and ADAMDEC1 in human ovarian carcinomas, and found that prototype membrane-anchored ADAM9m, but not secreted isoform ADAM9s, is significantly over-expressed in carcinomas than in control non-neoplastic ovarian tissue. Among the histological subtypes of serous, endometrioid, mucinous and clear cell carcinomas, ADAM9m expression was highest in clear cell carcinomas. Immunohistochemistry showed that all the clear cell carcinoma samples displayed ADAM9m primarily on the carcinoma cell membrane. By immunoblotting, ADAM9m was detected mainly in an active form in the clear cell carcinoma tissues. When two clear cell carcinoma cell lines (RMG-I and TOV21G cells) with ADAM9m expression were treated with cisplatin, viability was significantly reduced and apoptosis increased in ADAM9m knockdown cells compared with mock transfectants. In addition, treatment of the cells with neutralizing anti-ADAM9m antibody significantly decreased viability compared with non-immune IgG, whereas ADAM9m over-expression significantly increased viability compared with mock transfectants. Our data show, to the best of our knowledge, for the first time, that ADAM9m is over-expressed in an activated form in human ovarian clear cell carcinomas, and suggest that ADAM9m plays a key role in cisplatin resistance.

Vermeulen MA, Doebar SC, van Deurzen CHM, et al.
Copy number profiling of oncogenes in ductal carcinoma
Endocr Relat Cancer. 2018; 25(3):173-184 [PubMed] Related Publications
Characterizing male breast cancer (BC) and unraveling male breast carcinogenesis is challenging because of the rarity of this disease. We investigated copy number status of 22 BC-related genes in 18 cases of pure ductal carcinoma

Lin CY, Cho CF, Bai ST, et al.
ADAM9 promotes lung cancer progression through vascular remodeling by VEGFA, ANGPT2, and PLAT.
Sci Rep. 2017; 7(1):15108 [PubMed] Free Access to Full Article Related Publications
Lung cancer has a very high prevalence of brain metastasis, which results in a poor clinical outcome. Up-regulation of a disintegrin and metalloproteinase 9 (ADAM9) in lung cancer cells is correlated with metastasis to the brain. However, the molecular mechanism underlying this correlation remains to be elucidated. Since angiogenesis is an essential step for brain metastasis, microarray experiments were used to explore ADAM9-regulated genes that function in vascular remodeling. The results showed that the expression levels of vascular endothelial growth factor A (VEGFA), angiopoietin-2 (ANGPT2), and tissue plasminogen activator (PLAT) were suppressed in ADAM9-silenced cells, which in turn leads to decreases in angiogenesis, vascular remodeling, and tumor growth in vivo. Furthermore, simultaneous high expression of ADAM9 and VEGFA or of ADAM9 and ANGPT2 was correlated with poor prognosis in a clinical dataset. These findings suggest that ADAM9 promotes tumorigenesis through vascular remodeling, particularly by increasing the function of VEGFA, ANGPT2, and PLAT.

Lei D, Zhang F, Yao D, et al.
Galangin increases ERK1/2 phosphorylation to decrease ADAM9 expression and prevents invasion in A172 glioma cells.
Mol Med Rep. 2018; 17(1):667-673 [PubMed] Related Publications
Galangin (3,5,7‑trihydroxyflavone), is a natural flavonoid present in plants. Galangin is reported to exhibit anti‑cancer properties against various cancer types. The aim of the present study was to display the effects of galangin on glioma and its mechanism of action in A172 human glioma cancer cells. The results clearly indicated that treatment of galangin inhibited A172 cell migration and invasion under non‑toxic doses. A human proteinase array assay was conducted to elucidate the potential effects of galangin, and the obtained results demonstrated that treatment of galangin inhibited ADAM9 protein expression and mRNA expression, that are known to contribute to cancer progression. Sustained extracellular signal‑regulated kinase (Erk)1/2 activation was also monitored, which contributed to ADAM9 protein expression and mRNA inhibition as investigated using western blotting analysis and reverse transcription‑quantitative polymerase chain reaction experiment. Erk1/2 inhibition by inhibitor or small interfering (si)Erk transfection markedly terminated galangin‑inhibited A172 migration and invasion via an Erk1/2 activation mechanism. Collective results suggested that galangin may act as an effective chemotherapeutic agent for glioma cancer depending on its ability to bring about ADAM9 and Erk1/2 activation.

Arai J, Goto K, Stephanou A, et al.
Predominance of regorafenib over sorafenib: Restoration of membrane-bound MICA in hepatocellular carcinoma cells.
J Gastroenterol Hepatol. 2018; 33(5):1075-1081 [PubMed] Related Publications
BACKGROUND AND AIM: The multi-kinase inhibitor regorafenib (REG) was recently demonstrated to be effective in patients with sorafenib (SOR)-resistant hepatocellular carcinoma (HCC). Interestingly, SOR is known to enhance the accumulation of membrane-bound MHC class I polypeptide-related sequence A (mMICA) in HCC cells and to block the production of soluble MICA (sMICA), an immunological decoy. In addition, MICA is associated with HCC in patients with chronic hepatitis C. We have now compared the impact of REG and SOR on MICA in HCC cells, as well as the immunotherapeutic implications thereof.
METHODS: HepG2 and PLC/PRF/5 cells were exposed to REG and SOR, and levels of sMICA and mMICA were measured by ELISA and flow cytometry, respectively. The drugs were also tested in vitro for inhibitory activity against recombinant human A disintegrin and metalloprotease 9 (ADAM9), a sheddase that releases MICA from the membrane.
RESULTS: To a greater extent than SOR, but without marked difference in cytotoxicity, REG significantly suppressed mRNA and protein expression of ADAM9 and ADAM10, thereby decreasing production of sMICA and boosting accumulation of mMICA. Accumulation of mMICA in response to REG was reversed by siRNA against ADAM9. However, the drugs did not inhibit the enzymatic activity of ADAM9 in vitro.
CONCLUSIONS: The clinical superiority of REG over SOR is partially attributable to reduced MICA shedding via transcriptional suppression of ADAM9 and ADAM10.

Ji T, Zhang X, Li W
MicroRNA‑543 inhibits proliferation, invasion and induces apoptosis of glioblastoma cells by directly targeting ADAM9.
Mol Med Rep. 2017; 16(5):6419-6427 [PubMed] Related Publications
Glioma is the most common type of malignant brain tumor in humans and accounts for 81% of all malignant brain tumor cases in adults. The abnormal expression of microRNAs (miRs) has been reported to be important in the formation and progression of various types of human cancer, including glioblastoma (GBM). Therefore, studies into the expression, and roles of microRNAs as diagnostic and prognostic markers, as well as their therapeutic value for patients with GBM are warranted. The expression and roles of miR‑543 have been reported in several types of human cancer. However, the role of miR‑543 in GBM remains unclear. In the current study, the expression pattern of miR‑543 in GBM, the effects of miR‑543 on GBM cells and the underlying molecular mechanism was determined. The results of the present study demonstrated that miR‑543 was significantly downregulated in GBM tissue samples and cell lines. Furthermore, the upregulation of miR‑543 inhibited GBM cell proliferation and invasion, as well as promoted cell apoptosis. In addition, a disintegrin and metalloproteinase 9 (ADAM9) was identified to be a direct target gene of miR‑543. Furthermore, ADAM9 was significantly upregulated in GBM tissue samples and its expression was inversely correlated with miR‑543 expression in GBM tissue, suggesting that miR‑543 downregulation may contribute to ADAM9 upregulation in GBM. Finally, the results of the rescue experiment indicated that ADAM9 overexpression significantly reversed the effects of miR‑543 on the proliferation, invasion and apoptosis of GBM cells, suggesting that miR‑543 serves as a tumor suppressor in GBM through ADAM9 regulation. Overall, these findings indicate that the miR‑543/ADAM9 signaling pathway may provide as a potential therapeutic strategy for GBM.

Yang X, Cui Y, Yang F, et al.
MicroRNA‑302a suppresses cell proliferation, migration and invasion in osteosarcoma by targeting ADAM9.
Mol Med Rep. 2017; 16(3):3565-3572 [PubMed] Related Publications
Osteosarcoma (OS) is the most frequent malignant primary bone tumor arising from primitive bone‑forming mesenchymal cells in children and adolescents. The dysregulation of microRNAs (miRNAs) has been reported in OS, and these aberrantly expressed miRNAs are involved in the initiation and progression of OS. The aim of the present study was to investigate the expression and functions of miRNA‑302a (miR‑302a) in OS and its underlying mechanism. It was found that the expression of miR‑302a was reduced in OS tissues and cell lines. The low expression of miR‑302a was significantly correlated with tumor‑node‑metastasis stage and metastasis. The ectopic overexpression of miR‑302a inhibited the proliferation, migration and invasion of OS cells. Bioinformatics analysis showed that a disintegrin and metalloproteinase 9 (ADAM9) was a potential target gene of miR‑302a. Subsequently, reverse transcription‑quantitative polymerase chain reaction and western blot analyses revealed that miR‑302a regulated the expression of ADAM9 at the post‑transcriptional level in OS cells. In addition, a luciferase reporter assay demonstrated that miR‑302a directly targeted the 3'untranslated region of ADAM9. In clinical OS tissues, the mRNA expression of ADAM9 was upregulated and inversely correlated with the expression of miR‑302a. In addition, the effects of ADAM9 knockdown on cell proliferation, migration and invasion were similar to those induced by the overexpression of miR‑302a in OS cells. These findings suggested that miR‑302a inhibited OS cell growth and metastasis by targeting ADAM9. miR‑302a may serve as a potential therapeutic target for patients with OS.

Kossmann CM, Annereau M, Thomas-Schoemann A, et al.
ADAM9 expression promotes an aggressive lung adenocarcinoma phenotype.
Tumour Biol. 2017; 39(7):1010428317716077 [PubMed] Related Publications
A disintegrin and metalloproteinase 9 (ADAM9) possesses potent metastasis-inducing capacities and is highly expressed in several cancer cells. Previous work has shown that ADAM9 participates in the adhesive-invasive phenotype in lung cancer cells in vitro. In this study, we evaluated whether ADAM9 expression plays a critical role in metastatic processes in vivo and in angiogenesis. We first found that high ADAM9 expression was correlated with poor lung adenocarcinoma patient prognosis on Prognoscan data base. In vivo model based on intravenous injection in nude mice showed that a stable downregulation of ADAM9 in A549 (TrA549 A9-) cells was associated with a lower number of nodules in the lung, suggesting lower potentials for extravasation and metastasis. On a subcutaneous xenograft we showed that TrA549 A9- produced significantly smaller tumours and exhibited fewer neovessels. In addition, in vitro human umbilical vein endothelial cells exposed to supernatant from TrA549 A9- could reduce the formation of more vessel-like structures. To further understand the mechanism, a human antibody array analysis confirmed that five cytokines were downregulated in TrA549 A9- cells. Interleukin 8 was the most significantly downregulated, and its interaction with CXCR2 was implicated in angiogenesis on an in vitro model. These results emphasize the critical influence of ADAM9 on lung cancer progression and aggressiveness. ADAM9 should at least be a marker of cancer aggressiveness and a potential therapeutic target for cancer treatment.

Chang JH, Lai SL, Chen WS, et al.
Quercetin suppresses the metastatic ability of lung cancer through inhibiting Snail-dependent Akt activation and Snail-independent ADAM9 expression pathways.
Biochim Biophys Acta Mol Cell Res. 2017; 1864(10):1746-1758 [PubMed] Related Publications
Metastasis is the major cause of death from lung cancer. Quercetin, a widely distributed bioflavonoid, is well known to induce growth inhibition in a variety of human cancer cells, but how it affects lung cancer cell invasion and metastasis is unclear. Herein, we found that quercetin inhibited the migration/invasion of non-small cell lung cancer (NSCLC) cell lines and bone metastasis in an orthotopic A549 xenograft model by suppressing the Snail-mediated epithelial-to-mesenchymal transition (EMT). Moreover, survival times of animals were also prolonged after quercetin treatment. Mechanistic investigations found that quercetin suppressed Snail-dependent Akt activation by upregulating maspin and Snail-independent a disintegrin and metalloproteinase (ADAM) 9 expression pathways to modulate the invasive ability of NSCLC cells. In clinical samples, we observed that patients with Snail

Xiang LY, Ou HH, Liu XC, et al.
Loss of tumor suppressor miR-126 contributes to the development of hepatitis B virus-related hepatocellular carcinoma metastasis through the upregulation of ADAM9.
Tumour Biol. 2017; 39(6):1010428317709128 [PubMed] Related Publications
Hepatocellular carcinoma is the most common histological type of primary liver cancer, which represents the second leading cause of cancer-related mortality. MiR-126 was reported to be downregulated in hepatocellular carcinoma tissues, compared with its levels in noncancerous tissues. However, baseline miR-126 expression levels in hepatitis B virus-related hepatocellular carcinoma patients who did not undergo pre-operational treatment remains unknown since hepatitis B virus infection and pre-operational transcatheter arterial chemoembolization were shown to upregulate miR-126 expression. Here, we demonstrated that miR-126 is generally downregulated in a homogeneous population of pre-operational treatment-naïve hepatitis B virus-related hepatocellular carcinoma patients (84.0%, 84/100), and its expression is significantly associated with pre-operational alpha-fetoprotein levels ( p < 0.05), microvascular invasion ( p < 0.05), tumor metastasis ( p < 0.05), as well as early recurrence (12 months after surgery; p < 0.01). Furthermore, the results of our study revealed that miR-126 is negatively correlated with ADAM9 expression in hepatitis B virus-related hepatocellular carcinoma patients. Overexpression of miR-126 was shown to attenuate ADAM9 expression in hepatocellular carcinoma cells, which subsequently inhibits cell migration and invasion in vitro. In addition, Cox proportional hazards regression model analysis showed that ADAM9 levels, tumor number, microvascular invasion, and tumor metastasis rate represent independent prognostic factors for shorter recurrence-free survival. In conclusion, we demonstrated that the loss of tumor suppressor miR-126 in hepatitis B virus-related hepatocellular carcinoma cells contributes to the development of metastases through the upregulated expression of its target gene, ADAM9. MiR-126-ADAM9 pathway-based therapeutic targeting may represent a novel approach for the inhibition of hepatitis B virus-related hepatocellular carcinoma metastases.

Chiu KL, Lin YS, Kuo TT, et al.
ADAM9 enhances CDCP1 by inhibiting miR-1 through EGFR signaling activation in lung cancer metastasis.
Oncotarget. 2017; 8(29):47365-47378 [PubMed] Free Access to Full Article Related Publications
MicroRNAs (miRNAs), which are endogenous short noncoding RNAs, can regulate genes involved in important biological and pathological functions. Therefore, dysregulation of miRNAs plays a critical role in cancer progression. However, whether the aberrant expression of miRNAs is regulated by oncogenes remains unclear. We previously demonstrated that a disintegrin and metalloprotease domain 9 (ADAM9) promotes lung metastasis by enhancing the expression of a pro-migratory protein, CUB domain containing protein 1 (CDCP1). In this study, we found that this process occurred via miR-1 down-regulation. miR-1 expression was down-regulated in lung tumors, but increased in ADAM9-knockdown lung cancer cells, and was negatively correlated with CDCP1 expression as well as the migration ability of lung cancer cells. Luciferase-based reporter assays showed that miR-1 directly bound to the 3'-untranslated region of CDCP1 and inhibited its translation. Treatment with a miR-1 inhibitor restored CDCP1 protein levels and enhanced tumor cell mobility. Overexpression of miR-1 decreased tumor metastases and increased the survival rate in mice. ADAM9 knockdown reduced EGFR signaling and increased miR-1 expression. These results revealed that ADAM9 down-regulates miR-1 via activating EGFR signaling pathways, which in turn enhances CDCP1 expression to promote lung cancer progression.

Wang J, Zhou Y, Fei X, et al.
ADAM9 functions as a promoter of gastric cancer growth which is negatively and post-transcriptionally regulated by miR-126.
Oncol Rep. 2017; 37(4):2033-2040 [PubMed] Related Publications
A disintegrin and metalloproteinase domain 9 (ADAM9) is a membrane-anchored protein implicated in cell-cell and cell-matrix interactions, including the process of tumorigenesis. However, the role of ADAM9 in gastric cancer (GC) has not been clearly illustrated. In the present study, we found aberrant overexpression of ADAM9 in both GC tissues and cell lines. The expression of ADAM9 was significantly correlated with patient clinicopathological features including tumor size, local invasion, lymph node metastasis and tumor‑node‑metastasis (TNM) stage. Knockdown of ADAM9 in GC SGC-7901 cells, which presented the highest ADAM9 expression among the cell lines, induced a dramatic suppression of cell proliferation along with the arrest of the cell cycle in the G0/G1 phase. Furthermore, we validated that the 3' untranslated region of ADAM9 mRNA could be bound by miR-126, a suppressor in GC, and overexpression of miR-126 significantly downregulated ADAM9 in the GC cells. In conclusion, ADAM9 functions as a tumor promoter in GC by modulating GC cell proliferation. ADAM9 could possibly be regarded as a biomarker for GC diagnosis and prevention. Moreover, as directly targeted by miR-126 in GC, ADAM9 may be a potential target for GC therapeutic treatment which warrants intensive study.

van Kampen JGM, van Hooij O, Jansen CF, et al.
miRNA-520f Reverses Epithelial-to-Mesenchymal Transition by Targeting
Cancer Res. 2017; 77(8):2008-2017 [PubMed] Related Publications
Reversing epithelial-to-mesenchymal transition (EMT) in cancer cells has been widely considered as an approach to combat cancer progression and therapeutic resistance, but a limited number of broadly comprehensive investigations of miRNAs involved in this process have been conducted. In this study, we screened a library of 1120 miRNA for their ability to transcriptionally activate the E-cadherin gene

Fu Q, Cheng J, Zhang J, et al.
miR-20b reduces 5-FU resistance by suppressing the ADAM9/EGFR signaling pathway in colon cancer.
Oncol Rep. 2017; 37(1):123-130 [PubMed] Related Publications
Chemoresistance is a major obstacle to cancer therapy including that of colon cancer (CC). Although the dysregulation of many miRNAs has been implicated in 5-fluorouracil (5-FU) resistance in CC cells, the specific role of miR-20b in chemoresistance has not been documented. In the present study, we first determined the expression of miR-20b by RT-PCR and the levels of a disintegrin and metalloprotease 9 (ADAM9) and epidermal growth factor receptor (EGFR) by western blotting in CC and adjacent non-cancerous tissues from 5-FU-sensitive or -resistant CC patients. Subsequently, 5-FU-sensitive (HCT116) and -resistant (HCT116-R) cells were obtained, and the levels of miR-20b, ADAM9 and EGFR were detected. Meanwhile, the 5-FU resistance of the cells was examined by assessing cell viability (by MTT assay) and apoptosis (by flow cytometry). After transfection of miR-20b into HCT116-R cells, drug resistance was reexamined. We then confirmed the relationship between miR-20b and ADAM9 by luciferase reporter assay. Finally, 5-FU resistance in HCT116 and HCT116-R cells was compared after transfection with miR-20b. Our results showed that miR-20b was expressed at lower levels in the 5-FU-resistant tissues and cells than in the 5-FU-sensitive tissues and cells. The opposite was the case for expression of ADAM9 and EGFR. In addition, we demonstrated that ADAM9 is a direct target of miR-20b and that miR-20b decreased the 5-FU resistance of HCT116-R cells. Our findings suggest that miR-20b reduces 5-FU resistance to induce apoptosis in vitro by suppressing ADAM9/EGFR in CC cells.

Wang FF, Wang S, Xue WH, Cheng JL
microRNA-590 suppresses the tumorigenesis and invasiveness of non-small cell lung cancer cells by targeting ADAM9.
Mol Cell Biochem. 2016; 423(1-2):29-37 [PubMed] Related Publications
microRNAs (miRNAs), a family of small non-coding RNA molecules, are implicated in cancer growth and progression. In the present study, we examined the expression and biological roles of miR-590 in non-small cell lung cancer (NSCLC). Compared to normal lung tissues, miR-590 expression was downregulated in primary NSCLCs and, to a greater extent, in corresponding brain metastases. NSCLC cell lines with high metastatic potential had significantly (P < 0.05) lower levels of miR-590 than those with low metastatic potential. Re-expression of miR-590 suppressed NSCLC cell proliferation, colony formation, migration, and invasion in vitro and tumorigenesis in vivo. In contrast, inhibition of miR-590 enhanced the migration and invasion of NSCLC cells. Mechanistic studies revealed that a disintegrin and metalloproteinase 9 (ADAM9) was a direct target of miR-590. Delivery of miR-590 mimic was found to decrease endogenous ADAM9 expression in NSCLC cells. Enforced expression of a miRNA-resistant form of ADAM9 significantly restored the aggressive behaviors in miR-590-overexpressing NSCLC cells. Taken together, our data reveal miR-590 as a tumor suppressor in NSCLC, which is at least partially mediated through targeting of ADAM9. Restoration of miR-590 may provide a promising therapeutic strategy for NSCLC.

Yuan P, He XH, Rong YF, et al.
KRAS/NF-κB/YY1/miR-489 Signaling Axis Controls Pancreatic Cancer Metastasis.
Cancer Res. 2017; 77(1):100-111 [PubMed] Related Publications
KRAS activation occurring in more than 90% of pancreatic ductal adenocarcinomas (PDAC) drives progression and metastasis, but the underlying mechanisms involved in these processes are still poorly understood. Here, we show how KRAS acts through inflammatory NF-κB signaling to activate the transcription factor YY1, which represses expression of the tumor suppressor gene miR-489. In PDAC cells, repression of miR-489 by KRAS signaling inhibited migration and metastasis by targeting the extracellular matrix factors ADAM9 and MMP7. miR-489 downregulation elevated levels of ADAM9 and MMP7, thereby enhancing the migration and metastasis of PDAC cells. Together, our results establish a pivotal mechanism of PDAC metastasis and suggest miR-489 as a candidate therapeutic target for their attack. Cancer Res; 77(1); 100-11. ©2016 AACR.

Rooprai HK, Martin AJ, King A, et al.
Comparative gene expression profiling of ADAMs, MMPs, TIMPs, EMMPRIN, EGF-R and VEGFA in low grade meningioma.
Int J Oncol. 2016; 49(6):2309-2318 [PubMed] Related Publications
MMPs (matrix metalloproteinases), ADAMs (a disintegrin and metalloproteinase) and TIMPs (tissue inhibitors of metalloproteinases) are implicated in invasion and angiogenesis: both are tissue remodeling processes involving regulated proteolysis of the extracellular matrix, growth factors and their receptors. The expression of these three groups and their correlations with clinical behaviour has been reported in gliomas but a similar comprehensive study in meningiomas is lacking. In this study, we aimed to evaluate the patterns of expression of 23 MMPs, 4 TIMPs, 8 ADAMs, selective growth factors and their receptors in 17 benign meningiomas using a quantitative real-time polymerase chain reaction (qPCR). Results indicated very high gene expression of 13 proteases, inhibitors and growth factors studied: MMP2 and MMP14, TIMP-1, -2 and -3, ADAM9, 10, 12, 15 and 17, EGF-R, EMMPRIN and VEGF-A, in almost every meningioma. Expression pattern analysis showed several positive correlations between MMPs, ADAMs, TIMPs and growth factors. Furthermore, our findings suggest that expression of MMP14, ADAM9, 10, 12, 15 and 17, TIMP-2, EGF-R and EMMPRIN reflects histological subtype of meningioma such that fibroblastic subtype had the highest mRNA expression, transitional subtype was intermediate and meningothelial type had the lowest expression. In conclusion, this is the first comprehensive study characterizing gene expression of 8 ADAMs in meningiomas. These neoplasms, although by histological definition benign, have invasive potential. Taken together, the selected elevated gene expression pattern may serve to identify targets for therapeutic intervention or indicators of biological progression and recurrence.

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.

Liu X, Wang S, Yuan A, et al.
MicroRNA-140 represses glioma growth and metastasis by directly targeting ADAM9.
Oncol Rep. 2016; 36(4):2329-38 [PubMed] Related Publications
Glioma is the most frequent primary malignant tumor of the human brain. Recently, great progress has been made in the combined therapy of glioma. However, the clinical effects of these treatments and prognosis for patients with glioma remains poor. MicroRNAs (miRNAs) have been demonstrated to play important roles in the initiation and progression of various types of human cancers, also including glioma. The present study investigated the expression patterns of microRNA‑140 (miR-140) in glioma, and the roles of miR-140 in glioma cell proliferation, migration and invasion. The results showed that miR-140 was significantly downreuglated in glioma tissues and cell lines, and low expression levels of miR-140 were correlated with World Health Organization (WHO) grade and Karnofsky performance score (KPS) of glioma patients. Restoration of miR-140 obviously suppressed glioma cell proliferation, migration and invasion. In addition, a disintegrin and metalloproteinase 9 (ADAM9) was identified as a novel direct target gene of miR-140 in glioma. Furthermore, knockdown of ADAM9 simulated the tumor suppressor functions of miR-140, while overexpression of ADAM9 abrogated these suppressive effects induced by miR-140 in glioma cells. In conclusion, the present study demonstrated the expression and clinical roles of miR-140 in glioma and suggested that miR-140 inhibited proliferation, migration and invasion of glioma cells, partially at least via suppressing ADAM9 expression. Therefore, miR-140 may be a novel candidate target for the development of therapeutic strategies for patients with glioma.

Chiu KL, Kuo TT, Kuok QY, et al.
ADAM9 enhances CDCP1 protein expression by suppressing miR-218 for lung tumor metastasis.
Sci Rep. 2015; 5:16426 [PubMed] Free Access to Full Article Related Publications
Metastasis is the leading cause of death in cancer patients due to the difficulty of controlling this complex process. MicroRNAs (miRNA), endogenous noncoding short RNAs with important biological and pathological functions, may play a regulatory role during cancer metastasis, but this role has yet to be fully defined. We previously demonstrated that ADAM9 enhanced the expression of the pro-migratory protein CDCP1 to promote lung metastasis; however, the regulatory process remains unknown. Here we demonstrate that endogenous miR-218, which is abundant in normal lung tissue but suppressed in lung tumors, is regulated during the process of ADAM9-mediated CDCP1 expression. Suppression of miR-218 was associated with high migration ability in lung cancer cells. Direct interaction between miR-218 and the 3'-UTR of CDCP1 mRNAs was detected in luciferase-based transcription reporter assays. CDCP1 protein levels decreased as expression levels of miR-218 increased, and increased in cells treated with miR-218 antagomirs. Induction of miR-218 inhibited tumor cell mobility, anchorage-free survival, and tumor-initiating cell formation in vitro and delayed tumor metastases in mice. Our findings revealed an integrative tumor suppressor function of miR-218 in lung carcinogenesis and metastasis.

Zhang C, Zhang Y, Ding W, et al.
MiR-33a suppresses breast cancer cell proliferation and metastasis by targeting ADAM9 and ROS1.
Protein Cell. 2015; 6(12):881-9 [PubMed] Free Access to Full Article Related Publications
MicroRNAs (miRNAs) are small noncoding RNAs that have a pivotal role in the post-transcriptional regulation of gene expression by sequence-specifically targeting multiple mRNAs. Although miR-33a was recently reported to play an important role in lipid homeostasis, atherosclerosis, and hepatic fibrosis, the functions of miR-33a in tumor progression and metastasis are largely unknown. Here, we found that downregulated miR-33a in breast cancer tissues correlates with lymph node metastasis. MiR-33a expression is significantly lower in the highly metastatic breast cancer cell lines than the noncancerous breast epithelial cells and non-metastatic breast cancer cells. Moreover, the overexpression of miR-33a in metastatic breast cancer cells remarkably decreases cell proliferation and invasion in vitro and significantly inhibits tumor growth and lung metastasis in vivo, whereas its knockdown in non-metastatic breast cancer cells significantly enhances cell proliferation and invasion in vitro and promotes tumor growth and lung metastasis in vivo. Combining bioinformatics prediction and biochemical analyses, we showed that ADAM9 and ROS1 are direct downstream targets of miR-33a. These findings identified miR-33a as a negative regulator of breast cancer cell proliferation and metastasis.

Wang S, Wang X, Guo Q, et al.
MicroRNA-126 Overexpression Inhibits Proliferation and Invasion in Osteosarcoma Cells.
Technol Cancer Res Treat. 2016; 15(5):NP49-59 [PubMed] Related Publications
This study investigated the biological effects of microRNA-126 overexpression in human MG63 osteosarcoma cells. A recombinant plasmid expressing microRNA-126, pcDNA6.2-microRNA-126, was constructed and transfected into MG63 cells. Using real-time fluorogenic quantitative polymerase chain reaction, the microRNA-126 expression was measured in microRNA-126-MG63 group, Ctrl-MG63 group, and blank group. Cell proliferation, cell cycle distribution, cell migration, and invasion were analyzed using methyl thiazolyl tetrazolium assay, flow cytometer, wound-healing assay, and transwell assay, respectively. As expected, microRNA-126 expression was higher in microRNA-126-MG63 group than in Ctrl-MG63 group and blank group (both P < .05). After 48/72 hours of transfection, cell proliferation in microRNA-126-MG63 group was significantly reduced compared to blank group (both P < .05). Compared to blank group, cell population in G0/G1 stage was significantly higher in microRNA-126-MG63 group, accompanied by lower cell numbers in the S and G2/M phases and decreased proliferation index (all P < .05). Wound-healing assay showed a wider scratch width in microRNA-126-MG63 group and reduced cell migration than blank group (both P < .05). Cells overexpressing microRNA-126 exhibited reduced ADAM9 expression levels compared to other 2 groups (all P < .05), suggesting ADAM9 is a target of microRNA-126. Cell proliferation, migration, and invasion rates were reduced in microRNA-126 group after 48/72 hours of transfection, compared with blank group (all P < .05). Cotransfection of pcDNA6.2-microRNA-126 and pMIR-ADAM9 into MG63 cells led to higher cell proliferation, invasion, and migration rates, compared with transfection of pcDNA6.2-microRNA-126 alone (all P < .05). In summary, our data show that microRNA-126 inhibits cell proliferation, migration, and invasion in human osteosarcoma cells by targeting ADAM9.

Wang CZ, Yuan P, Li Y
MiR-126 regulated breast cancer cell invasion by targeting ADAM9.
Int J Clin Exp Pathol. 2015; 8(6):6547-53 [PubMed] Free Access to Full Article Related Publications
Accumulating evidence has shown that microRNAs (miRNAs) deregulation is commonly observed in human malignancies and crucial to cancer metastasis. Herein, we demonstrated that miR-126 play a suppressor role in human breast cancer cells invasion through the direct repression of a disintegrin and metalloprotease 9 (ADAM9). MiR-126 expression was investigated in forty cases of breast cancer specimens by real-time PCR. Transwell assay was conducted to explore the effects of miR-126 on the invasion of human breast cancer cell lines. The impact of miR-126 overexpression on putative target ADAM9 was subsequently confirmed by Western blot analysis. Our results indicated that miR-126 expression was frequently down-regulated in breast cancer specimens compared with adjacent normal tissues (P<0.05). Overexpression of miR-126 significantly reduced (P<0.05) the protein levels of ADAM9, further suppressed (P<0.05) breast cancer cell invasion in vitro. Meanwhile, knockdown of ADAM9 by small interfering RNA (siRNA) also inhibited (P<0.05) breast cancer cell invasion. Thus, our study revealed that miR-126 may act as a tumor suppressor via inhibition of cell invasion by downregulating ADAM9 in breast cancer development.

Xiong Y, Kotian S, Zeiger MA, et al.
miR-126-3p Inhibits Thyroid Cancer Cell Growth and Metastasis, and Is Associated with Aggressive Thyroid Cancer.
PLoS One. 2015; 10(8):e0130496 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Previous studies have shown that microRNAs are dysregulated in thyroid cancer and play important roles in the post-transcriptional regulation of target oncogenes and/or tumor suppressor genes.
METHODOLOGY/PRINCIPAL FINDINGS: We studied the function of miR-126-3p in thyroid cancer cells, and as a marker of disease aggressiveness. We found that miR-126-3p expression was significantly lower in larger tumors, in tumor samples with extrathyroidal invasion, and in higher risk group thyroid cancer in 496 papillary thyroid cancer samples from The Cancer Genome Atlas study cohort. In an independent sample set, lower miR-126-3p expression was observed in follicular thyroid cancers (which have capsular and angioinvasion) as compared to follicular adenomas. Mechanistically, ectopic overexpression of miR-126-3p significantly inhibited thyroid cancer cell proliferation, in vitro (p<0.01) and in vivo (p<0.01), colony formation (p<0.01), tumor spheroid formation (p<0.05), cellular migration (p<0.05), VEGF secretion and endothelial tube formation, and lung metastasis in vivo. We found 14 predicted target genes, which were significantly altered upon miR-126-3p transfection in thyroid cancer cells, and which are involved in cancer biology. Of these 14 genes, SLC7A5 and ADAM9 were confirmed to be inhibited by miR-126-3p overexpression and to be direct targets of miR-136-3p.
CONCLUSIONS/SIGNIFICANCE: To our knowledge, this is the first study to demonstrate that miR-126-3p has a tumor-suppressive function in thyroid cancer cells, and is associated with aggressive disease phenotype.

Martin AC, Cardoso AC, Selistre-de-Araujo HS, Cominetti MR
Recombinant disintegrin domain of human ADAM9 inhibits migration and invasion of DU145 prostate tumor cells.
Cell Adh Migr. 2015; 9(4):293-9 [PubMed] Free Access to Full Article Related Publications
One of the most important features of malignant cells is their capacity to invade adjacent tissues and metastasize to distant organs. This process involves the creation, by tumor and stroma cells, of a specific microenvironment, suitable for proliferation, migration and invasion of tumor cells. The ADAM family of proteins has been involved in these processes. This work aimed to investigate the role of the recombinant disintegrin domain of the human ADAM9 (rADAM9D) on the adhesive and mobility properties of DU145 prostate tumor cells. rADAM9D was able to support DU145 cell adhesion, inhibit the migration of DU145 cells, as well as the invasion of this cell line through matrigel in vitro. Overall this work demonstrates that rADAM9D induces specific cellular migratory properties when compared with different constructs having additional domains, specially those of metalloproteinase and cysteine-rich domains. Furthermore, we showed that rADAM9D was able to inhibit cell adhesion, migration and invasion mainly through interacting with α6β1 in DU145 tumor cell line. These results may contribute to the development of new therapeutic strategies for prostate cancer.

Vranic S, Marchiò C, Castellano I, et al.
Immunohistochemical and molecular profiling of histologically defined apocrine carcinomas of the breast.
Hum Pathol. 2015; 46(9):1350-9 [PubMed] Related Publications
Despite the marked improvement in the understanding of molecular mechanisms and classification of apocrine carcinoma, little is known about its specific molecular genetic alterations and potentially targetable biomarkers. In this study, we explored immunohistochemical and molecular genetic characteristics of 37 invasive apocrine carcinomas using immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), and next-generation sequencing (NGS) assays. IHC revealed frequent E-cadherin expression (89%), moderate (16%) proliferation activity [Ki-67, phosphohistone H3], infrequent (~10%) expression of basal cell markers [CK5/6, CK14, p63, caveolin-1], loss of PTEN (83%), and overexpression of HER2 (32%), EGFR (41%), cyclin D1 (50%), and MUC-1 (88%). MLPA assay revealed gene copy gains of MYC, CCND1, ZNF703, CDH1, and TRAF4 in 50% or greater of the apocrine carcinomas, whereas gene copy losses frequently affected BRCA2 (75%), ADAM9 (54%), and BRCA1 (46%). HER2 gain, detected by MLPA in 38% of the cases, was in excellent concordance with HER2 results obtained by IHC/FISH (κ = 0.915, P < .001). TOP2A gain was observed in one case, while five cases (21%) exhibited TOP2A loss. Unsupervised hierarchical cluster analysis revealed two distinct clusters: HER2-positive and HER2-negative (P = .03 and .04, respectively). NGS assay revealed mutations of the TP53 (2 of 7, 29%), BRAF/KRAS (2 of 7, 29%), and PI3KCA/PTEN genes (7 of 7, 100%). We conclude that morphologically defined apocrine carcinomas exhibit complex molecular genetic alterations that are consistent with the "luminal-complex" phenotype. Some of the identified molecular targets are promising biomarkers; however, functional studies are needed to prove these observations.

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