ADAM9 in Cancers: History
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Subjects: Biochemistry & Molecular Biology
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Yuh-Pyng Sher

ADAM9 plays an important role in tumor biology. It is overexpressed in several cancer types and is correlated with tumor aggressiveness and poor prognosis. Through either proteolytic or non-proteolytic pathways, ADAM9 promotes tumor progression, therapeutic resistance, and metastasis of cancers. Therefore, comprehensively understanding the mechanism of ADAM9 is crucial for the development of therapeutic anti-cancer strategies.

  • ADAM9
  • cancer
  • metastasis

1. Introduction

The “a disintegrin and metalloproteases” (ADAMs) family, a subset of the zinc protease superfamily, consists of transmembrane proteins with a multidomain extracellular region, a single transmembrane sequence, and a relatively short cytoplasmic domain [1][2]. So far, around 40 family members have been identified in the mammalian genome, and among them, 22 are expressed in humans [3]. Extracellular regions of ADAMs contain several distinct domains: A prodomain followed by metalloproteinase, disintegrin, and cysteine-rich domains [4]. A majority of ADAMs—all except ADAM10 and ADAM17—also have an epidermal growth factor (EGF)-like domain, whose function is yet to be clarified [2][5][6]. ADAM proteins have been reported in numerous biological functions involving development, fertility, ectodomain shedding, cell adhesion, cell–cell interaction, vascular endothelial cell function, inflammation, immunity, signaling transduction, neurodegenerative disease, and cancer biology [1][7][8][9]. Therefore, ADAMs have important roles in diverse physiological contexts.

ADAM9 (also known as metalloprotease/disintegrin/cysteine-rich protein 9 (MDC9) or meltrin-γ), one of the ADAM proteins, was first identified in 1996 in breast carcinoma [10]. It is widely expressed in human tissues, and shows an abundant increase in pathological conditions [11]. ADAM9 expression is detected in multiple cell types, including monocytes [12], macrophages [13], neutrophils [14], keratinocytes [15], and fibroblasts [16]; and in multiple tissues, including lung [17], colon [18], kidney [19], vascular smooth muscle [20][21], nervous system [1][22], reproductive system [23], and secretary organs [24]. This indicates that ADAM9 is involved in a multitude of biological functions as well as pathophysiological conditions, such as inflammation and tumorigenesis [25][26].

In inflammation, ADAM9 contributes to monocyte fusion, mediating the conversion of monocytes-macrophages to multinucleated giant cells (MGCs) as a response to foreign bodies or bacteria; the resulting granulomatous lesions help to isolate the pathogens and also enhance phagocytotic activity [12]. ADAM9 also stimulates the inflammatory process through polymorphonuclear leukocytes, macrophages, and epithelial cells in some inflammatory diseases, such as acute lung injury or chronic obstructive pulmonary disease (COPD) [11][13][14][27]. ADAM9 is also expressed in the epidermis, where it delays wound healing by increasing collagen XVII shedding and matrix metalloproteinase-9 (MMP-9) secretion to decrease keratinocyte migration [28]. ADAM9 promotes neuropilin-1 proteolysis in the angiogenic signaling pathway of vascular endothelial cells [29]. ADAM9 has been demonstrated to be involved in neurodegenerative disease by regulating the cleavage of amyloid precursor protein (APP), which might be relevant in Alzheimer’s disease [4][30][31]. ADAM9 was also shown to be involved in myogenesis and formation of myotubes, which might contribute to the endocardial cushion during embryonic development [32]. Recently, ADAM9 was reported to shed the interleukin-11 receptor, which is involved in inflammatory conditions, bone homeostasis, hematopoiesis, and fertility [33]. Altogether, ADAM9 is expressed broadly in human tissues, and participates in the development, inflammatory processes, and degenerative diseases.

Despite its wide distribution in mammalian tissue and its regulatory function in development, the Adam9−/− mouse model showed no apparent morphological changes or histopathological defects during development and adult life [34]. Therefore, the effects of ADAM9 deficiency might be compensated by other ADAM family members, but no further investigation to address the potential ADAM family members [21]. However, subsequent animal studies demonstrated that the deletion in the ADAM9 induced photoreceptor degeneration of both retinal rods and cones, resulting in visual acuity impairment in young canine models. Malformation of retinal pigment epithelium, disrupted contact with photoreceptor outer segments, and abnormal gaps between retinal layers were demonstrated, leading to the degeneration of the retina [35][36]. These mice showed less ocular neovascularization than wild-type mice during the pathological neovascularization, which was not associated with developmental retinal angiogenesis. Furthermore, ADAM9 null mutations were shown to cause retinal degeneration in human patients, leading to cone–rod dystrophy (CRD) [36]. In the opposite direction, overexpression of ADAM9 enhances angiogenesis by increasing the shedding of several angiogenesis-related endothelial membrane proteins including Tie-2, vascular endothelial growth factor receptor-2, VE-cadherin, ephrin type B receptor 4 (EphB4), CD40, and vascular cell adhesion molecule 1 (VCAM-1) [37].

2. Role of ADAM9 in Cancers

ADAM9 participates in the regulation of various tumor processes. In addition to metastasis, ADAM9 also plays an important role in tumor proliferation, angiogenesis, and even immune evasion (Table 1).

Table 1. Studies of ADAM9 in various cancers.

Type

Role of ADAM9 in Cancer

Reference

Lung Cancer

Clinical

Significance

Overexpressed in cancer

[25][26][38][39]

Negative correlation with OS

[25][38][39][40][41][42]

Mechanism

ADAM9-tPA-CDCP1-Metastasis

[25]

ADAM9-ANGPT2-Metastasis

[26]

ADAM9-IL8/VEGFA-Angiogenesis

[26][40]

Prostate Cancer

Clinical Relevance

Overexpressed in cancer

[43][44]

Negative correlation with RFS

[43]

Mechanism

Naa10p-ADAM9-Tumorigenesis/Metastasis

[45]

ADAM9-Integrin Degradation

[46]

Liver Cancer

Clinical Relevance

Negative correlation with immunotherapy response

[47][48]

Mechanism

ADAM9-MICA cleavage-immune evasion

[48]

IL-6-ADAM9-JNK-Metastasis

[49]

Breast Cancer

Clinical Relevance

Overexpressed in cancer

[50]

Positive correlation with progression

[51]

Mechanism

NSD2-ADAM9-Tumorigenesis

[52]

Pancreatic Cancer

Clinical Relevance

Overexpressed in cancer

[24][53]

Positive correlation with progression

[54]

Negative correlation with OS

[24][53]

Mechanism

KRAS-ADAM9-Tumorigenesis

[55]

ADAM9-MEK-ERK-Tumorigenesis

[24]

Circ-ADAM9-ERK-Tumorigenesis

[56]

Brain Cancer

Clinical Relevance

Overexpressed in cancer

[57][58]

Negative correlation with OS/PFS

[57][58]

Mechanism

TNC-ADAM9-Metastasis

[58]

OS, overall survival; PFS, progression-free survival; RFS, relapse-free survival.

2.1. Lung Cancer

In lung cancer, the dysregulation of ADAM9 was documented long ago. Various studies demonstrate that ADAM9 is a major player in lung cancer progression and metastasis [25][26]. Studies show the overexpression of ADAM9 shortens overall survival, and the same pattern was found in various cohorts by different groups [38][39][40]. By immunohistochemical staining, high protein expression of ADAM9 was found to be correlated with a poor 5-year survival rate in an Asian cohort (10/17, 59%) [25], and in resected stage I lung cancer (29/63, 46%) [41][42].

Metastasis is the leading cause of lung cancer-related death, and nearly 50% of late-stage patients with lung cancer exhibit brain metastasis. ADAM9 has been reported as a major player in several steps of this process [59]. Shintani et al. first described that overexpression of ADAM9 promotes the adhesion of tumor cells to vascular endothelial cells, which suggests the importance of ADAM9 during metastasis. In addition, ADAM9 enhances cell migration and anoikis resistance to promote metastasis by a novel mechanism. Silencing ADAM9 down-regulates the RNA expression of CUB domain-containing protein 1 (CDCP1) and tissue-type plasminogen activator (tPA) but up-regulates the expression of plasminogen activator inhibitor-1 (PAI-1) [25]. Moreover, ADAM9 enhances the activity of tPA to cleave CDCP1, resulting in CDCP1 activation that promotes metastatic processes of cell migration and anoikis resistance. Thus, ADAM9 promotes the CDCP1 activation for lung cancer metastases to the brain through a tPA-based pathway.

This ADAM9-CDCP1 axis to lung cancer metastasis is also validated in several other reports as well [60][61]. The ADAM9-CDCP1 axis was confirmed to be necessary for lung cancer cell migration and survival in vitro and in vivo; and moreover, the authors demonstrated that ADAM9 decreases the expression of miR-1 and miR-218, which target the 3′-UTR of CDCP1 to suppress its expression. Thus, ADAM9 promotes the elevated protein levels of CDCP1. To achieve brain metastasis, the disruption of the blood–brain barrier is necessary for tumor cell entry. ADAM9 also participates in this process by up-regulating angiopoietins 2 and tPA. Silencing ADAM9 enhances the membrane expression of VE-cadherin, which is responsible for maintaining the restrictive barrier between endothelial cells and reduces the cell permeability of endothelial cells in vitro [26]. These findings illustrate the multiple roles of ADAM9 in lung cancer metastasis.

The essential role of angiogenesis in tumor progression is well-defined in numerous cancer types, including lung cancer, and chemical stimulation performed by various angiogenic proteins is crucial and necessary. Meanwhile, the conditioned medium from ADAM9-silenced cells suppresses tube formation of human umbilical vein endothelial cells; moreover, silencing ADAM9 inhibits angiogenesis in vivo. By angiogenesis antibody array and further ELISA, a previous study identified that ADAM9 mediates the expression of angiogenesis factor, interleukin 8 (IL-8). And IL-8 is known to bind and then activate its high-affinity receptor, C-X-C Motif Chemokine Receptor 2 (CXCR-2). Moreover, the neutralizing antibody of CXCR-2 reverses the ADAM9-mediated HUVAC tube formation. These evidences suggest a possible mechanism of ADAM9-mediated angiogenesis through the IL-8-CXCR2 axis [40]. In another study, vascular endothelial growth factor, a well-known angiogenic protein, was down-regulated in the ADAM9-silenced cell-conditioned medium [26]. Taken together, these results suggest that ADAM9 participates in tumor angiogenesis by increasing the activity of various angiogenic proteins in lung cancer.

Micro-RNAs (miRNAs), such as miR-425, miR-488 and miR-590, have been reported as regulators of ADAM9 in lung cancer. Via prediction tools and luciferase reporter assay, the 3′-UTR of ADAM9 is identified as the target sites of 3 micro-RNAs to down-regulate ADAM9 mRNA expression [38][62][63].

2.2. Prostate Cancer

Fritzsche et al., demonstrated that both mRNA and protein overexpression of ADAM9 is correlated with poor relapse-free survival of prostate cancer [43]. By immunohistochemistry, more than 60% of recurrent prostate tumors have elevated protein expression of ADAM9 [44].

The progression and growth of prostate cancer is dependent on androgens; thus, androgen deprivation by castration or target therapy has become the predominant therapies for advanced prostate cancer. However, tumors treated in this way develop into a more aggressive and castration-resistant type, called androgen-independent prostate cancer (AIPC). Lin et al., uncovered the mechanism of maintaining ADAM9 protein stability in AIPC. N-α-Acetyltransferase 10 protein (Naa10p) has been identified as an oncoprotein in prostate cancer [45]. Silencing Naa10p down-regulates the protein expression of ADAM9 to suppress tumor growth and metastasis in vitro and in vivo. Silencing Naa10p also accelerates ADAM9 protein degradation, and the direct interaction between Naa10p and ADAM9 has been confirmed by co-immunoprecipitation. Taken together, the protein stability of ADAM9 is highly maintained by Naa10p to drive AIPC tumor outgrowth and metastasis. And this Naa10p-mediated stabilization of ADAM9 maybe exist in other cancer types to drive tumorigenesis as well.

ADAM9 regulates prostate cancer progression and outcome in other ways as well. Silencing ADAM9 impairs the endocytosis of integrin β1 to increases its expression on cell membrane to enhance the integrin-mediated cell adhesion and suppress cell migration in vitro. Notably, metalloproteinase inhibitors (Batimastat or GM6001) cannot reverse the integrin β1 expression or integrin-mediated migration effects, which suggests the proteolytic activity of ADAM9 is dispensable for this mechanism. In contrast, the direct interaction between ADAM9 and integrin β1 has been confirmed by co-immunoprecipitation, and both proteins co-localize on early endosomes in vitro. These findings suggest ADAM9 mediates integrin β1 stability in a non-catalytic manner [46].

MiRNAs also play a role in regulating ADAM9 in prostate cancer, especially miR-126. Hua et al. identified the binding site and the effect of miR-126 on reducing ADAM9 expression via luciferase reporter assay. And silencing ADAM9 by miRNA has similar inhibitory effects on cell proliferation, migration, and invasion in vitro as did miR-126 overexpression [47].

2.3. Liver Cancer

Several pieces of evidence suggest the overexpression of ADAM9 contributes to poor patient outcomes and lower response to immune checkpoint blockade therapy [47]. Kohga et al. identified MHC Class I polypeptide-related sequence A (MICA), which is a ligand on cancer cells to elicit attack by natural killer cells, as a novel target of ADAM9. Membrane-bound MICA (mMICA) can be cleaved by ADAM9 to release soluble MICA (sMICA) by ADAM9 as an immunological decoy to suppress immune surveillance. The knockdown of ADAM9 up-regulates the expression of mMICA on the cell membrane and down-regulates sMICA in culture supernatant in vitro [48].

Metastasis is also an urgent issue in liver cancer therapy. IL-6 is a major mediator of invasion and metastasis in liver cancer [81,96]. Dong et al. have demonstrated that IL-6 enhances ADAM9 expression through activating the JNK pathway in vitro. Silencing ADAM9 not only reduces the primary tumor size but also suppresses the metastasis rate to lung; in contrast, overexpressing ADAM9 accelerates primary tumor growth and promotes the metastasis to the lung [49].

Numerous studies identify the negative regulation of ADAM9 by miRNAs in liver cancer. MiR-126 [64]. miR-203 [65], and miR-488 [66], target the 3’-UTR of ADAM9 and down-regulate ADAM9 to suppress cell migration and invasion in vitro.

2.4. Breast Cancer

In breast cancer, the expression of ADAM9 is up-regulated compared to normal tissue [50]. ADAM9 also contributes to disease progression by promoting tumor extravasation and migration ability [51]. An upstream role of ADAM9 in the trans-endothelial migration pathway was suggested by Micocci et al. Knockdown of ADAM9 down-regulates the mRNA expression of ADAM15 and MMP2 but not ADAM10, ADAM17, or MMP9 in vitro [67].

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer. In some subtypes of TNBC, methylation deregulation causes the overexpression of EGFR to enhance cell proliferation and survival. ADAM9 shares EGFR’s methyltransferase, according to chromatin precipitation assays, and nuclear receptor-binding SET domain protein 2, a member of the histone methyltransferase family, up-regulates the expression of both ADAM9 and EGFR and promotes TNBC cell resistance to EGFR inhibitors [52].

Several miRNA expression profiles and target sites on ADAM9 have been studied in breast cancer, including miR-126 [68][69], miR-154 [70], and miR-33a [71]. The binding sites of these miRNAs are located on 3′-UTR of ADAM9, and lower expression of these miRNAs results in the overexpression of ADAM9 and promotes cancer cell migration and invasion in vitro.

2.5. Pancreatic Cancer

In recent years, several studies have suggested that elevated mRNA expression of ADAM9 shortens the overall survival of pancreatic cancer patients [53], a finding that was confirmed by immunohistochemistry [24]. Increased ADAM9 expression also correlates with higher tumor grade and progression [54].

KRAS signaling is necessary to maintain tumorigenesis in pancreatic cancer. Yuan et al. discovered that dysregulated KRAS signaling enhanced the expression of ADAM9 via NF-kB cascade [55]. Notably, the knockdown of ADAM9 suppresses the downstream pathway of KRAS and MEK-ERK signaling as well [24]. Taken together, a feedback loop between ADAM9 and KRAS is implied.

Circular RNA, a type of single-stranded RNA produced by non-canonical linear splicing, called back-splicing, takes on a covalently closed-form in the cytoplasm and regulates biological function by acting as a micro-RNA or protein inhibitor [72]. Studies have demonstrated that circular ADAM9 (circ-ADAM9) is up-regulated in pancreatic cancer cells and is correlated with poor prognosis. Circ-ADAM9 absorbs and inhibits miR-127, which is a tumor suppressor. Overexpressing circ-ADAM9 increases ERK signaling to promote cell proliferation and migration in vitro, and silencing circ-ADAM9 delays pancreatic tumor growth in vivo [56].

ADAM9 is also regulated by various miRNAs in pancreatic cancer. MiR-489 [55], miR-126 [73][74], and miR-502f [53] target the 3′-UTR of ADAM9 and down-regulate ADAM9 directly to suppress cell migration and invasion in vitro.

2.6. Glioma

Glioma causes nearly 8% of all cancer-related deaths every year, and glioblastoma (GBM) is an advanced and aggressive glioma that has only a 10% 5-year survival rate. Based on the RNA-seq data from 303 glioma patients, the elevated mRNA expression of ADAM9 is correlated with poor progression-free survival and overall survival [57]. In addition, both mRNA and protein expression of ADAM9 are up-regulated in GBM patients and correlated with short overall survival in different cohorts as well [58].

Tumor invasion highly depends on the interaction between the ECM and tumor cells for most cancer types. Tenascin-C (TNC), a major component of the ECM, activates the JNK pathway to promote tumor invasion in GBM. One study demonstrated that both mRNA and protein expression of ADAM9 are up-regulated in TNC-treated GBM cells [58]. Moreover, treatment with JNK inhibitor (SP600125) inhibited TNC-induced ADAM9 expression, and silencing ADAM9 in TNC-treated GBM cells suppressed cell migration and invasion.

ADAM9 regulation by miRNAs is also well-studied in glioma. MiR-543 [75] and miR-140 [76] are two down-regulated miRNAs in GBM tumor tissue. Similar to other miRNAs in various tumor types, the binding sites are located in the 3′-UTR of ADAM9. Overexpression of ADAM9 reverses the inhibitory effects of miR-543 and miR-140 on cell proliferation, migration, and invasion of GBM cells in vitro.

This entry is adapted from the peer-reviewed paper 10.3390/ijms21207790

References

  1. Hsia, H.E.; Tüshaus, J.; Brummer, T.; Zheng, Y.; Scilabra, S.D.; Lichtenthaler, S.F. Functions of ‘A disintegrin and metalloproteases (ADAMs)’ in the mammalian nervous system. Mol. Life Sci. 2019, 76, 3055–3081, doi:10.1007/s00018-019-03173-7.
  2. Seals, D.F.; Courtneidge, S.A. The ADAMs family of metalloproteases: Multidomain proteins with multiple functions. Genes Dev. 2003, 17, 7–30, doi:10.1101/gad.1039703.
  3. Weber, S.; Saftig, P. Ectodomain shedding and ADAMs in development. Development 2012, 139, 3693–3709, doi:10.1242/dev.076398.
  4. Giebeler, N.; Zigrino, P. A Disintegrin and Metalloprotease (ADAM): Historical Overview of Their Functions. Toxins 2016, 8, 122, doi:10.3390/toxins8040122.
  5. Janes, P.W.; Saha, N.; Barton, W.A.; Kolev, M.V.; Wimmer-Kleikamp, S.H.; Nievergall, E.; Blobel, C.P.; Himanen, J.P.; Lackmann, M.; Nikolov, D.B. Adam meets Eph: An ADAM substrate recognition module acts as a molecular switch for ephrin cleavage in trans. Cell 2005, 123, 291–304, doi:10.1016/j.cell.2005.08.014.
  6. Matthews, A.L.; Noy, P.J.; Reyat, J.S.; Tomlinson, M.G. Regulation of A disintegrin and metalloproteinase (ADAM) family sheddases ADAM10 and ADAM17: The emerging role of tetraspanins and rhomboids. Platelets 2017, 28, 333–341, doi:10.1080/09537104.2016.1184751.
  7. Edwards, D.R.; Handsley, M.M.; Pennington, C.J. The ADAM metalloproteinases. Asp. Med. 2008, 29, 258–289, doi:10.1016/j.mam.2008.08.001.
  8. Lambrecht, B.N.; Vanderkerken, M.; Hammad, H. The emerging role of ADAM metalloproteinases in immunity. Rev. Immunol. 2018, 18, 745–758, doi:10.1038/s41577-018-0068-5.
  9. English, W.R.; Siviter, R.J.; Hansen, M.; Murphy, G. ADAM9 is present at endothelial cell-cell junctions and regulates monocyte-endothelial transmigration. Biophys. Res. Commun. 2017, 493, 1057–1062, doi:10.1016/j.bbrc.2017.09.089.
  10. Weskamp, G.; Krätzschmar, J.; Reid, M.S.; Blobel, C.P. MDC9, a widely expressed cellular disintegrin containing cytoplasmic SH3 ligand domains. Cell Biol. 1996, 132, 717–726, doi:10.1083/jcb.132.4.717.
  11. Rinchai, D.; Kewcharoenwong, C.; Kessler, B.; Lertmemongkolchai, G.; Chaussabel, D. Increased abundance of ADAM9 transcripts in the blood is associated with tissue damage. F1000Res 2015, 4, 89, doi:10.12688/f1000research.6241.2.
  12. Namba, K.; Nishio, M.; Mori, K.; Miyamoto, N.; Tsurudome, M.; Ito, M.; Kawano, M.; Uchida, A.; Ito, Y. Involvement of ADAM9 in multinucleated giant cell formation of blood monocytes. Immunol. 2001, 213, 104–113, doi:10.1006/cimm.2001.1873.
  13. Wang, X.; Polverino, F.; Rojas-Quintero, J.; Zhang, D.; Sánchez, J.; Yambayev, I.; Lindqvist, E.; Virtala, R.; Djukanovic, R.; Davies, D.E.; et al. A Disintegrin and A Metalloproteinase-9 (ADAM9): A Novel Proteinase Culprit with Multifarious Contributions to COPD. J. Respir. Crit. Care Med. 2018, 198, 1500–1518, doi:10.1164/rccm.201711-2300OC.
  14. Roychaudhuri, R.; Hergrueter, A.H.; Polverino, F.; Laucho-Contreras, M.E.; Gupta, K.; Borregaard, N.; Owen, C.A. ADAM9 is a novel product of polymorphonuclear neutrophils: Regulation of expression and contributions to extracellular matrix protein degradation during acute lung injury. Immunol. 2014, 193, 2469–2482, doi:10.4049/jimmunol.1303370.
  15. Zigrino, P.; Steiger, J.; Fox, J.W.; Löffek, S.; Schild, A.; Nischt, R.; Mauch, C. Role of ADAM-9 disintegrin-cysteine-rich domains in human keratinocyte migration. Biol. Chem. 2007, 282, 30785–30793, doi:10.1074/jbc.M701658200.
  16. Abety, A.N.; Fox, J.W.; Schönefuß, A.; Zamek, J.; Landsberg, J.; Krieg, T.; Blobel, C.; Mauch, C.; Zigrino, P. Stromal fibroblast-specific expression of ADAM-9 modulates proliferation and apoptosis in melanoma cells in vitro and in vivo. Investig. Dermatol. 2012, 132, 2451–2458, doi:10.1038/jid.2012.153.
  17. Dreymueller, D.; Uhlig, S.; Ludwig, A. ADAM-family metalloproteinases in lung inflammation: Potential therapeutic targets. J. Physiol. Lung Cell. Mol. Physiol. 2015, 308, L325–L343, doi:10.1152/ajplung.00294.2014.
  18. Fu, Q.; Cheng, J.; Zhang, J.; Zhang, Y.; Chen, X.; Luo, S.; Xie, J. miR-20b reduces 5-FU resistance by suppressing the ADAM9/EGFR signaling pathway in colon cancer. Rep. 2017, 37, 123–130, doi:10.3892/or.2016.5259.
  19. Mahimkar, R.M.; Visaya, O.; Pollock, A.S.; Lovett, D.H. The disintegrin domain of ADAM9: A ligand for multiple beta1 renal integrins. J. 2005, 385, 461–468, doi:10.1042/bj20041133.
  20. Shen, G.; Sun, Q.; Yao, Y.; Li, S.; Liu, G.; Yuan, C.; Li, H.; Xu, Y.; Wang, H. Role of ADAM9 and miR-126 in the development of abdominal aortic aneurysm. Atherosclerosis 2020, 297, 47–54, doi:10.1016/j.atherosclerosis.2020.01.014.
  21. Zhang, P.; Shen, M.; Fernandez-Patron, C.; Kassiri, Z. ADAMs family and relatives in cardiovascular physiology and pathology. Mol. Cell. Cardiol. 2016, 93, 186–199, doi:10.1016/j.yjmcc.2015.10.031.
  22. Fadl, N.N.; Ahmed, H.H.; Booles, H.F.; Sayed, A.H. Serrapeptase and nattokinase intervention for relieving Alzheimer's disease pathophysiology in rat model. Exp. Toxicol. 2013, 32, 721–735, doi:10.1177/0960327112467040.
  23. Cho, C. Testicular and epididymal ADAMs: Expression and function during fertilization. Rev. Urol. 2012, 9, 550–560, doi:10.1038/nrurol.2012.167.
  24. Grützmann, R.; Lüttges, J.; Sipos, B.; Ammerpohl, O.; Dobrowolski, F.; Alldinger, I.; Kersting, S.; Ockert, D.; Koch, R.; Kalthoff, H.; et al. ADAM9 expression in pancreatic cancer is associated with tumour type and is a prognostic factor in ductal adenocarcinoma. J. Cancer 2004, 90, 1053–1058, doi:10.1038/sj.bjc.6601645.
  25. Lin, C.Y.; Chen, H.J.; Huang, C.C.; Lai, L.C.; Lu, T.P.; Tseng, G.C.; Kuo, T.T.; Kuok, Q.Y.; Hsu, J.L.; Sung, S.Y.; et al. ADAM9 promotes lung cancer metastases to brain by a plasminogen activator-based pathway. Cancer Res. 2014, 74, 5229–5243, doi:10.1158/0008-5472.Can-13-2995.
  26. Lin, C.Y.; Cho, C.F.; Bai, S.T.; Liu, J.P.; Kuo, T.T.; Wang, L.J.; Lin, Y.S.; Lin, C.C.; Lai, L.C.; Lu, T.P.; et al. ADAM9 promotes lung cancer progression through vascular remodeling by VEGFA, ANGPT2, and PLAT. Rep. 2017, 7, 15108, doi:10.1038/s41598-017-15159-1.
  27. Schouten, L.R.; Helmerhorst, H.J.; Wagenaar, G.T.; Haltenhof, T.; Lutter, R.; Roelofs, J.J.; van Woensel, J.B.; van Kaam, A.H.; Bos, A.P.; Schultz, M.J.; et al. Age-Dependent Changes in the Pulmonary Renin-Angiotensin System Are Associated With Severity of Lung Injury in a Model of Acute Lung Injury in Rats. Care Med. 2016, 44, e1226–e1235, doi:10.1097/ccm.0000000000002008.
  28. Mauch, C.; Zamek, J.; Abety, A.N.; Grimberg, G.; Fox, J.W.; Zigrino, P. Accelerated wound repair in ADAM-9 knockout animals. Investig. Dermatol. 2010, 130, 2120–2130, doi:10.1038/jid.2010.60.
  29. Mehta, V.; Fields, L.; Evans, I.M.; Yamaji, M.; Pellet-Many, C.; Jones, T.; Mahmoud, M.; Zachary, I. VEGF (Vascular Endothelial Growth Factor) Induces NRP1 (Neuropilin-1) Cleavage via ADAMs (a Disintegrin and Metalloproteinase) 9 and 10 to Generate Novel Carboxy-Terminal NRP1 Fragments That Regulate Angiogenic Signaling. Thromb. Vasc. Biol. 2018, 38, 1845–1858, doi:10.1161/atvbaha.118.311118.
  30. Moss, M.L.; Powell, G.; Miller, M.A.; Edwards, L.; Qi, B.; Sang, Q.X.; De Strooper, B.; Tesseur, I.; Lichtenthaler, S.F.; Taverna, M.; et al. ADAM9 inhibition increases membrane activity of ADAM10 and controls α-secretase processing of amyloid precursor protein. Biol. Chem. 2011, 286, 40443–40451, doi:10.1074/jbc.M111.280495.
  31. Asai, M.; Hattori, C.; Szabó, B.; Sasagawa, N.; Maruyama, K.; Tanuma, S.; Ishiura, S. Putative function of ADAM9, ADAM10, and ADAM17 as APP alpha-secretase. Biophys. Res. Commun. 2003, 301, 231–235, doi:10.1016/s0006-291x(02)02999-6.
  32. Horiuchi, K.; Zhou, H.M.; Kelly, K.; Manova, K.; Blobel, C.P. Evaluation of the contributions of ADAMs 9, 12, 15, 17, and 19 to heart development and ectodomain shedding of neuregulins beta1 and beta2. Biol. 2005, 283, 459–471, doi:10.1016/j.ydbio.2005.05.004.
  33. Sammel, M.; Peters, F.; Lokau, J.; Scharfenberg, F.; Werny, L.; Linder, S.; Garbers, C.; Rose-John, S.; Becker-Pauly, C. Differences in Shedding of the Interleukin-11 Receptor by the Proteases ADAM9, ADAM10, ADAM17, Meprin α, Meprin β and MT1-MMP. J. Mol. Sci. 2019, 20, 3677, doi:10.3390/ijms20153677.
  34. Weskamp, G.; Cai, H.; Brodie, T.A.; Higashyama, S.; Manova, K.; Ludwig, T.; Blobel, C.P. Mice lacking the metalloprotease-disintegrin MDC9 (ADAM9) have no evident major abnormalities during development or adult life. Cell. Biol. 2002, 22, 1537–1544, doi:10.1128/mcb.22.5.1537-1544.2002.
  35. Goldstein, O.; Mezey, J.G.; Boyko, A.R.; Gao, C.; Wang, W.; Bustamante, C.D.; Anguish, L.J.; Jordan, J.A.; Pearce-Kelling, S.E.; Aguirre, G.D.; et al. An ADAM9 mutation in canine cone-rod dystrophy 3 establishes homology with human cone-rod dystrophy 9. Vis. 2010, 16, 1549–1569.
  36. Parry, D.A.; Toomes, C.; Bida, L.; Danciger, M.; Towns, K.V.; McKibbin, M.; Jacobson, S.G.; Logan, C.V.; Ali, M.; Bond, J.; et al. Loss of the metalloprotease ADAM9 leads to cone-rod dystrophy in humans and retinal degeneration in mice. J. Hum. Genet. 2009, 84, 683–691, doi:10.1016/j.ajhg.2009.04.005.
  37. Guaiquil, V.; Swendeman, S.; Yoshida, T.; Chavala, S.; Campochiaro, P.A.; Blobel, C.P. ADAM9 is involved in pathological retinal neovascularization. Cell. Biol. 2009, 29, 2694–2703, doi:10.1128/mcb.01460-08.
  38. Liu, R.; Wang, F.; Guo, Y.; Yang, J.; Chen, S.; Gao, X.; Wang, X. MicroRNA-425 promotes the development of lung adenocarcinoma via targeting A disintegrin and metalloproteinases 9 (ADAM9). Onco Targets Ther. 2018, 11, 4065–4073.
  39. Chang, J.H.; Lai, S.L.; Chen, W.S.; Hung, W.Y.; Chow, J.M.; Hsiao, M.; Lee, W.J.; Chien, M.H. 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, 1746–1758.
  40. Kossmann, C.M.; Annereau, M.; Thomas-Schoemann, A.; Nicco-Overney, C.; Chéreau, C.; Batteux, F.; Alexandre, J.; Lemare, F. ADAM9 expression promotes an aggressive lung adenocarcinoma phenotype. Tumour Biol. 2017, 39, 1010428317716077.
  41. Zhang, J.; Qi, J.; Chen, N.; Fu, W.; Zhou, B.; He, A. High expression of a disintegrin and metalloproteinase-9 predicts a shortened survival time in completely resected stage I non-small cell lung cancer. Oncol. Lett. 2013, 5, 1461–1466.
  42. Zhang, J.; Chen, N.; Qi, J.; Zhou, B.; Qiu, X. HDGF and ADAM9 are novel molecular staging biomarkers, prognostic biomarkers and predictive biomarkers for adjuvant chemotherapy in surgically resected stage I non-small cell lung cancer. J. Cancer Res. Clin. Oncol. 2014, 140, 1441–1449.
  43. Fritzsche, F.R.; Jung, M.; Tölle, A.; Wild, P.; Hartmann, A.; Wassermann, K.; Rabien, A.; Lein, M.; Dietel, M.; Pilarsky, C.; et al. ADAM9 expression is a significant and independent prognostic marker of PSA relapse in prostate cancer. Eur. Urol. 2008, 54, 1097–1106.
  44. Hua, Y.; Liang, C.; Miao, C.; Wang, S.; Su, S.; Shao, P.; Liu, B.; Bao, M.; Zhu, J.; Xu, A.; et al. MicroRNA-126 inhibits proliferation and metastasis in prostate cancer via regulation of ADAM9. Oncol. Lett. 2018, 15, 9051–9060.
  45. Lin, Y.-W.; Wen, Y.-C.; Chu, C.-Y.; Tung, M.-C.; Yang, Y.-C.; Hua, K.-T.; Pan, K.-F.; Hsiao, M.; Lee, W.-J.; Chien, M.-H. Stabilization of ADAM9 by N-α-acetyltransferase 10 protein contributes to promoting progression of androgen-independent prostate cancer. Cell Death Dis. 2020, 11, 591.
  46. Mygind, K.J.; Schwarz, J.; Sahgal, P.; Ivaska, J.; Kveiborg, M. Loss of ADAM9 expression impairs β1 integrin endocytosis, focal adhesion formation and cancer cell migration. J. Cell Sci. 2018, 131, jcs205393.
  47. Oh, S.; Park, Y.; Lee, H.J.; Lee, J.; Lee, S.H.; Baek, Y.S.; Chun, S.K.; Lee, S.M.; Kim, M.; Chon, Y.E.; et al. A Disintegrin and Metalloproteinase 9 (ADAM9) in Advanced Hepatocellular Carcinoma and Their Role as a Biomarker During Hepatocellular Carcinoma Immunotherapy. Cancers 2020, 12, 745.
  48. Kohga, K.; Takehara, T.; Tatsumi, T.; Ishida, H.; Miyagi, T.; Hosui, A.; Hayashi, N. Sorafenib inhibits the shedding of major histocompatibility complex class I-related chain A on hepatocellular carcinoma cells by down-regulating a disintegrin and metalloproteinase 9. Hepatology 2010, 51, 1264–1273.
  49. Dong, Y.; Wu, Z.; He, M.; Chen, Y.; Chen, Y.; Shen, X.; Zhao, X.; Zhang, L.; Yuan, B.; Zeng, Z. ADAM9 mediates the interleukin-6-induced Epithelial-Mesenchymal transition and metastasis through ROS production in hepatoma cells. Cancer Lett. 2018, 421, 1–14.
  50. O’Shea, C.; McKie, N.; Buggy, Y.; Duggan, C.; Hill, A.D.; McDermott, E.; O’Higgins, N.; Duffy, M.J. Expression of ADAM-9 mRNA and protein in human breast cancer. Int. J. Cancer 2003, 105, 754–761.
  51. Oria, V.O.; Lopatta, P.; Schilling, O. The pleiotropic roles of ADAM9 in the biology of solid tumors. Cell. Mol. Life Sci. 2018, 75, 2291–2301.
  52. Wang, J.J.; Zou, J.X.; Wang, H.; Duan, Z.J.; Wang, H.B.; Chen, P.; Liu, P.Q.; Xu, J.Z.; Chen, H.W. Histone methyltransferase NSD2 mediates the survival and invasion of triple-negative breast cancer cells via stimulating ADAM9-EGFR-AKT signaling. Acta Pharmacol. Sin. 2019, 40, 1067–1075.
  53. van Kampen, J.G.M.; van Hooij, O.; Jansen, C.F.; Smit, F.P.; van Noort, P.I.; Schultz, I.; Schaapveld, R.Q.J.; Schalken, J.A.; Verhaegh, G.W. miRNA-520f Reverses Epithelial-to-Mesenchymal Transition by Targeting ADAM9 and TGFBR2. Cancer Res. 2017, 77, 2008–2017.
  54. Oria, V.O.; Lopatta, P.; Schmitz, T.; Preca, B.T.; Nyström, A.; Conrad, C.; Bartsch, J.W.; Kulemann, B.; Hoeppner, J.; Maurer, J.; et al. ADAM9 contributes to vascular invasion in pancreatic ductal adenocarcinoma. Mol. Oncol. 2019, 13, 456–479.
  55. Yuan, P.; He, X.H.; Rong, Y.F.; Cao, J.; Li, Y.; Hu, Y.P.; Liu, Y.; Li, D.; Lou, W.; Liu, M.F. KRAS/NF-κB/YY1/miR-489 Signaling Axis Controls Pancreatic Cancer Metastasis. Cancer Res. 2017, 77, 100–111.
  56. Xing, C.; Ye, H.; Wang, W.; Sun, M.; Zhang, J.; Zhao, Z.; Jiang, G. Circular RNA ADAM9 facilitates the malignant behaviours of pancreatic cancer by sponging miR-217 and upregulating PRSS3 expression. Artif. Cells Nanomed. Biotechnol. 2019, 47, 3920–3928.
  57. Fan, X.; Wang, Y.; Zhang, C.; Liu, L.; Yang, S.; Wang, Y.; Liu, X.; Qian, Z.; Fang, S.; Qiao, H.; et al. ADAM9 Expression Is Associate with Glioma Tumor Grade and Histological Type, and Acts as a Prognostic Factor in Lower-Grade Gliomas. Int. J. Mol. Sci. 2016, 17, 1276.
  58. Sarkar, S.; Zemp, F.J.; Senger, D.; Robbins, S.M.; Yong, V.W. ADAM-9 is a novel mediator of tenascin-C-stimulated invasiveness of brain tumor-initiating cells. Neuro Oncol. 2015, 17, 1095–1105.
  59. Shintani, Y.; Higashiyama, S.; Ohta, M.; Hirabayashi, H.; Yamamoto, S.; Yoshimasu, T.; Matsuda, H.; Matsuura, N. Overexpression of ADAM9 in Non-Small Cell Lung Cancer Correlates with Brain Metastasis. Cancer Res. 2004, 64, 4190–4196.
  60. Chiu, K.L.; Kuo, T.T.; Kuok, Q.Y.; Lin, Y.S.; Hua, C.H.; Lin, C.Y.; Su, P.Y.; Lai, L.C.; Sher, Y.P. ADAM9 enhances CDCP1 protein expression by suppressing miR-218 for lung tumor metastasis. Sci. Rep. 2015, 5, 16426.
  61. Chiu, K.L.; Lin, Y.S.; Kuo, T.T.; Lo, C.C.; Huang, Y.K.; Chang, H.F.; Chuang, E.Y.; Lin, C.C.; Cheng, W.C.; Liu, Y.N.; et al. ADAM9 enhances CDCP1 by inhibiting miR-1 through EGFR signaling activation in lung cancer metastasis. Oncotarget 2017, 8, 47365–47378.
  62. Wang, F.F.; Wang, S.; Xue, W.H.; Cheng, J.L. microRNA-590 suppresses the tumorigenesis and invasiveness of non-small cell lung cancer cells by targeting ADAM9. Mol. Cell. Biochem. 2016, 423, 29–37.
  63. Wan, J.; Hao, L.; Zheng, X.; Li, Z. Circular RNA circ_0020123 promotes non-small cell lung cancer progression by acting as a ceRNA for miR-488-3p to regulate ADAM9 expression. Biochem. Biophys. Res. Commun. 2019, 515, 303–309.
  64. Xiang, L.Y.; Ou, H.H.; Liu, X.C.; Chen, Z.J.; Li, X.H.; Huang, Y.; Yang, D.H. 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, 1010428317709128.
  65. Wan, D.; Shen, S.; Fu, S.; Preston, B.; Brandon, C.; He, S.; Shen, C.; Wu, J.; Wang, S.; Xie, W.; et al. miR-203 suppresses the proliferation and metastasis of hepatocellular carcinoma by targeting oncogene ADAM9 and oncogenic long non-coding RNA HULC. Anticancer Agents Med. Chem. 2016, 16, 414–423.
  66. Hu, D.; Shen, D.; Zhang, M.; Jiang, N.; Sun, F.; Yuan, S.; Wan, K. MiR-488 suppresses cell proliferation and invasion by targeting ADAM9 and lncRNA HULC in hepatocellular carcinoma. Am. J. Cancer Res. 2017, 7, 2070–2080.
  67. Micocci, K.C.; Moritz, M.N.; Lino, R.L.; Fernandes, L.R.; Lima, A.G.; Figueiredo, C.C.; Morandi, V.; Selistre-de-Araujo, H.S. ADAM9 silencing inhibits breast tumor cells transmigration through blood and lymphatic endothelial cells. Biochimie 2016, 128, 174–182.
  68. Zhu, N.; Zhang, D.; Xie, H.; Zhou, Z.; Chen, H.; Hu, T.; Bai, Y.; Shen, Y.; Yuan, W.; Jing, Q.; et al. Endothelial-specific intron-derived miR-126 is down-regulated in human breast cancer and targets both VEGFA and PIK3R2. Mol. Cell. Biochem. 2011, 351, 157–164.
  69. Wang, C.Z.; Yuan, P.; Li, Y. MiR-126 regulated breast cancer cell invasion by targeting ADAM9. Int. J. Clin. Exp. Pathol. 2015, 8, 6547–6553.
  70. Qin, C.; Zhao, Y.; Gong, C.; Yang, Z. MicroRNA-154/ADAM9 axis inhibits the proliferation, migration and invasion of breast cancer cells. Oncol. Lett. 2017, 14, 6969–6975.
  71. Zhang, C.; Zhang, Y.; Ding, W.; Lin, Y.; Huang, Z.; Luo, Q. MiR-33a suppresses breast cancer cell proliferation and metastasis by targeting ADAM9 and ROS1. Protein Cell 2015, 6, 881–889.
  72. Kristensen, L.S.; Andersen, M.S.; Stagsted, L.V.W.; Ebbesen, K.K.; Hansen, T.B.; Kjems, J. The biogenesis, biology and characterization of circular RNAs. Nat. Rev. Genet. 2019, 20, 675–691.
  73. Wu, D.M.; Wen, X.; Han, X.R.; Wang, S.; Wang, Y.J.; Shen, M.; Fan, S.H.; Zhang, Z.F.; Shan, Q.; Li, M.Q.; et al. Bone Marrow Mesenchymal Stem Cell-Derived Exosomal MicroRNA-126-3p Inhibits Pancreatic Cancer Development by Targeting ADAM9. Mol. Ther. Nucleic Acids 2019, 16, 229–245.
  74. Hamada, S.; Satoh, K.; Fujibuchi, W.; Hirota, M.; Kanno, A.; Unno, J.; Masamune, A.; Kikuta, K.; Kume, K.; Shimosegawa, T. MiR-126 acts as a tumor suppressor in pancreatic cancer cells via the regulation of ADAM9. Mol. Cancer Res. 2012, 10, 3–10.
  75. 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, 6419–6427.
  76. Liu, X.; Wang, S.; Yuan, A.; Yuan, X.; Liu, B. MicroRNA-140 represses glioma growth and metastasis by directly targeting ADAM9. Oncol. Rep. 2016, 36, 2329–2338.
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