Human glioblastomas overexpress ADAMTS-5 that degrades brevican

Nakada, Mitsutoshi; Miyamori, Hisashi; Kita, Daisuke; Takahashi, Tomoya; Yamashita, Junkoh; Sato, Hiroshi; Miura, Ryu; Yamaguchi, Yu; Okada, Yasunori

doi:10.1007/s00401-005-1032-6

Cited by 104 publications

(81 citation statements)

References 13 publications

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“…However, little is known about the involvement of ADAMTS members in cell invasion except for ADAMTS1 and ADAMTS5. Fulllength ADAMTS1 and ADAMTS5 are reported to promote metastasis whereas fragment of ADAMTS1 was shown to be antimetastatic (2,39). Here, we also identified that ADAMTS8 suppressed tumor cell migration by disrupting actin polymerization.…”

Section: Discussionsupporting

confidence: 52%

The Metalloprotease ADAMTS8 Displays Antitumor Properties through Antagonizing EGFR–MEK–ERK Signaling and Is Silenced in Carcinomas by CpG Methylation

Choi

Wang

et al. 2014

Molecular Cancer Research

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A disintegrins and metalloproteinases with thrombospondin motifs (ADAMTS) family members have been reported dysregulated in various cancers. Through refining a loss of heterozygosity locus at 11q25 by array-CGH, we identified ADAMTS8 as a novel candidate tumor suppressor gene. Although ADAMTS8 downregulation has been reported in several tumors, its biologic function and underlying mechanism remain largely unknown. Here, we found that ADAMTS8 is broadly expressed in normal tissues but frequently downregulated or silenced by promoter methylation in common carcinoma cell lines, including nasopharyngeal, esophageal squamous cell, gastric, and colorectal carcinomas. Pharmacologic or genetic demethylation restored ADAMTS8 expression, indicating that promoter methylation mediates its silencing. Aberrant methylation of ADAMTS8 was also detected in several types of primary tumors but rarely in normal tissues. Further functional studies showed that restoring ADAMTS8 expression suppressed tumor cell clonogenicity through inducing apoptosis. ADAMTS8 as a secreted protease inhibited epidermal growth factor receptor (EGFR) signaling along with decreased levels of phosphorylated MEK and ERK. We further found that ADAMTS8 disrupted actin stress fiber organization and inhibited tumor cell motility. Thus, our data demonstrate that ADAMTS8 metalloprotease acts as a functional tumor suppressor through antagonizing EGFR-MEK-ERK signaling, in addition to its previously reported anti-angiogenesis function, and is frequently methylated in common tumors.

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Section: Discussionsupporting

confidence: 52%

The Metalloprotease ADAMTS8 Displays Antitumor Properties through Antagonizing EGFR–MEK–ERK Signaling and Is Silenced in Carcinomas by CpG Methylation

Choi

Wang

et al. 2014

Molecular Cancer Research

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“…Current evidence strongly suggests ADAMTS-4 (aggrecanase-1) and ADAMTS-5 (aggrecanase-2) as the most likely candidates, which are also upregulated in gliomas [36,51,52]. These two proteases also cleave two other members of the lectican family, aggrecan [53] and versican [54], and have a restricted additional spectrum of ECM substrates [55][56][57].…”

Section: Discussionmentioning

confidence: 99%

BEHAB/brevican requires ADAMTS-mediated proteolytic cleavage to promote glioma invasion

2008

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Malignant gliomas are the most common and deadly primary brain tumors, due to their infiltrative invasion of the normal neural tissue that makes them virtually impossible to completely eliminate. We have previously identified and characterized the proteoglycan BEHAB/brevican in gliomas and have demonstrated that upregulation and cleavage of this CNS-specific molecule promote glioma invasion. Here, we have further investigated if the proteolytic processing of BEHAB/ brevican by metalloproteases of the ADAMTS family is a necessary step in mediating its proinvasive effect in glioma. By generating a site-specific ( 396 SRG 398 → NVY) mutant form resistant to ADAMTS cleavage, we have shown that the predominant proteolytic processing of BEHAB/ brevican by glioma cells occurs only at this site. More importantly, "uncleavable" BEHAB/ brevican is unable to enhance glioma cell invasion in vitro and tumor progression in vivo. In addition, our results suggest that the full-length protein and its cleavage products may act independently because the mutant form does not exert a dominant negative effect on normal BEHAB/brevican expression or cleavage. These results illustrate how the regulated processing of major components of the neural extracellular matrix has important functional implications in glioma progression. In addition, our findings underscore the relevance of the ADAMTS family of metalloproteases as attractive targets for novel pharmacological approaches in glioma therapy.

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“…We have also shown that TGF-b2 is capable of increasing MMP-2 activity and thereby induces the degradation of versican V1 . Cleavage of brevican, another member of the lectican family by ADAMTS-5 is functionally involved in glioma invasion in vivo (Nakada et al, 2005). There is a strong likelihood that breakdown products of versican will also have biological activity in glioma probably paving the way for the invasion into tissue (Zheng et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

The role of versican isoforms V0/V1 in glioma migration mediated by transforming growth factor-β2

et al. 2007

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Versican is a large chondroitin sulphate proteoglycan produced by several tumour cell types, including high-grade glioma. The increased expression of certain versican isoforms in the extracellular matrix (ECM) plays a role in tumour cell growth, adhesion and migration. Transforming growth factor-b2 (TGF-b2) is an important modulator of glioma invasion, partially by remodeling the ECM. However, it is unknown whether it interacts with versican during malignant progression of glioma cells. Here, we analysed the effect of TGF-b2 on the expression of versican isoforms. The expression of versican V0/V1 was upregulated by TGF-b2 detected by quantitative polymerase chain reaction and immunoprecipitation, whereas V2 was not induced. Using time-lapse scratch and spheroid migration assays, we observed that the glioma migration rate is significantly increased by exogenous TGF-b2 and inhibited by TGF-b2-specific antisense oligonucleotides. Interestingly, an antibody specific for the DPEAAE region of glycosaminoglycan-b domain of versican was able to reverse the effect of TGF-b2 on glioma migration in a dose-dependent manner. Taken together, we report here that TGF-b2 triggers the malignant phenotype of high-grade gliomas by induction of migration, and that this effect is, at least in part, mediated by versican V0/V1.

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Human glioblastomas overexpress ADAMTS-5 that degrades brevican

Cited by 104 publications

References 13 publications

The Metalloprotease ADAMTS8 Displays Antitumor Properties through Antagonizing EGFR–MEK–ERK Signaling and Is Silenced in Carcinomas by CpG Methylation

The Metalloprotease ADAMTS8 Displays Antitumor Properties through Antagonizing EGFR–MEK–ERK Signaling and Is Silenced in Carcinomas by CpG Methylation

BEHAB/brevican requires ADAMTS-mediated proteolytic cleavage to promote glioma invasion

The role of versican isoforms V0/V1 in glioma migration mediated by transforming growth factor-β2

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