神経膠芽腫の浸潤に関与する転写因子と細胞外マトリックス分解酵素の解析

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Author: 山下, 純宏ほか

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Publication date: 2004-04-13

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Note (General)：: 金沢大学医薬保健研究域医学系Proteolytic extracellular matrix (ECM) degradation is a key step in glioblastoma invasion. Although various proteinases are involved in ...

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Material Type: 文書・図像類
Title: 神経膠芽腫の浸潤に関与する転写因子と細胞外マトリックス分解酵素の解析
Author/Editor: 山下, 純宏
Yamashita, Junkoh
Author Heading: 山下, 純宏
Yamashita, Junkoh
Publication Date: 2004-04-13
Publication Date (W3CDTF): 2004-04-13
Alternative Title: The analysis of transcription factor and ECM degradation enzyme associated with invasion of glioblastoma
Periodical title: 平成14(2002)年度科学研究費補助金基盤研究(B) 研究成果報告書概要 = 2002 Fiscal Year Final Research Report Summary
No. or year of volume/issue: 2001-2002
Volume: 2001-2002
Pages: 2p.-
Text Language Code: jpn
Subject Heading: 神経膠芽腫
浸潤
MMP
testican
細胞外マトリックス
glioblastoma
invasion
ECM
Target Audience: 一般
Note (General): 金沢大学医薬保健研究域医学系
Proteolytic extracellular matrix (ECM) degradation is a key step in glioblastoma invasion. Although various proteinases are involved in the process, members of matrix metalloproteinases (MMPs), especially MMP-2, may play a central role in the degradation. To exert its enzymatic activity, pro-MMP-2 requires proteolytic activation by membrane-type MMPs (MT-MMPs) such as MT1-MMP. In the present study, we have screened a human fetal cDNA library by expression cloning for the regulator of pro-MMP-2 processing mediated by MT1-MMP and isolated a cDNA whose product interfered with pro-MMP-2 activation. It encodes N-terminal 313 amino acids regions of testican 3, and thus it was named N-Tes. Expression of testican 1 and testican 3 but not testican 2 also inhibited pro-MMP-2 activation by MT1-MMP. Deletion and substitution of amino acids residues in N-Tes revealed that N-terminal 110 amino acid region of N-Tes is enough for the inhibition of pro-MMP-2 activation by MT1-MMP. In addition, we showe d that testican 2 inactivates N-Tes by binding to the C-terminal extracellular calcium-binding (EC) domain of N-Tes through its N-terminal unique domain. Migration of U251 cells on collagen was dependent on MT1-MMP activity and was inhibited by N-Tes or N-Tes deletion mutant lacking the EC domain (N-Tes-Δ122) deposited on collagen. Binding of testican 2 to N-Tes deposited on collagen allowed migration of cells expressing MT1-MMP. Unlike N-Tes, N-Tes-Δ122 did not bind to testican 2, and thus expression of testican 2 did not recover cell migration blocked by N-Tes-Δ122. In situ hybridization showed that neurons are major source of all testican family members in the normal brain. The quantitative reverse transcription-polyraerase chain reaction analysis demonstrated that all members of testican family are expressed predominantly in normal brain, and their expression levels decrease as tumor grade increases. The expression level of testican 2 was the highest among testican family members regardless of histological grade of astrocytic tumors. These results suggest that N-Tes and testican 1, 3, which are brain ECM, interfere with tumor invasion by inhibiting MT-MMPs and that abundant distribution of testican 2 may contribute to glioma invasion by inactivating other testican family members including N-Tes, which all inhibit MT-MMPs. We propose that N-Tes-Δ122, which is resistant to testican 2, may have potential novel function as a barrier against glioma invasion.
我々はこれまでに神経膠芽腫の浸潤に細胞外マトリックス分解酵素であるmatrix metalloproteinase(MMP)が重要であると報告してきた。本研究ではMMPの中でも特に重要とされるMT1(membrane type1)-MMPに対する抑制分子の探索を行い,得られた遺伝子の機能解析を行った。発現クローニング法により、MT1-MMPの新規阻害因子として脳細胞外マトリックスの構成成分であるプロテオグリカンN-Tesを同定した。N-TesはMT1-MMPによるMMP-2の活性化を阻害し、阻害活性はN末端の110アミノ酸領域にマップされた。同様の阻害活性はTestican family(TF)のT-3,T-1でも認められたが、T-2は阻害しなかった。TF間の相互作用を検討した結果T-2はT-1,T-3,N-Tesと結合することによりその働きを阻害することが分かった。その結合サイトはT-1,T-3,N-Tesのextracellular calcium binding(EC) domainとT-2のunique domainであった。N-TesのEC domainを欠失した変異体(Δ122)はMT1-MMPを抑制し,かつT-2との結合を逃れた。Wound assayの結果もこれと矛盾しない所見であった。またヒトglioma組織におけるTFの発現および局在を検討した結果,TFの発現量はいずれもglioblastomaで有意に低く,その局在はneuronで強く,腫瘍細胞では弱かった。発現量はTFのうちT-2で最も高かった。T-1,T-3,N-TesはMT1-MMPを阻害することにより神経膠芽腫の浸潤を抑制するが,脳組織内に比較的多量に存在するT-2がT-1,T-3,N-TesのMT1-MMP阻害能を解除し浸潤を促進させる。Δ122は抗浸潤治療の候補分子になり得ることが示唆された。
研究課題/領域番号:13470290, 研究期間(年度):2001-2002
出典：研究課題「神経膠芽腫の浸潤に関与する転写因子と細胞外マトリックス分解酵素の解析」課題番号13470290（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/report/KAKENHI-PROJECT-13470290/134702902002kenkyu_seika_hokoku_gaiyo/）を加工して作成
DOI: 10.24517/00057356
Source: https://kanazawa-u.repo.nii.ac.jp/?action=repository_action_common_download&item_id=51053&item_no=1&attribute_id=26&file_no=1
https://kanazawa-u.repo.nii.ac.jp/?action=repository_action_common_download&item_id=51053&item_no=1&attribute_id=26&file_no=1
Access Restrictions: 限定公開
Rights (production): CC BY-NC-ND
Related Material: https://kaken.nii.ac.jp/search/?qm=90026948
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13470290/
https://kaken.nii.ac.jp/report/KAKENHI-PROJECT-13470290/134702902002kenkyu_seika_hokoku_gaiyo/
Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）
https://irdb.nii.ac.jp
Original Data Provider (Database): 金沢大学 : 金沢大学学術情報リポジトリKURA