{"created":"2023-07-27T06:58:34.623311+00:00","id":57218,"links":{},"metadata":{"_buckets":{"deposit":"6357f29a-4db3-44fd-9cf5-42e7038625e5"},"_deposit":{"created_by":18,"id":"57218","owners":[18],"pid":{"revision_id":0,"type":"depid","value":"57218"},"status":"published"},"_oai":{"id":"oai:kanazawa-u.repo.nii.ac.jp:00057218","sets":["2812:2813:2830"]},"author_link":["20357"],"item_9_biblio_info_8":{"attribute_name":"書誌情報","attribute_value_mlt":[{"bibliographicIssueDates":{"bibliographicIssueDate":"2005-04-18","bibliographicIssueDateType":"Issued"},"bibliographicPageStart":"2p.","bibliographicVolumeNumber":"2001 – 2003","bibliographic_titles":[{"bibliographic_title":"平成15(2003)年度 科学研究費補助金 基盤研究(B) 研究成果報告書概要"},{"bibliographic_title":"2003 Fiscal Year Final Research Report Summary","bibliographic_titleLang":"en"}]}]},"item_9_creator_33":{"attribute_name":"著者別表示","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{}],"nameIdentifiers":[{},{},{}]}]},"item_9_description_21":{"attribute_name":"抄録","attribute_value_mlt":[{"subitem_description":"上咽頭癌の頸部転移機序を分子生物学的に解明し、それを予防する治療法を開発する目的でEBウイルスの唯一の発癌遺伝子といわれるLMP1発現と相関する転移関連遺伝子群のスクリーニングをおこなった。その結果、細胞外基質破壊、細胞接着、血管新生、細胞運動能亢進に関与する転移関連遺伝子群が明らかになった。次いでLMP1によるMMP9の発現誘導をI-κBが阻害することを明らかにした。つまり、NF-κBシグナルを抑制することでLMP1によるMMP9の転写が抑制されることを証明した。しかしLMP1遺伝子発現の直接制御は難しく、LMP1下流のシグナル伝達経路を遮断することで癌の浸潤・転移を抑制する分子標的治療の可能性について検討を加えることにした。最初に、I-κBキナーゼ(IKK)を不活化し、NF-κBの活性を抑制することが知られているアスピリン及びその関連物質であるサリチル酸ナトリウムについて検討した。その結果、アスピリンはLMP1導入後のMMP9の発現を抑制することをゼラチンザイモグラフィーで観察した。ゲルシフトアッセイの実験から、アスピリンはLMP1によるNF-κB, AP-1の活性を抑制したことから、MMP9の発現抑制はLMP1下流シグナル伝達経路の抑制によるものであると考えられた。また、MMP9の転写に関するプロモーターの活性を調べたCATアッセイでも、アスピリンによる抑制が証明されたので、ヌードマウスを用いて、臨床応用への可能性を検討した。\n形質転換した子宮頚痛由来C33A上皮系細胞とLMP1発現C33A細胞を作成し、それぞれの細胞をヌードマウス背部へ皮下注射により移植した。次いで腫瘍形成ヌードマウスヘアスピリンを3日間、皮下注射した。この移植腫瘍からウェスタンブロット用及びゼラチンザイモグラフィー用細胞抽出液を採取し、それぞれの材料においてLMP1及びMMP9の誘導を確認した後、アスピリン投与有無での両者の発現の差を比較検討した。結果は期待どおりアスピリンはそれらの発現を有意に抑制し、上咽頭癌の頸部転移抑制のための分子標的療法の可能性が証明できた。","subitem_description_type":"Abstract"},{"subitem_description":"Nasopharyngeal carcinoma(NPC), an epithelial tumor which is characterized by marked geographic and population differences in incidence, is found to be associated with Epstein-Barr virus(EBV) by serologic evidence, and the relationship was confirmed by the detection of EBVDNA and EB-encoded RNAs in NPC cells. While, NPC is highly metastatic carcinoma whose consistent associated with EBV has been established. Latent membrane protein 1(LMP1), an EBV membrane protein expressed in latent infection is considered to be the EBV oncoprotein. Matrix metalloproteinase 9(MMP9), one of the MMP families, degrades Type IV collagen, a major 4 component of extracellural matrix and is believed to be crucial for cancer invasion and metastasis. Although MMP9 is reported to be expressed in a variety of cancers, no reports concerning NPC have been published. We have shown that LMP1 induces MMP9 in vitro cell line, which suggests the possibility of mechanism in which LMP1 of EBV contributes to the metastasis and tumorgenesis of NPC by the induction of MMP9. Then the expression of LMP1 and MMP9 were immunohistochemically examined, and the relation of these proteins was statistically analyzed. We also analyzed the association of these proteins with clinical features. As results, both LMP1 and MMP9 proteins were predominantly immunolocalized in cancer nests. The expression of MMP9 showed a significant positive correlation with the expression of LMP1. Also, the expression of MMP9 correlated with lymphnode metastasis.\nWe also demonstrated that LMP1 enhances MMP9 expression by activation of nuclear factor(NF)κB and activator protein(AP)-1. We therefore tested whether up-regulation of MMP9 by LMP1 could be correlated with enhanced invasiveness of tumor cells in vitro. Whether aspirin and sodium salicylate could reduce invasiveness and whether LMP1 could enhance MMP9 expression in tumors grown in nude mice were also tested. CS3A cells stably expressing LMP1 had increased expression of MMP9 and showed greater invasion through reconstituted basement membrane compared with vector-transfected C33A cells. Treatment with aspirin and sodium salicylate inhibited invasiveness of the LMP1-expressing C33A cells and suppressed both the LMP1-induced MMP9 expewssion in zymographic analyses and LMP1-induced MMP9 promoter activity in CAT reporter assays. The inhibitory effect of aspirin on NF-κB activity was attributable to the inhibition of I-κB kinase activity. Finally, tumors derived from vector-transfected C3SA cells stably expressing LMP1 grown in nude mice showed enhanced MMP9 levels compared with tumors derived from vector-trancfected C33A cells. This enhancement was inhibited by treatment of the mice with aspirin. These results suggest that aspirin may be able to suppress invasion and metastasis of EBV-associated tumors that express LMP1 by suppression of MMP-9.","subitem_description_type":"Abstract"}]},"item_9_description_22":{"attribute_name":"内容記述","attribute_value_mlt":[{"subitem_description":"研究課題/領域番号:13470358, 研究期間(年度):2001 – 2003","subitem_description_type":"Other"},{"subitem_description":"出典：「上咽頭癌の頸部転移機構に関する分子生物学的解析」研究成果報告書　課題番号13470358\n（KAKEN：科学研究費助成事業データベース（国立情報学研究所））\n（https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-13470358/134703582003kenkyu_seika_hokoku_gaiyo/)を加工して作成","subitem_description_type":"Other"}]},"item_9_description_5":{"attribute_name":"提供者所属","attribute_value_mlt":[{"subitem_description":"金沢大学医学系研究科","subitem_description_type":"Other"}]},"item_9_identifier_registration":{"attribute_name":"ID登録","attribute_value_mlt":[{"subitem_identifier_reg_text":"10.24517/00063488","subitem_identifier_reg_type":"JaLC"}]},"item_9_relation_28":{"attribute_name":"関連URI","attribute_value_mlt":[{"subitem_relation_name":[{"subitem_relation_name_text":"https://kaken.nii.ac.jp/ja/search/?kw=40092803"}],"subitem_relation_type_id":{"subitem_relation_type_id_text":"https://kaken.nii.ac.jp/ja/search/?kw=40092803","subitem_relation_type_select":"URI"}},{"subitem_relation_name":[{"subitem_relation_name_text":"https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-13470358/"}],"subitem_relation_type_id":{"subitem_relation_type_id_text":"https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-13470358/","subitem_relation_type_select":"URI"}},{"subitem_relation_name":[{"subitem_relation_name_text":"https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-13470358/134703582003kenkyu_seika_hokoku_gaiyo/"}],"subitem_relation_type_id":{"subitem_relation_type_id_text":"https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-13470358/134703582003kenkyu_seika_hokoku_gaiyo/","subitem_relation_type_select":"URI"}}]},"item_9_version_type_25":{"attribute_name":"著者版フラグ","attribute_value_mlt":[{"subitem_version_resource":"http://purl.org/coar/version/c_ab4af688f83e57aa","subitem_version_type":"AM"}]},"item_files":{"attribute_name":"ファイル情報","attribute_type":"file","attribute_value_mlt":[{"accessrole":"open_date","date":[{"dateType":"Available","dateValue":"2021-11-04"}],"displaytype":"detail","filename":"ME-PR-FURUKAWA-M-kaken 2005-2p.pdf","filesize":[{"value":"113.2 kB"}],"format":"application/pdf","licensetype":"license_11","mimetype":"application/pdf","url":{"label":"ME-PR-FURUKAWA-M-kaken 2005-2p.pdf","url":"https://kanazawa-u.repo.nii.ac.jp/record/57218/files/ME-PR-FURUKAWA-M-kaken 2005-2p.pdf"},"version_id":"3c3577c5-1e7a-4c05-99ff-744c776134d2"}]},"item_language":{"attribute_name":"言語","attribute_value_mlt":[{"subitem_language":"jpn"}]},"item_resource_type":{"attribute_name":"資源タイプ","attribute_value_mlt":[{"resourcetype":"research report","resourceuri":"http://purl.org/coar/resource_type/c_18ws"}]},"item_title":"上咽頭癌の頸部転移機構に関する分子生物学的解析","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"上咽頭癌の頸部転移機構に関する分子生物学的解析"},{"subitem_title":"Molecular, biological studies on the mechanism of neck metastasis from nasopharyngeal carcinoma","subitem_title_language":"en"}]},"item_type_id":"9","owner":"18","path":["2830"],"pubdate":{"attribute_name":"公開日","attribute_value":"2021-11-04"},"publish_date":"2021-11-04","publish_status":"0","recid":"57218","relation_version_is_last":true,"title":["上咽頭癌の頸部転移機構に関する分子生物学的解析"],"weko_creator_id":"18","weko_shared_id":-1},"updated":"2023-07-27T14:29:57.016510+00:00"}