{"created":"2023-05-15T16:50:04.148492+00:00","id":27778,"links":{},"metadata":{"_buckets":{"deposit":"8d075f7e-f852-476f-80e9-c8d54862b85f"},"_deposit":{"created_by":6,"id":"27778","owners":[6],"pid":{"revision_id":0,"type":"depid","value":"27778"},"status":"published"},"_oai":{"id":"oai:nagasaki-u.repo.nii.ac.jp:00027778","sets":["10:11"]},"author_link":["123535","123533","123536","123537","123534"],"item_2_biblio_info_6":{"attribute_name":"書誌情報","attribute_value_mlt":[{"bibliographicIssueDates":{"bibliographicIssueDate":"2022-11-15","bibliographicIssueDateType":"Issued"},"bibliographicIssueNumber":"1","bibliographicPageStart":"352","bibliographicVolumeNumber":"22","bibliographic_titles":[{"bibliographic_title":"Cancer Cell International"}]}]},"item_2_description_4":{"attribute_name":"抄録","attribute_value_mlt":[{"subitem_description":"Background: Head and neck squamous cell carcinoma (HNSCC) is the most common malignant tumor of the head and neck. We identified cancer‑specific genes in HNSCC and focused on DKK3 expression. DKK3 gene codes two iso‑forms of proteins (secreted and non‑secreted) with two distinct cysteine rich domains (CRDs). It is reported that DKK3 functions as a negative regulator of oncogenic Wnt signaling and, is therefore, considered to be a tumor suppressor gene. However, our series of studies have demonstrated that DKK3 expression is specifically high in HNSCC tissues and cells, and that DKK3 might determine the malignant potentials of HNSCC cells via the activation of Akt. Further analyses strongly suggested that both secreted DKK3 and non‑secreted DKK3 could activate Akt signaling in discrete ways, and consequently exert tumor promoting effects. We hypothesized that DKK3 might be a specific druggable target, and it is necessary to establish a DKK3 inhibitor that can inhibit both secreted and non‑secreted isoforms of DKK3.\nMethods: Using inverse polymerase chain reaction, we generated mutant expression plasmids that express DKK3 without CRD1, CRD2, or both CRD1 and CRD2 (DKK3ΔC1, DKK3ΔC2, and DKK3ΔC1ΔC2, respectively). These plasmids were then transfected into HNSCC‑derived cells to determine the domain responsible for DKK3‑mediated Akt activation. We designed antisense peptides using the MIMETEC program, targeting DKK3‑specific amino acid sequences within CRD1 and CRD2. The structural models for peptides and DKK3 were generated using Raptor X, and then a docking simulation was performed using CluPro2. Afterward, the best set of the peptides was applied into HNSCC‑derived cells, and the effects on Akt phosphorylation, cellular proliferation, invasion, and migration were assessed. We also investigated the therapeutic effects of the peptides in the xenograft models.\nResults: Transfection of mutant expression plasmids and subsequent functional analyses revealed that it is necessary to delete both CRD1 and CRD2 to inhibit Akt activation and inhibition of proliferation, migration, and invasion. The inhibitory peptides for CRD1 and CRD2 of DKK3 significantly reduced the phosphorylation of Akt, and consequently suppressed cellular proliferation, migration, invasion and in vivo tumor growth at very low doses.\nConclusions: This inhibitory peptide represents a promising new therapeutic strategy for HNSCC treatment.","subitem_description_type":"Abstract"}]},"item_2_description_63":{"attribute_name":"引用","attribute_value_mlt":[{"subitem_description":"Cancer Cell International, 22(1), art. no. 352; 2022　","subitem_description_type":"Other"}]},"item_2_publisher_33":{"attribute_name":"出版者","attribute_value_mlt":[{"subitem_publisher":"BMC"}]},"item_2_relation_12":{"attribute_name":"DOI","attribute_value_mlt":[{"subitem_relation_type":"isIdenticalTo","subitem_relation_type_id":{"subitem_relation_type_id_text":"10.1186/s12935-022-02783-9","subitem_relation_type_select":"DOI"}}]},"item_2_rights_13":{"attribute_name":"権利","attribute_value_mlt":[{"subitem_rights":"© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data."}]},"item_2_source_id_7":{"attribute_name":"ISSN","attribute_value_mlt":[{"subitem_source_identifier":"1475-2867","subitem_source_identifier_type":"ISSN"}]},"item_2_version_type_16":{"attribute_name":"著者版フラグ","attribute_value_mlt":[{"subitem_version_resource":"http://purl.org/coar/version/c_970fb48d4fbd8a85","subitem_version_type":"VoR"}]},"item_creator":{"attribute_name":"著者","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"Katase, Naoki"}],"nameIdentifiers":[{}]},{"creatorNames":[{"creatorName":"Nishimatsu, Shin-ichiro"}],"nameIdentifiers":[{}]},{"creatorNames":[{"creatorName":"Yamauchi, Akira"}],"nameIdentifiers":[{}]},{"creatorNames":[{"creatorName":"Okano, Shinji"}],"nameIdentifiers":[{}]},{"creatorNames":[{"creatorName":"Fujita, Shuichi"}],"nameIdentifiers":[{}]}]},"item_files":{"attribute_name":"ファイル情報","attribute_type":"file","attribute_value_mlt":[{"accessrole":"open_date","date":[{"dateType":"Available","dateValue":"2022-11-29"}],"displaytype":"detail","filename":"CCI22_352.pdf","filesize":[{"value":"6.4 MB"}],"format":"application/pdf","licensetype":"license_note","mimetype":"application/pdf","url":{"label":"CCI22_352.pdf","url":"https://nagasaki-u.repo.nii.ac.jp/record/27778/files/CCI22_352.pdf"},"version_id":"8ae14326-00c9-48a6-a227-58c39a70003b"}]},"item_keyword":{"attribute_name":"キーワード","attribute_value_mlt":[{"subitem_subject":"DKK3","subitem_subject_scheme":"Other"},{"subitem_subject":"Head and neck squamous cell carcinoma","subitem_subject_scheme":"Other"},{"subitem_subject":"Inhibitory peptide","subitem_subject_scheme":"Other"}]},"item_language":{"attribute_name":"言語","attribute_value_mlt":[{"subitem_language":"eng"}]},"item_resource_type":{"attribute_name":"資源タイプ","attribute_value_mlt":[{"resourcetype":"journal article","resourceuri":"http://purl.org/coar/resource_type/c_6501"}]},"item_title":"Establishment of anti-DKK3 peptide for the cancer control in head and neck squamous cell carcinoma (HNSCC)","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"Establishment of anti-DKK3 peptide for the cancer control in head and neck squamous cell carcinoma (HNSCC)"}]},"item_type_id":"2","owner":"6","path":["11"],"pubdate":{"attribute_name":"公開日","attribute_value":"2022-11-29"},"publish_date":"2022-11-29","publish_status":"0","recid":"27778","relation_version_is_last":true,"title":["Establishment of anti-DKK3 peptide for the cancer control in head and neck squamous cell carcinoma (HNSCC)"],"weko_creator_id":"6","weko_shared_id":-1},"updated":"2023-05-15T19:17:09.979244+00:00"}