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T-box転写因子BRACHYURYと転写因子SOX2は腺様嚢胞癌の自己再生能と浸潤能を亢進する : 新規治療法創出の可能性
http://hdl.handle.net/10232/00030542
http://hdl.handle.net/10232/00030542d78228f7-6747-40ff-b4aa-d9483d7d9873
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Diss_中村_康大_ISK505_2018（テーシス形式） (1.2 MB)
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Abstract_中村_康大_4515810133_2018 (236.5 kB)
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Result_Nakamura_Koudai_isk_505 (1.2 MB)
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Comments_Nakamura_Koudai_isk_505 (598.0 kB)
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| Item type | 学位論文 / Thesis or Dissertation(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2019-04-19 | |||||
| タイトル | ||||||
| タイトル | T-box Transcription Factor BRACHYURY and SOX2 Increase Self-Renewal and Invasive Phenotype in Adenoid Cystic Carcinoma : Implication for a New Therapeutic Principle | |||||
| タイトル言語 | en | |||||
| タイトル | ||||||
| タイトル | T-box転写因子BRACHYURYと転写因子SOX2は腺様嚢胞癌の自己再生能と浸潤能を亢進する : 新規治療法創出の可能性 | |||||
| タイトル言語 | ja | |||||
| 著者 |
中村, 康大
× 中村, 康大 |
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| 言語 | ||||||
| 言語 | eng | |||||
| キーワード | ||||||
| 主題言語 | en | |||||
| 主題Scheme | Other | |||||
| 主題 | BRACHYURY | |||||
| キーワード | ||||||
| 主題言語 | en | |||||
| 主題Scheme | Other | |||||
| 主題 | SOX2 | |||||
| キーワード | ||||||
| 主題言語 | en | |||||
| 主題Scheme | Other | |||||
| 主題 | Epithelial–Mesenchymal transition (EMT) | |||||
| キーワード | ||||||
| 主題言語 | en | |||||
| 主題Scheme | Other | |||||
| 主題 | cancer stem cell (CSC) | |||||
| キーワード | ||||||
| 主題言語 | en | |||||
| 主題Scheme | Other | |||||
| 主題 | Adenoid cystic carcinoma (ACC) | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_db06 | |||||
| 資源タイプ | doctoral thesis | |||||
| アクセス権 | ||||||
| アクセス権 | open access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_abf2 | |||||
| 要約 | ||||||
| 内容記述タイプ | Other | |||||
| 内容記述 | Background: The high frequencies of recurrence and distant metastasis of adenoid cystic carcinoma (ACC) emphasize the need to better understand the biological factors associated with these outcomes. Recent studies suggest that epithelial–mesenchymal transition (EMT) correlates with cancer metastasis. In addition, there is growing evidence of the association of EMT with cancer stem cells (CSCs). Recently, we showed that the T-box transcription factor BRACHYURY could be a strong regulator of EMT. Further, we previously established the metastatic ACCS-M GFP cell line and reported that SOX2 knockdown partially inhibits EMT phenotypes of ACCS-M GFP cells. Thus, in this study, we further tested whether BRACHYURY and SOX2 is a regulator of cancer stemness by means of forced expression and silencing of these genes in adenoid cystic carcinoma (ACC) cell lines. Methods: BRACHYURY, SOX2, or both were transfected into ACC cell lines. Short hairpin RNA (shRNA) silencing of these genes was also performed. We analysed these cell lines with respect to self-renewal phenotypes using a sphere-formation assay, and we assessed the expression levels of EMT markers and stem cell markers using real-time reverse transcription-polymerase chain reaction (RT-PCR). Cell migration and invasiveness in vitro were evaluated using a wound healing assay and a tumor cell dissemination assay, respectively. Characteristics of CSCs were also analyzed by sphere-forming ability and in vivo tumorigenicity. Results: Forced expression of BRACHYURY or SOX2 slightly increased expression of EMT and stem cell markers and the self-renewal phenotype. The expression levels, however, were much lower compared to those of cancer stem cell-like cells. Forced co-expression of BRACHYURY and SOX2 strongly upregulated EMT and stem cell markers and the self-renewal phenotype. Cell migration and invasiveness in vitro were also remarkably enhanced. These synergistic effects increased expression levels of FIBRONECTIN, SNAIL, SLUG, ZEB1, and TGF-β2. In particular, the effects on FIBRONECTIN and TGF-β2 were significant. BRACHYURY knockdown significantly inhibited cell migration and invasion, and decreased tumorigenicity in ACC cells. Conclusions: We found that BRACHYURY and SOX2 synergistically promote cancer stemness in ACC cells. This finding points to the importance of gene or protein networks associated with BRACHYURY and SOX2 in the development and maintenance of the CSC phenotype. This study demonstrates that BRACHYURY knockdown reduces invasiveness of CSCs in vivo, suggesting that BRACHYURY silencing may be a useful therapeutic tool for salivary gland carcinoma including adenoid cystic carcinoma. The part of this thesis is originally based on: Naonari Akimoto, Kodai Nakamura, Hiroshi Hijioka, Kenichi Kume, Yoshiaki Matsumura and Tsuyoshi Sugiura Transfection of T-Box Transcription Factor BRACHYURY and SOX2 Synergistically Promote Self-Renewal and Invasive Phenotype in Oral Cancer Cells International Journal of Molecular Sciences 2018, 19(11):3620 DOI: 10.3390/ijms19113620 |
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| 内容記述言語 | en | |||||
| 作成日 | ||||||
| 日付 | 2019-03-07 | |||||
| 日付タイプ | Collected | |||||
| 出版タイプ | ||||||
| 出版タイプ | VoR | |||||
| 出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 | |||||
| NDC | ||||||
| 主題Scheme | NDC | |||||
| 主題 | 494 | |||||
| ファイル（説明） | ||||||
| 内容記述 | 博士論文全文, 博士論文要旨, 最終試験結果の要旨, 論文審査の要旨 | |||||
| 公開者・出版者 | ||||||
| 出版者 | 鹿児島大学 | |||||
| 出版者言語 | ja | |||||
| 公開者・出版者 | ||||||
| 出版者 | カゴシマ ダイガク | |||||
| 出版者言語 | ja-Kana | |||||
| 公開者・出版者 | ||||||
| 出版者 | Kagoshima University | |||||
| 出版者言語 | en | |||||
| 備考 | ||||||
| 備考 | 【指導教員:杉浦剛】 | |||||
| date.appl | ||||||
| appl | 【学位申請日】2019-01-09 | |||||
| 学位名 | ||||||
| 学位名の言語 | ja | |||||
| 学位名 | 博士(歯学) | |||||
| 学位名 | ||||||
| 学位名の言語 | en | |||||
| 学位名 | Doctor of Philosophy in Dental Science | |||||
| 学位授与機関名 | ||||||
| 学位授与機関識別子Scheme | kakenhi | |||||
| 学位授与機関識別子 | 17701 | |||||
| 学位授与機関名の言語 | ja | |||||
| 学位授与機関名 | 鹿児島大学 | |||||
| 学位授与年月日 | ||||||
| 学位授与年月日 | 2019-03-25 | |||||
| 学位授与番号 | ||||||
| 学位授与番号 | 甲総研第505号 | |||||
