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Mutant GNAS limits tumor aggressiveness in established pancreatic cancer via antagonizing the KRAS-pathway
https://asahikawa-med.repo.nii.ac.jp/records/2000301
https://asahikawa-med.repo.nii.ac.jp/records/2000301a649ccd5-5cea-444c-a3f5-6ca2f683d43e
| 名前 / ファイル | ライセンス | アクション |
|---|---|---|
K578 Kawabata Hidemasa_TD.pdf (1.7 MB)
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| Item type | 学位論文 / Thesis or Dissertation_02(1) | |||||||||||
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| 公開日 | 2022-09-07 | |||||||||||
| タイトル | ||||||||||||
| タイトル | Mutant GNAS limits tumor aggressiveness in established pancreatic cancer via antagonizing the KRAS-pathway | |||||||||||
| 言語 | en | |||||||||||
| 言語 | ||||||||||||
| 言語 | eng | |||||||||||
| キーワード | ||||||||||||
| 言語 | en | |||||||||||
| 主題Scheme | Other | |||||||||||
| 主題 | GNAS | |||||||||||
| キーワード | ||||||||||||
| 言語 | en | |||||||||||
| 主題Scheme | Other | |||||||||||
| 主題 | Intraductal papillary mucinous neoplasm | |||||||||||
| キーワード | ||||||||||||
| 言語 | en | |||||||||||
| 主題Scheme | Other | |||||||||||
| 主題 | NOTCH | |||||||||||
| キーワード | ||||||||||||
| 言語 | en | |||||||||||
| 主題Scheme | Other | |||||||||||
| 主題 | Primary culture | |||||||||||
| 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 | |||||||||||
| その他（別言語等）のタイトル | ||||||||||||
| その他のタイトル | GNAS変異はKRAS経路に拮抗することにより、膵癌の悪性度を抑える | |||||||||||
| 言語 | ja | |||||||||||
| 著者 |
河端, 秀賢
× 河端, 秀賢
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| bibliographic_information |
en : Journal of gastroenterology 巻 57, 号 3, p. 208-220, 発行日 2022-05-01 |
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| ISSN | ||||||||||||
| 収録物識別子タイプ | PISSN | |||||||||||
| 収録物識別子 | 0944-1174 | |||||||||||
| DOI | ||||||||||||
| 関連タイプ | isIdenticalTo | |||||||||||
| 識別子タイプ | DOI | |||||||||||
| 関連識別子 | https://doi.org/10.1007/s00535-021-01846-4 | |||||||||||
| 識別番号 その他 | ||||||||||||
| 内容記述タイプ | Other | |||||||||||
| 内容記述 | PMID:35018527 | |||||||||||
| 言語 | en | |||||||||||
| dissertation_number | ||||||||||||
| 学位授与番号 | 甲第578号 | |||||||||||
| 学位授与年月日 | ||||||||||||
| 学位授与年月日 | 2022-06-30 | |||||||||||
| 学位名 | ||||||||||||
| 言語 | ja | |||||||||||
| 学位名 | 博士（医学） | |||||||||||
| item_10_degree_grantor_32 | ||||||||||||
| 言語 | ja | |||||||||||
| 学位授与機関名 | 旭川医科大学 | |||||||||||
| item_10_description_33 | ||||||||||||
| 内容記述タイプ | Abstract | |||||||||||
| 内容記述 | Background: Mutations in GNAS drive pancreatic tumorigenesis and frequently occur in intraductal papillary mucinous neoplasm (IPMN); however, their value as a therapeutic target is yet to be determined. This study aimed at evaluating the involvement of mutant GNAS in tumor aggressiveness in established pancreatic cancer. Methods: CRISPR/Cas9-mediated GNAS R201H silencing was performed using human primary IPMN-associated pancreatic cancer cells. The role of oncogenic GNAS in tumor maintenance was evaluated by conducting cell culture and xenograft experiments, and western blotting and transcriptome analyses were performed to uncover GNAS-driven signatures. Results: Xenografts of GNAS wild-type cells were characterized by a higher Ki-67 labeling index relative to GNAS-mutant cells. Phenotypic alterations in the GNAS wild-type tumors resulted in a significant reduction in mucin production accompanied by solid with massive stromal components. Transcriptional profiling suggested an apparent conflict of mutant GNAS with KRAS signaling. A significantly higher Notch intercellular domain (NICD) was observed in the nuclear fraction of GNAS wild-type cells. Meanwhile, inhibition of protein kinase A (PKA) induced NICD in GNAS-mutant IPMN cells, suggesting that NOTCH signaling is negatively regulated by the GNAS-PKA pathway. GNAS wild-type cells were characterized by a significant invasive property relative to GNAS-mutant cells, which was mediated through the NOTCH regulatory pathway. Conclusions: Oncogenic GNAS induces mucin production, not only via MUC2 but also via MUC5AC/B, which may enlarge cystic lesions in the pancreas. The mutation may also limit tumor aggressiveness by attenuating NOTCH signaling; therefore, such tumor-suppressing effects must be considered when therapeutically inhibiting the GNAS pathway. |
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| 言語 | en | |||||||||||
| 出版タイプ | ||||||||||||
| 出版タイプ | VoR | |||||||||||
| 出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 | |||||||||||
