| Item type |
学術雑誌論文 / Journal Article_02(1) |
| 公開日 |
2018-06-11 |
| タイトル |
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タイトル |
Critical role of Myc activation in mouse hepatocarcinogenesis induced by the activation of AKT and RAS pathways |
| 言語 |
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言語 |
eng |
| 資源タイプ |
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資源タイプ |
journal article |
| 著者 |
Xin, Bing
山本, 雅大
藤井, 清永
大塩, 貴子
Chen, Xi
岡田, 陽子
渡邉, 賢二
三代川, 斉之
古川, 博之
西川, 祐司
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| 著者 ローマ字 |
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| 著者 ローマ字 |
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Yamamoto, Masahiro |
| 著者 ローマ字 |
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Fujii, Kiyonaga |
| 著者 ローマ字 |
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Ooshio, Takako |
| 著者 ローマ字 |
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| 著者 ローマ字 |
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Okada, Yoko |
| 著者 ローマ字 |
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Watanabe, Kenji |
| 著者 ローマ字 |
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Miyokawa, Naoyuki |
| 著者 ローマ字 |
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Furukawa, Hiroyuki |
| 著者 ローマ字 |
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Nishikawa, Yuji |
| 書誌情報 |
Oncogene
巻 36,
p. 5087-5097,
発行日 2017-09-01
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| ISSN |
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収録物識別子タイプ |
ISSN |
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収録物識別子 |
0950-9232 |
| DOI |
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関連タイプ |
isIdenticalTo |
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識別子タイプ |
DOI |
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関連識別子 |
10.1038/onc.2017.114 |
| 識別番号 その他 |
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内容記述タイプ |
Other |
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内容記述 |
PMID：28481866 |
| 抄録 |
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内容記述タイプ |
Abstract |
|
内容記述 |
MYC activation at modest levels has been frequently found in hepatocellular carcinoma. However, its significance in hepatocarcinogenesis has remained obscure. Here we examined the role of Myc activation in mouse liver tumours induced by hepatocytic expression of myristoylated AKT (AKT) and/or mutant HRASV12 (HRAS) via transposon-mediated gene integration. AKT or HRAS alone required 5 months to induce liver tumours, whereas their combination generated hepatocellular carcinoma within 8 weeks. Co-introduction of AKT and HRAS induced lipid-laden preneoplastic cells that grew into nodules composed of tumour cells with or without intracytoplasmic lipid, with the latter being more proliferative and associated with spontaneous Myc expression. AKT/HRAS-induced tumorigenesis was almost completely abolished when MadMyc, a competitive Myc inhibitor, was expressed simultaneously. The Tet-On induction of MadMyc in preneoplastic cells significantly inhibited the progression of AKT/HRAS-induced tumours; its induction in transformed cells suppressed their proliferative activity with alterations in lipid metabolism and protein translation. Transposon-mediated Myc overexpression facilitated tumorigenesis by AKT or HRAS, and when it was co-introduced with AKT and HRAS, diffusely infiltrating tumours without lipid accumulation developed as early as 2 weeks. Examination of the dose-responses of Myc in the enhancement of AKT/HRAS-induced tumorigenesis revealed that a reduction to one-third retained enhancing effect but three-times greater introduction damped the process with increased apoptosis. Myc overexpression suppressed the mRNA expression of proteins involved in the synthesis of fatty acids, and when combined with HRAS introduction, it also suppressed the mRNA expression of proteins involved in their degradation. Finally, the MYC-positive human hepatocellular carcinoma was characterized by the cytoplasm devoid of lipid accumulation, prominent nucleoli and a higher proliferative activity. Our results demonstrate that in hepatocarcinogenesis induced by both activated AKT and HRAS, activation of endogenous Myc is an enhancing factor and adequate levels of Myc deregulation further facilitate the process with alterations in cellular metabolism. |
| 注記 |
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内容記述タイプ |
Other |
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注記 |
http://creativecommons.org/licenses/by-nc-sa/4.0/ |
| 資源タイプ |
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内容記述タイプ |
Other |
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資源タイプ |
text |
| 著者版フラグ |
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出版タイプ |
VoR |
| フォーマット |
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内容記述タイプ |
Other |
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内容記述 |
application/pdf |
| ID(XooNIps) |
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28481866 |
| 閲覧数(XooNIps) |
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| ダウンロード数(XooNIps) |
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565 |
7015.pdf (6.8 MB)
