| Item type |
文献 / Documents(1) |
| 公開日 |
2022-01-06 |
| アクセス権 |
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アクセス権 |
open access |
| 資源タイプ |
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資源タイプ識別子 |
http://purl.org/coar/resource_type/c_db06 |
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資源タイプ |
doctoral thesis |
| 出版社版DOI |
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関連識別子 |
https://doi.org/10.3390/cancers13194917 |
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関連名称 |
10.3390/cancers13194917 |
| 出版タイプ |
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出版タイプ |
NA |
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出版タイプResource |
http://purl.org/coar/version/c_be7fb7dd8ff6fe43 |
| タイトル |
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|
タイトル |
MiR-125b-5p Is Involved in Sorafenib Resistance through Ataxin-1-Mediated Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma |
| タイトル別表記 |
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その他のタイトル |
肝細胞癌においてmiR125b-5pはAtaxin1による上皮間葉転換を介してソラフェニブ耐性を示す |
| 著者 |
平尾, 章博
佐藤, 康史
田中, 宏典
西田, 憲生
友成, 哲
ヒラタ, ミサト
板東, 正浩
喜田, 慶史
田中, 貴大
川口, 智之
ワダ, ヒロノリ
谷口, 達哉
岡本, 耕一
宮本, 弘志
六車, 直樹
棚橋, 俊仁
高山, 哲治
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| 抄録 |
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内容記述 |
The mechanism of resistance to sorafenib in hepatocellular carcinoma (HCC) remains unclear. We analyzed miRNA expression profiles in sorafenib-resistant HCC cell lines (PLC/PRF5-R1/R2) and parental cell lines (PLC/PRF5) to identify the miRNAs responsible for resistance. Drug sensitivity, migration/invasion capabilities, and epithelial-mesenchymal transition (EMT) properties were analyzed by biochemical methods. The clinical relevance of the target genes to survival in HCC patients were assessed using a public database. Four miRNAs were significantly upregulated in PLC/PRF5-R1/-R2 compared with PLC/PRF5. Among them, miR-125b-5p mimic-transfected PLC/PRF5 cells (PLC/PRF5-miR125b) and showed a significantly higher IC50 for sorafenib compared with controls, while the other miRNA mimics did not. PLC/PRF5-miR125b showed lower E-cadherin and higher Snail and vimentin expression—findings similar to those for PLC/PRF5-R2—which suggests the induction of EMT in those cells. PLC/PRF5-miR125b exhibited significantly higher migration and invasion capabilities and induced sorafenib resistance in an in vivo mouse model. Bioinformatic analysis revealed ataxin-1 as a target gene of miR-125b-5p. PLC/PRF5 cells transfected with ataxin-1 siRNA showed a significantly higher IC50, higher migration/invasion capability, higher cancer stem cell population, and an EMT phenotype. Median overall survival in the low-ataxin-1 patient group was significantly shorter than in the high-ataxin-1 group. In conclusion, miR-125b-5p suppressed ataxin-1 and consequently induced Snail-mediated EMT and stemness, leading to a poor prognosis in HCC patients. |
| 抄録 |
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内容記述 |
The mechanism of resistance to multikinase inhibitors in hepatocellular carcinoma (HCC) remains unclear. We analyzed miRNA expression profiles in sorafenib-resistant HCC cell lines (PLC/PRF5-R1/R2) and parental cell lines (PLC/PRF5) to identify the responsible miRNAs and target genes involved in the mechanism of resistance. Four miRNAs were significantly upregulated. Among them, we found that miR-125-5p induced sorafenib resistance in HCC cells and in a mouse model. We also revealed that miR-125-5p suppressed ataxin-1 as a target gene and consequently induced Snail-mediated epithelial-mesenchymal transition (EMT) and cancer stemness. Moreover, we demonstrated that ataxin-1 expression has an impact on the prognosis of patients with HCCs. In the future, by comparing the expression status of miR-125b-5p/ataxin-1 and the effect of sorafenib in the clinical setting, it is expected that miR-125b-5p will be established as an effective drug selection marker for treatment selection in patients with HCC. |
| キーワード |
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|
主題 |
miR-125b-5p |
| キーワード |
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|
主題 |
sorafenib |
| キーワード |
|
|
主題 |
hepatocellular carcinoma |
| キーワード |
|
|
主題 |
ataxin-1 |
| キーワード |
|
|
主題 |
drug resistance |
| 書誌情報 |
en : Cancers
巻 13,
号 19,
p. 4917,
発行日 2021-09-30
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| 収録物ID |
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収録物識別子タイプ |
ISSN |
|
収録物識別子 |
20726694 |
| 出版者 |
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出版者 |
MDPI |
| 備考 |
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|
値 |
内容要旨・審査要旨・論文本文の公開
本論文は，著者Akihiro Hiraoの学位論文として提出され，学位審査・授与の対象となっている。
学位授与者所属 : 徳島大学大学院医科学教育部（医学専攻） |
| 権利情報 |
|
|
権利情報 |
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/ ). |
| EID |
|
|
識別子 |
382789 |
| 言語 |
|
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言語 |
eng |
| 報告番号 |
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学位授与番号 |
甲第3565号 |
| 学位記番号 |
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|
値 |
甲医第1516号 |
| 学位授与年月日 |
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学位授与年月日 |
2021-12-23 |
| 学位名 |
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学位名 |
博士（医学） |
| 学位授与機関 |
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学位授与機関名 |
徳島大学 |
k3565_abstract_review.pdf (213 KB)
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