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タイトル別表記
BAFF/NFκB経路はソラフェニブ耐性肝癌と癌関連線維芽細胞の相互作用に重要である
著者
高, 露萍 徳島大学大学院医科学教育部(医学専攻)
Tokuda, Kazunori Tokushima University
Miyazaki, Katsuki Tokushima University
Okikawa, Shouhei Tokushima University
キーワード
B-cell activating factor
cancer-associated fibroblasts
hepatocellular carcinoma
drug resistance
sorafenib
資料タイプ
学位論文
抄録
The tumor microenvironment affects malignancy in hepatocellular carcinoma (HCC) cells, and cancer-associated fibroblasts (CAFs) play an important role in the microenvironment. As recent studies indicated a difference between CAFs isolated from chemoresistant and non-resistant cancer tissues, therefore we investigated the intracellular mechanism in resistant HCC co-cultured CAFs and interactions between these CAFs with cancer cells. We established a sorafenib-resistant (SR) Huh7 (human HCC) cell line, and characterized it with cytokine assays, then developed CAFs by co-culturing human hepatic stellate cells with resistant or parental Huh7 cells. The 2 types of CAFs were co-cultured with parental Huh7 cells, thereafter the cell viability of these Huh7 cells was checked under sorafenib treatment. The SR Huh7 (Huh7SR) cells expressed increased B-cell activating factor (BAFF), which promoted high expression of CAF-specific markers in Huh7SR-co-cultured CAFs, showed activated BAFF, BAFF-R, and downstream of the NFκB-Nrf2 pathway, and aggravated invasion, migration, and drug resistance in co-cultured Huh7 cells. When we knocked down BAFF expression in Huh7SR cells, the previously increased malignancy and BAFF/NFκB axis in Huh7SR-co-cultured CAFs reversed, and enhanced chemoresistance in co-cultured Huh7 cells returned as well. In conclusion, the BAFF/NFκB pathway was activated in CAFs co-cultured with cell-culture medium from resistant Huh7, which promoted chemoresistance, and increased the malignancy in co-cultured non-resistant Huh7 cells. This suggests that the BAFF/NFκB axis in CAFs might be a potential therapeutic target in chemoresistance of HCC.
掲載誌名
Cancer Science
ISSN
13497006
出版者
Wiley|Japanese Cancer Association
112
9
開始ページ
3545
終了ページ
3554
発行日
2021-06-22
備考
内容要旨・審査要旨・論文本文の公開
本論文は,著者Luping Gao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。
権利情報
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
出版社版DOI
出版社版URL
フルテキストファイル
言語
eng
著者版フラグ
博士論文全文を含む
文科省報告番号
甲第3558号
学位記番号
甲医第1511号
学位授与年月日
2021-09-30
学位名
博士(医学)
学位授与機関
徳島大学
部局
医学系
病院