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ID 116388
Title Alternative
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
Author
Gao, Luping Tokushima University
Tokuda, Kazunori Tokushima University
Miyazaki, Katsuki Tokushima University
Okikawa, Shouhei Tokushima University
Keywords
B-cell activating factor
cancer-associated fibroblasts
hepatocellular carcinoma
drug resistance
sorafenib
Content Type
Thesis or Dissertation
Description
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.
Journal Title
Cancer Science
ISSN
13497006
Publisher
Wiley|Japanese Cancer Association
Volume
112
Issue
9
Start Page
3545
End Page
3554
Published Date
2021-06-22
Remark
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。
Rights
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.
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第3558号
Diploma Number
甲医第1511号
Granted Date
2021-09-30
Degree Name
Doctor of Medical Science
Grantor
Tokushima University
departments
Medical Sciences
University Hospital