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タイトル別表記
右側大腸癌ではTIMP1がFAK/Aktシグナル経路を介して細胞増殖活性及び浸潤能を促進する
著者
馬, 貝貝 徳島大学大学院医学研究科(医学専攻)
上田, 浩之 Tokushima University
板東, 正浩 Tokushima University
Fujimoto, Shota Tokushima University
Wada, Hironori Tokushima University
キーワード
TIMP1
Colorectal cancer
Tumor location
Prognosis
Organoids
資料タイプ
学位論文
抄録
Although right-sided colorectal cancer (CRC) shows a worse prognosis than left-sided CRC, the underlying mechanism remains unclear. We established patient-derived organoids (PDOs) from left- and right-sided CRCs and directly compared cell proliferation and invasion capability between them. We then analyzed the expression of numerous genes in signal transduction pathways to clarify the mechanism of the differential prognosis. Cell proliferation activity and invasion capability in right-sided cancer PDOs were significantly higher than in left-sided cancer PDOs and normal PDOs, as revealed by Cell Titer Glo and transwell assays, respectively. We then used quantitative RT-PCR to compare 184 genes in 30 pathways among right-sided and left-sided cancer and normal PDOs and found that the TIMP1 mRNA level was highest in right-sided PDOs. TIMP1 protein levels were upregulated in right-sided PDOs compared with normal PDOs but was downregulated in left-sided PDOs. TIMP1 knockdown with shRNA significantly decreased cell proliferation activity and invasion capability in right-sided PDOs but not in left-sided PDOs. Moreover, TIMP1 knockdown significantly decreased pFAK and pAkt expression levels in right-sided PDOs but not in left-sided PDOs. A database analysis of The Cancer Genome Atlas revealed that TIMP1 expression in right-sided CRCs was significantly higher than in left-sided CRCs. Kaplan–Meier survival analysis showed significantly shorter overall survival in high-TIMP1 patients versus low-TIMP1 patients with right-sided CRCs but not left-sided CRCs. Our data suggest that TIMP1 is overexpressed in right-sided CRCs and promotes cell proliferation and invasion capability through the TIMP1/FAK/Akt pathway, leading to a poor prognosis. The TIMP1/FAK/Akt pathway can be a target for therapeutic agents in right-sided CRCs.
掲載誌名
Cancer Science
ISSN
13497006
出版者
Japanese Cancer Association|John Wiley & Sons
発行日
2022-09-08
備考
内容要旨・審査要旨・論文本文の公開
本論文は,著者Beibei Ma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.
EDB ID
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3660号
学位記番号
甲医第1542号
学位授与年月日
2022-09-22
学位名
博士(医学)
学位授与機関
徳島大学
部局
医学系
病院