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CLC number: R735.7

On-line Access: 2020-03-05

Received: 2019-07-17

Revision Accepted: 2019-11-18

Crosschecked: 2020-02-22

Cited: 0

Clicked: 2393

Citations:  Bibtex RefMan EndNote GB/T7714

 ORCID:

Zhong-Quan Zhao

https://orcid.org/0000-0003-3992-9434

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Journal of Zhejiang University SCIENCE B 2020 Vol.21 No.3 P.234-245

http://doi.org/10.1631/jzus.B1900413


Amyloid precursor protein regulates 5-fluorouracil resistance in human hepatocellular carcinoma cells by inhibiting the mitochondrial apoptotic pathway


Author(s):  Xiao-Long Wu, Ying Chen, Wen-Cui Kong, Zhong-Quan Zhao

Affiliation(s):  Department of Oncology, 900 Hospital of the Joint Logistics Team, Fuzhou 350025, China

Corresponding email(s):   zhaozhonquan@sina.com

Key Words:  Amyloid precursor protein, 5-Fluorouracil resistance, Mitochondrial apoptotic pathway, Hepatocellular carcinoma


Xiao-Long Wu, Ying Chen, Wen-Cui Kong, Zhong-Quan Zhao. Amyloid precursor protein regulates 5-fluorouracil resistance in human hepatocellular carcinoma cells by inhibiting the mitochondrial apoptotic pathway[J]. Journal of Zhejiang University Science B, 2020, 21(3): 234-245.

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%T Amyloid precursor protein regulates 5-fluorouracil resistance in human hepatocellular carcinoma cells by inhibiting the mitochondrial apoptotic pathway
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%A Ying Chen
%A Wen-Cui Kong
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T1 - Amyloid precursor protein regulates 5-fluorouracil resistance in human hepatocellular carcinoma cells by inhibiting the mitochondrial apoptotic pathway
A1 - Xiao-Long Wu
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DOI - 10.1631/jzus.B1900413


Abstract: 
hepatocellular carcinoma (HCC) is a malignant tumor with high morbidity and mortality globally. It accounts for the majority of primary liver cancer cases. amyloid precursor protein (APP), a cell membrane protein, plays a vital role in the pathogenesis of Alzheimer’s disease, and has been found to be implicated in tumor growth and metastasis. Therefore, to understand the relationship between APP and 5-fluorouracil (5-FU) resistance in liver cancer, Cell Counting Kit-8, apoptosis and cell cycle assays, western blotting, and reverse transcription-quantitative polymerase chain reaction (qPCR) analysis were performed. The results demonstrated that APP expression in Bel7402-5-FU cells was significantly up-regulated, as compared with that in Bel7402 cells. Through successful construction of APP-silenced (siAPP) and overexpressed (OE) Bel7402 cell lines, data revealed that the Bel7402-APP751-OE cell line was insensitive, while the Bel7402-siAPP cell line was sensitive to 5-FU in comparison to the matched control group. Furthermore, APP overexpression decreased, while APP silencing increased 5-FU-induced apoptosis in Bel7402 cells. Mechanistically, APP overexpression and silencing can regulate the mitochondrial apoptotic pathway and the expression of apoptotic suppressor genes (B-cell lymphoma-2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xl)). Taken together, these results preliminarily revealed that APP overexpression contributes to the resistance of liver cancer cells to 5-FU, providing a new perspective for drug resistance.

淀粉样前体蛋白通过抑制线粒体凋亡通路调节人肝癌细胞对5-氟尿嘧啶的抗性

目的:探讨淀粉样前体蛋白(APP)是否与肝癌细胞5-氟尿嘧啶(5-FU)耐药的过程相关,并探索其发挥作用的分子机制.
创新点:首次探索并初步证实APP通过影响线粒体凋亡通路信号的传递可以促进肝癌5-FU耐药.
方法:为探究肝癌中APP与5-FU耐药性之间的关系,我们构建了APP沉默和过表达的Bel7402细胞系,并进行了细胞活性检测、细胞凋亡和细胞周期、蛋白质印迹和荧光定量聚合酶链式反应(qPCR)等实验, 验证过表达或沉默APP时,肝癌细胞的状态变化,以及APP发挥作用的分子机制.
结论:与Bel7402细胞相比,耐药细胞Bel7402-5-FU中APP的表达明显上调.在Bel7402细胞中过表达APP降低了细胞的5-FU敏感性,而沉默Bel7402细胞的APP表达提升了细胞对5-FU的敏感性.从机制上讲,APP的过表达和沉默可以调节线粒体的凋亡途径和凋亡抑制基因(BAXBIDBcl-2Bcl-xl)的表达,并进一步影响细胞凋亡的进程.综上所述,我们的结果初步表明APP在肝癌耐药过程中显著上调,APP能够通过影响线粒体凋亡通路调节肝癌细胞的5-FU敏感性,这为研究肝癌耐药机制提供了新的视角.

关键词:淀粉样前体蛋白;5-氟尿嘧啶抗性;线粒体凋亡通路;肝细胞癌

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

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