Loss of ABCB4 attenuates the caspase-dependent apoptosis regulating resistance to 5-Fu in colorectal cancer
Loss of ABCB4 attenuates the caspase-dependent apoptosis regulating resistance to 5-Fu in colorectal cancer
复制标题
ABCB4 的缺失减弱了半胱天冬酶依赖性细胞凋亡调节结直肠癌对 5-Fu 的耐药性
DOI：
10.1042/bsr20171428
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发表时间：
2018-02-28
影响因子：
4
通讯作者：
Wang, Xishan
中科院分区：
文献类型：
--
作者：
Hu, Hanqing;Wang, Meng;Wang, Xishan
三磷酸腺苷结合盒（ABC）是一组参与物质运输、细胞稳态并与化学耐药密切相关的蛋白质。atp结合盒蛋白B4 （ABCB4）是ABCs的一员，与ABCB1结构相似，但研究较少。本研究旨在探讨ABCB4在5-氟尿嘧啶（5-Fu）耐药中的可能机制。然后，我们通过聚合酶链反应（PCR）和Western blot发现，ABCB4在5-Fu耐药的HCT8细胞系中显著下调。小干扰RNA敲除ABCB4可减少HCT8R耐药细胞株5-Fu的凋亡，但不影响增殖。Western blot结果显示，敲除ABCB4后，cleaved caspase和PARP的表达均降低。而ABCB4基因的表达不影响细胞的增殖和凋亡。此外，通过对人类结直肠癌组织甚至5-Fu单药化疗后复发组织中ABCB4 mRNA水平的组织学检测，为ABCB4可能是调节结直肠癌化疗耐药的抑癌基因提供了更具体的证据。此外，一项109例患者队列研究显示，ABCB4预测无复发生存期和总生存期较差。综上所述，ABCB4在5-Fu耐药细胞中下调，ABCB4的下调减轻了细胞凋亡，预示着更短的无复发生存期和总生存期。
The adenosine triphosphate-binding cassette (ABC) is a large group of proteins involved in material transportation, cellular homeostasis, and closely associated with chemoresistance. ATP-binding cassette protein B4 (ABCB4) is a member of ABCs which has a similar structure to ABCB1, but fewer researches were performed. The present study is aimed to investigate the putative mechanism of ABCB4 in 5-fluorouracil (5-Fu) resistance. Then, we found that ABCB4 was significantly down-regulated in the 5-Fu resistant HCT8 cell lines by polymerase chain reaction (PCR) and Western blot. The knockdown of ABCB4 by small interfering RNA decreased the apoptosis by 5-Fu in resistant HCT8R cell lines without influencing the proliferation. Also, we found a lower expression of cleaved caspase and PARP by Western blot after the knockdown of ABCB4. However, the knockdown of ABCB4 did not influence the proliferation and apoptosis. Furthermore, the histological detection of ABCB4 mRNA level in human colorectal cancer tissues and even in the recurrent tissues after 5-Fu single-agent chemotherapy was employed to provide more concrete evidence that ABCB4 may be a tumor suppressor gene to regulate chemoresistance in colorectal cancer. Moreover, a 109-patient cohort revealed that ABCB4 predicted a poor recurrence-free survival and overall survival. In summary, ABCB4 was down-regulated in the 5-Fu resistant cells and knockdown of ABCB4 alleviated the cell apoptosis and predicts a shorter recurrence-free survival and overall survival.