Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, 200062, Shanghai, China.
Shanghai Putuo Central School of Clinical Medicine, Anhui Medical University, 230032, Hefei, China.
Br J Cancer. 2020 Apr;122(9):1342-1353. doi: 10.1038/s41416-020-0783-0. Epub 2020 Mar 16.
Recent studies have shown that multidrug resistance may be induced by the high stemness of cancer cells. Following prolonged chemotherapy, MDR protein 1 (MDR1) and CD133 increase in CRC, but the relationship between them is unclear.
The relationship between MDR and CSC properties in CRC was determined via CCK-8 assay, apoptosis assay, DOX uptake and retention, immunohistochemistry, immunofluorescence and flow cytometry. The correlations between their expression levels were evaluated using Spearman's rank statistical test and the Mann-Whitney test. Furthermore, the effect of CD133 on the repression of the AKT/NF-κB/MDR1 signalling pathway was investigated in vitro and in vivo.
We found that CD133 increased with the emergence of drug-resistance phenotypes, and the high expression of MDR1/P-gp was consistently accompanied by positive expression of CD133 as demonstrated by the analysis of patient samples. Up- or downregulation of CD133 could regulate MDR via AKT/NF-κB/MDR1 signalling in CRC. A rescue experiment showed that the AKT/NF-κB signalling pathway is the main mechanism by which CD133 regulates MDR1/P-gp expression in CRC.
Taken together, our results suggest that targeting CD133 reverses drug resistance via the AKT/NF-κB/MDR1 pathway and that this pathway might serve as a potential therapeutic target to reverse MDR in CRC.
最近的研究表明，多药耐药性可能是由癌细胞的高干性引起的。在长期化疗后，CRC 中 MDR 蛋白 1（MDR1）和 CD133 增加，但它们之间的关系尚不清楚。
通过 CCK-8 测定、凋亡测定、DOX 摄取和保留、免疫组织化学、免疫荧光和流式细胞术确定 CRC 中 MDR 与 CSC 特性之间的关系。使用 Spearman 秩统计检验和 Mann-Whitney 检验评估它们之间表达水平的相关性。此外，还在体外和体内研究了 CD133 对 AKT/NF-κB/MDR1 信号通路抑制作用的影响。
我们发现 CD133 随着耐药表型的出现而增加，并且 MDR1/P-gp 的高表达始终伴随着 CD133 的阳性表达，这一点通过对患者样本的分析得到了证实。CRC 中 CD133 的上调或下调可以通过 AKT/NF-κB/MDR1 信号通路调节 MDR。挽救实验表明，AKT/NF-κB 信号通路是 CD133 调节 CRC 中 MDR1/P-gp 表达的主要机制。
综上所述，我们的研究结果表明，靶向 CD133 可通过 AKT/NF-κB/MDR1 通路逆转耐药性，该通路可能成为逆转 CRC 中 MDR 的潜在治疗靶点。
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