NOR1 Suppresses Cancer Stem-Like Cells Properties of Tumor Cells via the Inhibition of the AKT-GSK-3β-Wnt/β-catenin-ALDH1A1 Signal Circuit
NOR1 Suppresses Cancer Stem-Like Cells Properties of Tumor Cells via the Inhibition of the AKT-GSK-3β-Wnt/β-catenin-ALDH1A1 Signal Circuit
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NOR1 通过抑制 AKT-GSK-3beta-Wnt/beta-Catenin-ALDH1A1 信号电路来抑制肿瘤细胞的癌症干细胞样特性。
DOI：
10.1002/jcp.25706
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发表时间：
2017-10-01
影响因子：
5.6
通讯作者：
Xiang, Bo
中科院分区：
文献类型：
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作者：
Wang, Wei;Yi, Mei;Xiang, Bo
肿瘤干细胞（Cancer stem cells, CSCs）在肿瘤放化疗耐药、复发和转移中起着关键作用，在体内主要维持在静息状态。常规疗法无法靶向CSCs是导致治疗失败的主要原因。CSCs在鼻咽癌（NPC）肿瘤中的发现越来越普遍；然而，对维持肿瘤干性的机制的理解仍然有限。我们之前克隆了一个在鼻咽癌细胞系和组织中下调的肿瘤抑制基因NOR1。在这项研究中，我们证明Wnt/ β -catenin和ALDH1A1形成一个信号回路，并且NOR1在鼻鼻癌细胞系中拮抗肿瘤干细胞样表型：NOR1的异位过表达降低β -catenin和ALDH1A1的表达；β -catenin/TCF4靶向调节鼻咽癌细胞ALDH1A1转录；沉默ALDH1A1可降低AKT（总磷酸化）和GSK-3 β（磷酸化）的表达；最终反馈降低了b-连环蛋白的表达水平。我们还发现，NOR1的表达降低了鼻咽癌细胞的癌症干细胞样细胞特性，降低了它们在体外形成肿瘤球体的能力，降低了裸鼠体内的致瘤性，并增加了对化疗药物的敏感性。综上所述，我们的研究结果说明了NOR1的一种新功能，即通过抑制AKT-GSK-3 β - wnt / β -catenin- ALDH1A1信号回路，抑制肿瘤细胞中的癌症干细胞样细胞特性。该研究提示，NOR1缺失在鼻咽癌细胞中的表达可能是癌症干细胞治疗的潜在分子靶点。
Cancer stem cells (CSCs) play a key role in tumor radiotherapy and chemotherapy resistance, relapse, and metastasis, and are primarily maintained in a resting state in vivo. The failure of conventional therapies to target CSCs is the main cause of treatment failure. The discovery of CSCs in nasopharyngeal carcinoma (NPC) tumors is becoming more prevalent; however, the understanding of the mechanisms underlying the maintenance of tumor stemness is still limited. We previously cloned NOR1, a tumor suppressor gene downregulated in NPC cell lines and tissues. In this study, we demonstrate that Wnt/beta-catenin and ALDH1A1 form a signal circuit and that NOR1 antagonizes the tumor stem cell-like phenotype in NPC cell lines: the ectopic overexpression of NOR1 reduced beta-catenin and ALDH1A1 expression; beta-catenin/TCF4 targeted the regulation of ALDH1A1 transcription in NPC cells; silencing ALDH1A1 reduced AKT (total and phosphorylated) and GSK-3 beta (phosphorylated) expression; and eventually feedback decreased b-catenin expression levels. We also found that NOR1 expression decreased cancer stem-like cell properties of NPC cells, reduced their ability to form tumor spheroids in vitro, reduced tumorigenicity in nude mice in vivo, and increased sensitivity to chemotherapy agents. Taken together, our findings illustrated a new function of NOR1 that suppresses cancer stem-like cell properties in tumor cells by inhibiting the AKT-GSK-3 beta-Wnt/beta-catenin- ALDH1A1 signal circuit. The study suggests that NOR1 deletion expression in NPC cells may be a potential molecular target for cancer stem cell therapy.