FOXM1/DVL2/Snail axis drives metastasis and chemoresistance of colorectal cancer.
FOXM1/DVL2/Snail axis drives metastasis and chemoresistance of colorectal cancer.
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FOXM1/DVL2/Snail轴驱动结直肠癌的转移和化疗耐药
DOI：
10.18632/aging.202300
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发表时间：
2020-12-03
期刊：
影响因子：
--
通讯作者：
Zhang K
中科院分区：
文献类型：
--
作者：
Yang Y;Jiang H;Li W;Chen L;Zhu W;Xian Y;Han Z;Yin L;Liu Y;Wang Y;Pan K;Zhang K
结直肠癌（CRC）是全球第三大常见癌症类型。转移和耐药是导致结直肠癌治疗失败和高死亡率的两大主要原因。叉头盒M1（Forkhead Box M1，FOXM 1）参与了肿瘤的恶性行为。然而，FOXM 1在同时调节结直肠癌的转移和耐药性中的作用和机制仍然知之甚少。在这里，我们发现FOXM 1在奥沙利铂和长春新碱耐药CRC细胞（HCT-8/L-OHP和HCT-8/VCR）中过表达，与HCT-8细胞相比，具有增强的转移潜力。过表达FOXM 1可增加HCT-8细胞的迁移、侵袭能力和对奥沙利铂和长春新碱的耐药性，而用shFOXM 1敲低FOXM 1可降低HCT-8/L-OHP和HCT-8/VCR细胞的转移和耐药性。FOXM 1上调Snail基因表达可引起上皮-间质转化样分子改变和多药耐药蛋白P-gp表达，而沉默Snail基因可抑制FOXM 1诱导的肿瘤转移和耐药。我们进一步确定，凌乱-2（DVL 2）是FOXM 1诱导的Snail表达，转移和化疗耐药性的关键。此外，FOXM 1与DVL 2结合，并增强DVL 2的核转位和DVL 2介导的Wnt/β-连环蛋白的转录活性，已知其诱导Snail表达。总之，FOXM 1/DVL 2/Snail轴触发CRC的侵袭性。阻断FOXM 1/DVL 2/Snail通路可同时抑制结直肠癌细胞的转移和耐药性，为成功治疗结直肠癌提供了新的策略。
Colorectal cancer (CRC) is the third most common type of cancer worldwide. Metastasis and chemoresistance are regarded as the two leading causes of treatment failure and high mortality in CRC. Forkhead Box M1 (FOXM1) has been involved in malignant behaviors of cancer. However, the role and mechanism of FOXM1 in simultaneously regulating metastasis and chemoresistance of CRC remain poorly understood. Here, we found that FOXM1 was overexpressed in oxaliplatin- and vincristine-resistant CRC cells (HCT-8/L-OHP and HCT-8/VCR) with enhanced metastatic potential, compared with HCT-8 cells. FOXM1 overexpression increased migration, invasion and drug-resistance to oxaliplatin and vincristine in HCT-8 cells, while FOXM1 knockdown using shFOXM1 impaired metastasis and drug-resistance in HCT-8/L-OHP and HCT-8/VCR cells. Moreover, FOXM1 up-regulated Snail to trigger epithelial-mesenchymal transition-like molecular changes and multidrug-resistance protein P-gp expression, while silencing Snail inhibited FOXM1-induced metastasis and drug-resistance. We further identified that disheveled-2 (DVL2) was crucial for FOXM1-induced Snail expression, metastasis and chemoresistance. Furthermore, FOXM1 bound to DVL2, and enhanced nuclear translocation of DVL2 and DVL2-mediated transcriptional activity of Wnt/β-catenin known to induce Snail expression. In conclusion, FOXM1/DVL2/Snail axis triggered aggressiveness of CRC. Blocking FOXM1/DVL2/Snail pathway simultaneously inhibited metastasis and chemoresistance in CRC cells, providing a new strategy for successful CRC treatment.
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