Abstract
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.
Highlights
Colorectal cancer (CRC) is reported as the third most frequently diagnosed malignancy, as well as the fourth leading cause of cancer-related mortality worldwide [1, 2]
The increased migratory and invasive potential in HCT-8/L-OHP and HCT-8/VCR cells were observed compared with HCT-8 cells (Figure 1E), suggesting that the drug-resistant CRC cells were endowed with enhanced metastasis
Forkhead Box M1 (FOXM1) was overexpressed in HCT-8/line HCT-8 through serial oxaliplatin (LOHP) and HCT-8/VCR cells compared with HCT-8 cells (Figure 1F), suggesting that FOXM1 was involved in metastasis and drug-resistance of CRC cells
Summary
Colorectal cancer (CRC) is reported as the third most frequently diagnosed malignancy, as well as the fourth leading cause of cancer-related mortality worldwide [1, 2]. Advances in surgical operation and the use of combined systemic drug therapy have contributed to a decrease in the rate of cancer mortality [3, 4], a large number of CRC patients still inexorably experience two persisting challenges, cancer cell metastasis and drugresistance in the following years [5, 6]. Numerous studies have shown that transcription factors, including Snail, Slug, and Twist closely participate in EMT [15] These transcription factors can down-regulate epithelial marker E-cadherin, while upregulate the mesenchymal markers such as N-cadherin and Vimentin, promoting the tendency of cell to mesenchymal-like features [16]. The effect of DVL on EMT and EMT-mediated metastasis and chemoresistance in CRC remains unclear
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