Reduction of NANOG Mediates the Inhibitory Effect of Aspirin on Tumor Growth and Stemness in Colorectal Cancer

Abstract

Background/Aims: Cancer stem cells (CSCs) are considered to be responsible for tumor relapse and metastasis, which serve as a potential therapeutic target for cancer. Aspirin has been shown to reduce cancer risk and mortality, particularly in colorectal cancer. However, the CSCs-suppressing effect of aspirin and its relevant mechanisms in colorectal cancer remain unclear. Methods: CCK8 assay was employed to detect the cell viability. Sphere formation assay, colony formation assay, and ALDH1 assay were performed to identify the effects of aspirin on CSC properties. Western blotting was performed to detect the expression of the stemness factors. Xenograft model was employed to identify the anti-cancer effects of aspirin in vivo. Unpaired Student t test, ANOVA test and Kruskal-Wallis test were used for the statistical comparisons. Results: Aspirin attenuated colonosphere formation and decreased the ALDH1 positive cell population of colorectal cancer cells. Aspirin inhibited xenograft tumor growth and reduced tumor cells stemness in nude mice. Consistently, aspirin decreased the protein expression of stemness-related transcription factors, including c-Myc, OCT4 and NANOG. Suppression of NANOG blocked the effect of aspirin on sphere formation. Conversely, ectopic expression of NANOG rescued the aspirin-repressed sphere formation, suggesting that NANOG is a key downstream target. Moreover, we found that aspirin repressed NANOG expression in protein level by decreasing its stability. Conclusion: We have provided new evidence that aspirin attenuates CSC properties through down-regulation of NANOG, suggesting aspirin as a promising therapeutic agent for colorectal cancer treatment.

ALDH1 Expression and Vasculogenic Mimicry Are Positively Associated with Poor Prognosis in Patients with Breast Cancer

“…Previous studies confirmed that high levels of ALDH1 activity are predictive of poor prognosis in breast cancer [10]. Moreover, it has been reported that aspirin decreases the stem cell properties of ALDH1-positive colorectal cancer [11].…”

Lgr5+CD44+EpCAM+ Strictly Defines Cancer Stem Cells in Human Colorectal Cancer

“…It is generally considered that the identification and characterization of colorectal CSCs may lead to revolutionary findings in targeted therapeutic strategies [19-21]. However, a long-standing problem has been the paucity of specific markers with which to identify and isolate colorectal CSCs and to investigate their involvement in cancer progression [22].…”

Aspirin-mediated DKK-1 increase rescues Wnt-driven stem-like phenotype in human intestinal organoids

“…Increased stem cell, specifically Lgr5, and mesenchymal marker expression is associated with poor survival in CRC (Xu et al, 2018) , . Cell line data suggests that aspirin decreases stem cell expression and function in breast and CRC (Maity et al, 2015;Wang et al, 2017). Here, we establish the in vivo relevance using Apcdriven mouse and human FAP organoid models to show that aspirin reduces stem cell marker expression in vivo.…”