Sestrin2 reduces the cancer stemness via the Wnt/β-catenin signaling in colorectal cancer

Abstract

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers in both men and women in China. In previous studies, Sestrin2 was demonstrated to have functions in CRC. However, the relationship between Sestrin2 and cancer stemness has not been reported. To investigate the contribution of Sestrin2 in CRC, we performed bioinformatics analysis of The Cancer Genome Atlas datasets and found that Sestrin2 was downregulated in CRC. Using a lentivirus vector, we verified that Sestrin2 suppressed CRC cell proliferation, migration, and colony formation. Furthermore, sphere formation, flow cytometry, quantitative PCR, and Western blot analysis verified the effect of Sestrin2 on the cancer stem ness, including the expression of cluster of differentiation 44, octamer-binding transcription factor 4, sex-determining region Y-box 2, CXC chemokine receptor 4, and the Wnt pathway downstream factors β-catenin and c-Myc. Consistently, the Wnt pathway activator BML-284 partially rescued the effects of Sestrin2 on the expression of proteins related to the cancer stemness. Furthermore, in a mouse xenoplant model, tumors with Sestrin2 were significantly reduced in size with corresponding changes in the cancer stemness. Collectively, our results suggest that Sestrin2 inhibits CRC cell progression by downregulating the Wnt signaling pathway. Thus, Sestrin2 may be a promising therapeutic target for CRC.