Abstract
BackgroundColorectal 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.Methods and resultsTo 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 influence of Sestrin2 on cancer stemness, 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 cancer stemness. Furthermore, in a mouse xenoplant model, tumors expressing Sestrin2 were significantly reduced in size with corresponding changes in cancer stemness.ConclusionsCollectively, 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.
Highlights
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers in both men and women in China
Collectively, our results suggest that Sestrin2 inhibits CRC cell progression by downregulating the Wnt signaling pathway
Sestrin2 inhibits CRC cell proliferation, migration, and colony formation To evaluate the effects of Sestrin2 on CRC, we first investigated the mRNA expression of Sestrin2 compared to the corresponding adjacent tissues in The Cancer Genome Atlas datasets using the UALCAN website (UALCAN: http://ualcan.path.uab.edu) (Fig. 1A) [17]
Summary
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers in both men and women in China. Sestrin was demonstrated to have functions in CRC. The relationship between Sestrin and cancer stemness has not been reported. Standard anticancer therapies for CRC include surgery and chemotherapy, but the survival rate is still unsatisfactory. The failure of standard anticancer treatments might be due to cancer stem cells (CSCs) [2]. CSCs are tumor cells that have stemness properties, namely, selfrenewal, tumor initiation capacity, and long-term repopulation potential [3]. In addition to CSCs, some cancer cells have stemness properties, and these cells might. Downregulation of Sestrin promoted cell proliferation, migration, and ROS production in endometrial cancer cells [10]. In CRC, our previous study demonstrated reduced expression of Sestrin relative to normal colorectal epithelial tissues [11].
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