Colorectal cancer tumor stem cells mediate bevacizumab resistance through the signal IL-22-STAT3 signaling pathway

Bevacizumab is the standard treatment for colorectal cancer (CRC) in the advanced stage. However, poor diagnosis identified due to the bevacizumab resistance in many CRC patients. Previous studies have found that CRC stem cells (CCSCs) and interleukin 22 (IL-22) are involved in the resistance of bevacizumab, however, the mechanism of remains unclear. In this study, we established the bevacizumab drug-resistant cell line HCT-116-R by concentration gradient method, and the cell viability was detected by CCK-8 assay. The resistance of bevacizumab in CRC cell lines HCT-116-R was identified by characterizing epithelial-mesenchymal transition (EMT). Additionally, HCT-116-R cell lines were isolated from CCSCs and their tumorigenicity was validated in nude mice. We observed that that compared with the matched group, the expression of IL-22, IL-22R, STAT3, and GP130 in drug-resistant cells increased distinctly, with blocked IL-22 cells were successfully constructed by lentiviral interference. The level of proteins in stem cell landmarks (EpCAM, CD133), and stem cell landmarks (Oct4, Sox2) was identified by western blotting. Furthermore, the IL-22 role was evaluated by xenograft model. We found that short hairpin RNA (shRNA) suppression of IL-22 expression can restore the sensitivity of drug-resistant CCSCs to bevacizumab, Moreover, xenograft tumor models show that suppression of IL-22 can increase the anti-tumor influence of bevacizumab. In summary, we demonstrated that CCSCs play a major part in bevacizumab-resistant CRC. Inhibiting the signaling pathway of IL-22/STAT3 can improve the anti-tumor influence on bevacizumab in vitro and in vivo. Thus, IL-22 may represent a new anti-bevacizumab target in CRC.

Automated summary

This study demonstrates that colorectal cancer stem cells play a significant role in bevacizumab resistance, and inhibiting the IL-22/STAT3 signaling pathway can enhance the anti-tumor effect of bevacizumab.