Targeting REV7 effectively reverses 5-FU and oxaliplatin resistance in colorectal cancer

Cancer Cell International

Xianjun Sun¹  Hongliang Guo¹  Jie Chai¹  Xin Liu¹  Wenhou Hou²  Jinming Yu² 

[1] Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academic Sciences;Department of Radiotherapy, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academic Sciences;

关键词: REV7;    TLS;    5-FU;    Oxaliplatin;    Resistance;    Colorectal cancer;   

DOI  :  10.1186/s12935-020-01668-z

来源: DOAJ

【 摘 要 】

Abstract Background Despite an enormous research effort, patients diagnosed with advanced colorectal cancer (CRC) still have low prognosis after surgical resection and chemotherapy. The major obstacle for CRC treatment is chemoresistance to front line anti-cancer drugs, such as 5-fluorouracil (5-FU) and oxaliplatin. However, the mechanism of chemoresistance to these drugs remains unclear. Methods Cell viability to 5-FU and oxaliplatin was measured by the CellTiter-Glo® 2.0 Cell Viability Assay. The endogenous REV7 protein in CRC cells was detected by western blotting. The translesion synthesis (TLS) events were measured by plasmid-based TLS efficiency assay. Cell apoptosis was evaluated by caspase3/7 activity assay. The in vivo tumor progression was analyzed by HT29 xenograft mice model. Results In this study, we found that expression of REV7, which is a key component of translesion synthesis (TLS) polymerase ζ (POL ζ), is significantly increased in both 5-FU and oxaliplatin resistant CRC cells. TLS efficiency analysis revealed that upregulated REV7 protein level results in enhanced TLS in response to 5-FU and oxaliplatin. Importantly, inhibition of REV7 by CRISPR/Cas9 knockout exhibited significant synergy with 5-FU and oxaliplatin in cell culture and murine xenograft model. Conclusion These results suggest that combination of REV7 deficiency and 5-FU or oxaliplatin has strong inhibitory effects on CRC cells and identified REV7 as a promising target for chemoresistant CRC treatment.

【 授权许可】

Unknown