Topoisomerase II beta binding protein 1 serves as a novel prognostic biomarker for stage II-III colorectal cancer patients

Background: Colorectal cancer (CRC) is a commonly diagnosed human malignancy worldwide. Accumulating evidence has suggested DNA repair related proteins widely participate in CRC initiation and development. TOPBP1 is recently identified as a novel regulator for DNA repair, however, its biological role in CRC remains unknown.Methods: Firstly, the bioinformatics analysis was utilized to investigate the expression and clinical significance of TOPBP1 in CRC patients. Then, a retrospective study enrolling 129 stage II/III CRC patients was performed for validation. The CCK-8, colony formation, transwell assay and xenograft model were used to clarify the biological impact of TOPBP1 on CRC cells. Finally, transcriptome sequencing was performed to investigate the potential oncogenic mechanisms regulated by TOPBP1 in CRC development.Results: The expression of TOPBP1 was significantly higher in CRC tissues than that in normal tissues. High TOPBP1 expression was an independent unfavorable prognostic factor for overall and disease-free survival in II/ III CRC patients. Knockdown of TOPBP1 not only significantly inhibited the proliferation, colony formation, invasion, migration and epithelial-mesenchymal transition (EMT) molecular phenotype of CRC cells, while the opposite was for TOPBP1 expression. Moreover, knockdown of TOPBP1 slowed down the growth speed of xe-nografts. The transcriptome sequencing identified MAP3K3 as a downstream gene of TOPBP1 and MAP3K3 knockdown inhibited the EMT molecular phenotype in CRC cells. Finally, the rescue assay indicated MAP3K3 overexpression counteracted the inhibitory effect of TOPBP1 knockdown on the proliferation, colony formation, invasion, migration and EMT phenotype of CRC cells.Conclusion: TOPBP1 promotes the malignant progression of CRC through MAP3K3 induced EMT. TOPBP1 is a promising clinical biomarker or therapeutical target for CRC patients.

Automated summary

In this study, researchers found that the expression of DNA repair-related protein TOPBP1 was significantly increased in colorectal cancer (CRC), and high TOPBP1 expression was associated with poor prognosis. TOPBP1 promotes the malignant progression of CRC through MAP3K3-induced epithelial-mesenchymal transition (EMT).