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

Ying Wang; Xuebing Yan; Xiao Qu; Jingxian Mao; Jiaxin Wang; Mengxue Yang; Min Tao

doi:10.1016/j.prp.2022.154287

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

Pathol Res Pract. 2023 Jan:241:154287. doi: 10.1016/j.prp.2022.154287. Epub 2022 Dec 21.

Authors

Ying Wang¹, Xuebing Yan², Xiao Qu³, Jingxian Mao², Jiaxin Wang², Mengxue Yang², Min Tao⁴

Affiliations

¹ Department of Oncology, the First Affiliated Hospital of Soochow University, Soochow University, Suzhou, China.
² Department of Oncology, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China.
³ Department of Gastrointestinal Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
⁴ Department of Oncology, the First Affiliated Hospital of Soochow University, Soochow University, Suzhou, China. Electronic address: taomin@suda.edu.cn.

PMID: 36586311
DOI: 10.1016/j.prp.2022.154287

Abstract

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 xenografts. 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.

Keywords: Biomarker and prognosis; Colorectal cancer; Epithelial-mesenchymal transition; Topoisomerase IIβ binding protein 1.

MeSH terms

Cell Line, Tumor
Cell Movement
Cell Proliferation
Colorectal Neoplasms* / pathology
Disease-Free Survival
Epithelial-Mesenchymal Transition
Gene Expression Regulation, Neoplastic
Humans
Prognosis
Retrospective Studies

Substances

TOPBP1 protein, human