Abstract
Background
In bladder cancer, up to 70% of patients will relapse after resection within 5 years, in which the mechanism underlying the recurrence remains largely unclear.
Methods
Quantitative real-time PCR, western blot and immunohistochemistry were conducted. The assays of tumor sphere formation and tumor xenograft were further performed to assess the potential biological roles of ATF5 (activating transcription factor 5). Chromatin immunoprecipitation-qPCR and luciferase activity assays were carried out to explore the potential molecular mechanism. A two-tailed paired Student's t-test, χ2 test, Kaplan Meier and Cox regression analyses, and Spearman's rank correlation coefficients were used for statistical analyses.
Results
ATF5 is elevated in bladder urothelial cancer (BLCA) tissues, especially in recurrent BLCA, which confers a poor prognosis. Overexpressing ATF5 significantly enhanced, whereas silencing ATF5 inhibited, the capability of tumor sphere formation in bladder cancer cells. Mechanically, ATF5 could directly bind to and stimulate the promoter of DVL1 gene, resulting in activation of Wnt/β-catenin pathway.
Conclusions
This study provides a novel insight into a portion of the mechanism underlying high recurrence potential of BLCA, presenting ATF5 as a prognostic factor or potential therapeutic target for preventing recurrence in BLCA.
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Background
Globally, bladder cancer is the 10th most prevalent cancer type, with about 549,000 newly diagnosed patients in 2018 [1]. Unfortunately, up to 70% of these patients will relapse upon transurethral resection of bladder cancer [2], which greatly increases the suffering of patients.
Cancer recurrence is highly associated with cancer cell drug resistance and high tumorigenic capability [3]. Moreover, these characteristics could be examined in a small cell subpopulation in bladder cancer tissue, which are called the cancer stem cells (CSC) or the tumor initiating cells (TICs) [3,35, 36]. Abnormal activations of this pathway can lead to unrestrained cells proliferation and malignant transformation [35, 36]. As one of the most relevant pathways associated with TICs, this pathway is often abnormally stimulated in various cancers, including bladder cancer [13, 37]. Stimulation of Wnt/β-catenin pathway by miR-543-3p could increase [38], whereas inhibition of this signaling by miR-139-5p may inhibit [39] TIC-like phenotype of BLCA cells, supporting the vital roles of Wnt/β-catenin pathway in regulating TIC-like phenotype of bladder cancer. Consistent with these studies, we detected that Wnt/β-catenin signaling was abnormally activated in BLCA. We showed that ATF5 could directly target and positively regulate DVL1, leading to the stimulation of Wnt/β-catenin signaling.
DVL1, as a main component of the Wnt pathway, takes part in transduction of Wnt signals to β-catenin, and then stimulates downstream effector factors [40]. In this study, we found that ATF5 could directly bind to DVL1 promoter and stimulate its expression, and then activate the downstream genes of the Wnt/β-catenin pathway, including active β-catenin, MYC, CD44, JUN as well as CCND1, whereas down-regulating ATF5 reduced the expression of DVL1 and these factors. These findings demonstrate a novel mechanism underpinning hyperactivation of the Wnt/β-catenin pathway in BLCA. Herein, this study indicates that ATF5 could simulate the Wnt/β-catenin pathway and promote tumorigenic capability.
Conclusion
The present study reveals that overexpression of ATF5 in BLCA directly promotes DVL1 expression and stimulates the Wnt/β-catenin signaling, therefore increasing tumorigenicity, enhancing a TIC-like phenotype as well as predicting poor survival. Evaluation of the role of ATF5 in BLCA will broaden our understanding of the mechanism underpinning the high recurrence rate of BLCA, and establish whether ATF5 serves as a prognosis marker or potential treatment target for BLCA recurrence.
Availability of data and materials
The public datasets of BLCA in NCBI (https://www.ncbi.nlm.nih.gov/gene/); gene set enrichment analysis software program (GSEA, http://software.broadinstitute.org/gsea/msigdb/index.jsp).
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This work was supported by National Natural Science Foundation of China (No. 81902991), Guangzhou Science and Technology Planning Project (No. 202102021056) and Youth Project of The Third Affiliated Hospital of Southern Medical University (No. QD2019N010).
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LCD and ZT designed the study. ZJH, TH and ZX carried out the experiments of cytobiology. XZY, CTY and YHY conducted the follow-up study. CQ, YJK and ZQZ participated in acquisition of data. XKY, WHY and CMK took part in collection of clinical samples. GWB, XM and BJM analyzed the experimental data. ZJH drafted the manuscript. YC, DHF and HZP participated in the revising of the manuscript. All authors read and approved the final manuscript.
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This study involved in human specimens was approved by the Clinical Trials Ethics Committee (The Third Affiliated Hospital of Southern Medical University, and Affiliated Cancer Hospital & Institute of Guangzhou Medical University). This study involved in animals was approved by the Ethics Committee of Experimental Animals, Southern Medical University.
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Zhou, J., Tian, H., Zhi, X. et al. Activating transcription factor 5 (ATF5) promotes tumorigenic capability and activates the Wnt/b-catenin pathway in bladder cancer. Cancer Cell Int 21, 660 (2021). https://doi.org/10.1186/s12935-021-02315-x
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DOI: https://doi.org/10.1186/s12935-021-02315-x