Blocking of CDC25B suppresses sarcoma progression via arresting cell cycle

Introduction

Despite advancements in local treatments such as surgery, chemotherapy, and radiotherapy have made successful progress in soft tissue sarcoma treatment, there are still disadvantages, such as postoperative recurrence, metastasis, poor prognosis, and poor chemotherapy efficacy in sarcoma (1-3). One of the key reasons for poor clinical outcomes is that most of the early soft tissue sarcoma has no obvious clinical symptoms, resulting in most patients in the advanced stage when diagnosed, missing the best period of radical surgical treatment and difficulty in getting the desired effect (4). Given these challenges, identifying novel diagnostic or therapeutic targets in sarcoma is of great significance for improving patient outcomes.

Cell division cycle protein 25B (CDC25B) is a member of the CDC25 phosphatases family (5). It has bispecific phosphatase activity and can catalyze the activation of cell cycle-dependent protein kinase (CDK), thereby regulating cell cycle progression and mitosis (6,7). Dysregulation of CDC25B in tumors can occur at multiple levels, including transcriptional, post-transcriptional, and post-translational regulation. Recent studies have shown that CDC25B is abnormally expressed in various malignant tumors, influencing the growth, proliferation, and migration of tumors (8-10). In gastric cancer, inhibition of CDC25B reduces the expression of CDC25B, thus affecting the rate of proliferation, migration, and invasion of gastric cancer cells, and blocking the cell cycle, ultimately slowing tumor progression (11). In liver cancer, CDC25B, as an oncogene, promotes tumor cell growth and migration, inhibition of CDC25B expression and activity lead to suppression of tumor cell growth by arresting G2 phage (12). Aressy et al. (13) demonstrated that CDC25B regulates growth inhibition and apoptosis of colorectal cancer cells through regulating cell cycle and in the checkpoint response to DNA damage. In non-small cell lung carcinoma, CDC25B plays a vital role in the angiogenic process and in determining the prognosis of patients (14). However, its role in sarcoma remains largely unexplored.

This study aimed to investigate the expression and functional role of CDC25B in sarcoma, and evaluate the effects of CDC25B inhibition on tumor progression. Our findings may provide new insights into the potential of CDC25B as a diagnostic biomarker and therapeutic target for sarcoma. We present this article in accordance with the TRIPOD, MDAR, and ARRIVE reporting checklists (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2328/rc).

Methods

Data acquisition and processing

RNA sequencing data and clinical information of sarcoma samples were downloaded from The Cancer Genome Atlas (TCGA; https://portal.gdc.cancer.gov/) and Gene Expression Omnibus (GEO; GSE21122; https://www.ncbi.nlm.nih.gov/geo/). The databases contain basic information, clinical characteristics, and survival results of sarcoma patients. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Bioinformatics analysis

The correlation between CDC25B expression and survival outcomes was analyzed using R software (4.2.0) by Kaplan-Meier (KM) analysis “survival” and “ggplot2” packages. The differences between different groups were analyzed by the Wilcoxon rank-sum test in R software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to identify the enriched in genes using the “clusterProfiler” package. Gene set enrichment analysis (GSEA) was then applied to identify potential pathways affected by genes using the “clusterProfiler” package. Area under the curve (AUC) of receiver operating characteristic (ROC) was analyzed by R software to evaluate the prediction effect of CDC25B in sarcoma. An AUC value greater than 0.5 indicates a significant predictive effect. Prognostic value was further assessed through univariate and multivariate Cox regression analyses. Univariate Cox analysis examined the impact of individual covariates on survival time, identifying significant factors affecting survival. Covariates with a P value less than 0.05 in the univariate analysis were subsequently included in the multivariate Cox analysis, which simultaneously evaluated multiple covariates to more accurately determine independent prognostic factors and their relative importance. Risk score analysis was conducted to explore the relationships between CDC25B expression, risk scores, and survival time. Finally, a nomogram and calibration curves were constructed to validate the predictive accuracy of CDC25B in sarcoma patient outcomes, providing a comprehensive assessment of its prognostic utility.

Cell culture

Sarcoma cell lines SW872 and HT1080 were purchased from the Typical Culture Preservation Committee of the Chinese Academy of Sciences. Cells were cultured in Dulbecco’s Modified Eagle Medium (DMEM; Procell, Wuhan, China) medium supplemented with 10% fetal bovine serum (FBS; Procell) and 1% penicillin/streptomycin (Procell) under a 5% CO₂ atmosphere at 37 ℃.

Cell Counting Kit-8 (CCK-8) assay

SW872 and HT1080 cells were inoculated on 96-well plates (3×10³ cells/well), and treated with varying concentrations of CDC25B-IN-1 (MedChemExpress, Monmouth Junction, NJ, USA) for 72 hours. Following treatment, CCK-8 reagent was added to each well and incubated for 2 hours at 37 ℃, and absorbance value was measured at 450 nm to assess cell viability.

Quantitative polymerase chain reaction (qPCR) detection

SW872 and HT1080 cells were inoculated on six-well plates (2×10⁵ cells/well), and treated with dimethyl sulfoxide (DMSO) or CDC25B-IN-1 for 48 hours. Total RNA was extracted using RNA Easy Fast Cell Kit (Tiangen, Beijing, China) following the manufacturer’s instructions. Complementary DNA (cDNA) synthesis was performed by reverse transcription using the ABScript II cDNA First-Strand Synthesis Kit (Abclonal, Wuhan, China). The expression of CDC25B in SW872 and HT1080 cells was quantified using the 2× Universal SYBR Green Fast qPCR Mix. The following primer sequences were used for amplification: CDC25B (forward: 5'-CATCCGAATCCTCCCTGTCG-3', reverse: 5'-TCTGATGGCAAACTGCTCGT-3') and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (forward: 5'-TGACATCAAGAAGGTGGTGAAGCAG-3', reverse: 5'-GTGTCGCTGTTGAAGTCAGAGGAG-3'). GAPDH served as an internal control to normalize gene expression levels.

5-ethynyl-2'-deoxyuridine (EdU) assay

SW872 and HT1080 cells were inoculated on 24-well plates (1×10⁵ cells/well), and treated with DMSO or CDC25B-IN-1 for 24 hours. After culture with 10 μM EdU for 2 hours, cells were fixed with 4% paraformaldehyde for 30 min, and stained nucleus with Hoechst 33342. The results were evaluated and captured under the fluorescence microscope.

Colony formation

SW872 and HT1080 cells were inoculated with 600 cells/well in six-well plates, and cultured with 5 mL completed medium which containing DMSO or CDC25B-IN-1 for 6 days. Then, cells were fixed with 4% paraformaldehyde for 30 min, and stained 1% crystal purple for 30 min. The colonies more than 50 cells were counted under the microscope.

Wound healing assay

SW872 and HT1080 cells were inoculated with 5×10⁵ cells/well in six-well plates. The cells were scratched in the center of the hole with a 200 µL tip, followed by washing with pre-cooled phosphate-buffered saline (PBS; Beyotime, Shanghai, China). Cells were then cultured in FBS-free medium containing DMSO (Abmole, Houston, TX, USA) or CDC25B-IN-1, and the wound closure was monitored and photographed under a microscope in 0 and 36 hours.

Transwell assay

SW872 and HT1080 cells were pretreated with DMSO or CDC25B-IN-1 for 24 hours, then re-suspended with serum-free medium in the upper layer with 5×10⁴ cells/well. A complete medium of 600 µL was added into the lower chamber. After 24 hours of incubation, cells were fixed with 4% paraformaldehyde for 30 min and stained with 1% crystal purple for 30 min. A sterile cotton swab was used to wiped the residual cells in the upper chamber, and the results were calculated under the microscope.

Flow cytometry

Cell cycle and cell apoptosis were assayed by flow cytometry method. SW872 and HT1080 cells were inoculated with 2×10⁵ cells/well in six-well plates, and treated with DMSO or CDC25B-IN-1 for 48 hours. The Cell Cycle and Apoptosis Analysis Kit (Beyotime) was used to detect cell cycle changes. The Annexin V-FITC Apoptosis Detection Kit (Beyotime) was used to detect cell apoptosis changes.

Western blot (WB)

SW872 and HT1080 cells were inoculated with 2×10⁵ cells/well in six-well plates, and treated with DMSO or CDC25B-IN-1 for 48 hours. The Membrane and Cytosol Protein Extraction Kit (Beyotime) was used to extract cell protein, and protein concentration was determined using the bicinchoninic acid (BCA) assay​ (Epizyme, Shanghai, China). A protocol was prepared before the study without registration. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE; Epizyme) gel electrophoresis was performed with 30 µg protein per gel hole, and then transferred to the polyvinylidene difluoride (PVDF; Millipore, Massachusetts, MA, USA) membrane. Then, the membrane was blocked by QuickBlock™ Blocking Buffer (Beyotime) for 30 min, then incubated with primary antibody cyclin D1 (1:1,000; Affinity, Centennial, CO, USA), CDK4 (1:1,000; Affinity), and GAPDH (1:10,000; Affinity) overnight. After that, the secondary antibody was used to incubate the membrane for 1 hour, and then the BeyoECL Moon Kit (Beyotime) was used to evaluate the protein bands. Finally, Image J software was used to analyze the results.

Nude mouse xenograft model

All animal experiments were performed under a project license (No. 2020-0013) granted by the Ethics Committee of Fujian Medical University, in compliance with Chinese national guidelines for the care and use of animals. Five-week-old female BALB/c nude mice were purchased from Charles River (Beijing, China). Approximately 2×10⁶ H1080 cells were inoculated subcutaneously into the flanks of nude mice. When the tumors grew to 200 mm³, the mice were randomly divided into two groups, and treated with DMSO or CDC25B, respectively. Tumor length, width, and body weight were measured after the mice were sacrificed.

Statistical analysis

R software (version 4.2.0) and GraphPad Prism9 (GraphPad Software, San Diego, CA, USA) software were used to analyze the associations between the expression of CDC25B and the clinicopathologic features of sarcoma. Differences between the two groups were evaluated using an independent sample t-test, with statistical significance set at P<0.05.

Results

CDC25B expression in sarcoma and its prognostic significance

The results of the TCGA and GEO databases revealed that CDC25B expression is significantly upregulated in sarcoma compared normal tissues (Figure 1A,1B). Furthermore, high expression of CDC25B is associated with poor overall survival across multiple tumor types (Figure 1C). The KM analysis of CDC25B in the sarcoma database showed that high CDC25B expression presents worse survival outcomes in sarcoma patients (Figure 1D; P<0.05).

Figure 1 The expression levels of CDC25B in sarcoma tissues. (A) The mRNA expression levels of CDC25B in pan-cancers samples from TCGA database. (B) The expression levels of CDC25B in sarcoma database from the GSE21122 dataset. (C) The overall survival analysis of CDC25B in pan-cancers samples from the TCGA database. (D) The KM survival analysis showed that high expression of CDC25B associated with poor DSS, PFI, and OS in sarcoma. *, P<0.05; **, P<0.01; ***, P<0.001. The full name of the TCGA abbreviations sees the website: https://gdc.cancer.gov/resources-tcga-users/tcga-code-tables/tcga-study-abbreviations. CDC25B, cell division cycle protein 25B; CI, confidence interval; DSS, disease-specific survival; HR, hazard ratio; KM, Kaplan-Meier; mRNA, messenger RNA; OS, overall survival; PFI, progress-free interval; TCGA, The Cancer Genome Atlas.

Association between CDC25B expression and clinical parameters

To further explore the clinical significance of CDC25B, we analyzed its correlation with clinical parameters using the TCGA sarcoma dataset. The results showed that high expression of CDC25B was significantly associated with tumor necrosis (P=0.02), but was not correlated with age, gender, race, residual tumor, tumor multifocal, tumor depth, metastasis, margin status, and radiation therapy (Figure 2A). Additionally, the ROC curve analysis demonstrated that CDC25B has moderate predictive accuracy for sarcoma prognosis, with AUC values of 0.650 for 3-year survival and 0.627 for 5-year survival (Figure 2B).

Figure 2 Associations between CDC25B expression and clinicopathologic variables. (A) High expression of CDC25B is related to tumor necrosis in sarcoma. (B) ROC curve showed that CDC25B expression has predictive value for sarcoma prognosis. AUC, area under the curve; FPR, false positive rate; CDC25B, cell division cycle protein 25B; ROC, receiver operating characteristic; TPM, transcripts per million; TPR, true positive rate.

Prognostic value of CDC25B expression in sarcoma

The univariate analysis found that residual tumor, tumor multifocal, metastasis, margin status, and CDC25B expression are negatively associated with survival outcomes in sarcoma patients. Moreover, the multivariate analysis identified that metastasis and CDC25B as independent risk factors for poor prognosis in patients with sarcoma (Figure 3A). As shown in Figure 3B, the risk score analysis found that high expression of CDC25B presents a higher risk score and lower survival time. The nomogram confirmed that CDC25B expression has prognostic value in sarcoma patients (Figure 3C), and calibration curves validated the predictive accuracy of the nomogram for patient outcomes (Figure 3D).

Figure 3 Univariate and multivariate Cox hazard regression analysis, and nomogram evaluation of CDC25B in sarcoma from the TCGA database. (A) Univariate and multivariate Cox hazard regression analysis found that metastasis and CDC25B expression are independently associated with clinical outcomes of sarcoma patients. (B) The risk scores analysis found that high expression of CDC25B correlates with high-risk group. (C) Nomogram evaluation based on clinicopathological variables. (D) Calibration curves for the nomogram demonstrate the accuracy of CDC25B in predicting patient outcomes. CDC25B, cell division cycle protein 25B; CI, confidence interval; HR, hazard ratio; TCGA, The Cancer Genome Atlas.

Inhibition of CDC25B expression reduces sarcoma proliferation

The effects of cell proliferation by CDC25B blocking (CDC25B-IN-1) in vitro were assessed using CCK-8, EdU, and colony formation methods. As shown in Figure 4A, the chemical structure of CDC25B-IN-1 has been demonstrated. After treatment with different concentrations of CDC25B-IN-1 for 72 hours, cell viability of SW872 and HT1080 significantly decreased in a dose-dependent manner (Figure 4B). Further, we used half-maximal inhibitory concentration (IC₅₀) to explore the effect of CDC25B-IN-1 in SW872 and HT1080 cell survival conditions, and results indicated that cell survival was restrained after being treated with CDC25B-IN-1 for 72 hours (Figure 4C). The qPCR results confirmed that CDC25B-IN-1 treatment significantly reduced CDC25B expression (Figure 4D). Additionally, EdU and colony formation assays showed that CDC25B-IN-1 suppressed the proliferation ability in SW872 and HT1080 cells (Figure 5).

Figure 4 Cell viability changes in SW872 and HT1080 cells after CDC25B blocking. (A) CDC25B-IN-1 chemical structure. (B) The cell viabilities were suppressed in SW872 and HT1080 cells after CDC25B-IN-1 treatment. (C) The cell survival was inhibited in SW872 and HT1080 cells after treated with CDC25B-IN-1 for 72 hours (cells were photographed under a microscope). (D) CDC25B-IN-1 treatment significantly reduced CDC25B expression in SW872 and HT1080 cells. ***, P<0.001. CDC25B, cell division cycle protein 25B; DMSO, dimethyl sulfoxide; IC₅₀, half-maximal inhibitory concentration; mRNA, messenger RNA.

Figure 5 The proliferation ability changes in SW872 and HT1080 cells after CDC25B blocking. (A) EdU assay showed that CDC25BIN-1 treatment suppresses the proliferation ability in SW872 and HT1080 cells (stained nucleus with Hoechst 33342). (B) Colony formation assay showed that CDC25B-IN-1 can reduce the formation of colonies in SW872 and HT1080 cells (stained with 1% crystal purple). ***, P<0.001. CDC25B, cell division cycle protein 25B; DMSO, dimethyl sulfoxide; EdU, 5-ethynyl-2'-deoxyuridine.

Inhibition of CDC25B expression reduces sarcoma cell migration, invasion, tumor growth in vivo, and promotes cell apoptosis

The migration and invasion abilities of SW872 and HT1080 cells were further examined by transwell assay, and the results showed that CDC25B inhibition significantly suppressed cell migration and invasion capabilities of these cells (Figure 6A). Moreover, the wound healing assay found that compared with the DMSO group, CDC25B-IN-1 intervention can inhibit the wound healing ability of SW872 and HT1080 cells (Figure 6B). The cell apoptosis detection revealed that CDC25B inhibition can promote cell apoptosis in SW872 and HT1080 cells (Figure 6C). The nude mouse xenograft model experiment found that CDC25B-IN-1 intervention can reduce tumor growth in vivo (Figure 6D).

Figure 6 The migration, invasion, cell apoptosis and tumor growth changes in SW872 and HT1080 cells after CDC25B blocking. (A) Transwell assay showed that migration and invasion ability are repressed in SW872 and HT1080 cells after CDC25B blocking (stained with 1% crystal purple). (B) Wound healing found that CDC25B-IN-1 treatment inhibits migration in SW872 and HT1080 cells. (C) The flow cytometry assay demonstrated that CDC25B-IN-1 treatment promotes cell apoptosis in SW872 and HT1080 cells. (D) The nude mouse xenograft model confirmed that CDC25B-IN-1 treatment can reduce tumor growth in vivo. ***, P<0.001. CDC25B, cell division cycle protein 25B; DMSO, dimethyl sulfoxide; PI, propidium iodide.

CDC25B expression regulates sarcoma progression through the cell cycle

To explore the mechanism through which CDC25B expression affects sarcoma progression, we conducted GO: KEGG and gene set enrichment analysis (GSEA). The biological process (BP) analysis found that regulation of mitotic cell cycle phase transition, regulation of cell cycle phase transition, regulation of mitotic cell cycle, mitotic cell cycle phase transition, negative regulation of cell cycle process, DNA-templated DNA replication, and DNA replication are enriched. The KEGG results found that cell cycle and DNA replication are enriched (Figure 7A). The GSEA analysis confirmed that cell cycle and DNA replication are enriched (Figure 7B). The results of the WB found that cyclin D1 and CDK4 proteins decreased after CDC25B was blocked by CDC25B-IN-1 (Figure 7C). In addition, the cell cycle detection showed that CDC25B-IN-1 treatments increased the G2 stage percent in SW872 and HT1080 cells (Figure 7D), which confirmed that CDC25B expression regulates cell cycle in sarcoma.

Figure 7 CDC25B suppresses sarcoma progression by arresting the cell cycle. (A) The GO: KEGG analysis showed that the cell cycle and DNA replication-related pathway are enriched. (B) GSEA analysis also found that the cell cycle and DNA replication are enriched. (C) The WB analysis revealed that the expression of cell cycle-related proteins cyclin D1 and CDK4 were decreased in SW872 and HT1080 cells after CDC25B blocking. (D) The cell cycle detection showed that CDC25B-IN-1 treatments increased the G2 stage proportion in SW872 and HT1080 cells. ***, P<0.001. BP, biological process; CDC25B, cell division cycle protein 25B; CDK, cycle-dependent protein kinase; DMSO, dimethyl sulfoxide; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GO, Gene Ontology; GSEA, gene set enrichment analysis; KEGG, Kyoto Encyclopedia of Genes and Genomes; WB, western blot.

Discussion

Sarcoma represents a group of highly heterogeneous malignancies that originate from mesenchymal tissue (15,16). Despite advances in treatment, the prognosis for patients with advanced soft tissue sarcoma remains poor. Therefore, identifying novel biomarkers is of great importance for improving the prognosis of sarcoma patients. In this study, we found that CDC25B is overexpressed in sarcoma, and its upregulation is significantly related to poor prognosis of sarcoma patients, and blocking CDC25B expression can effectively suppress sarcoma progression.

However, the exact mechanisms by which CDC25B regulates sarcoma cell progression remain unclear. CDC25B is a member of the cell cycle regulation protein family, which plays an important role in regulating the cell cycle and is a critical molecule in the transition of each phase. The rate of cell cycle progression directly affects cellular processes such as proliferation, differentiation, growth, repair, and regeneration (17-19). Dysregulation of the cell cycle is a hallmark of tumorigenesis, progression, and metastasis (20,21). Our study found that cell cycle-related proteins cyclin D1 and CDK4 were upregulated in SW872 and HT1080 cells after being treated with CDC25B-IN-1, suggesting that the cell cycle arrest occurred upon CDC25B inhibition. This finding aligns with previous research in other cancers. In cervical cancer, CDC25B was highly expressed and can regulate cell cycle progression through YTHDF1-dependent m6A modification (22). In breast cancer, CDC25B dephosphorylation decreased levels of cyclin proteins, and ultimately induced cell cycle arrest at the G2/M phase (23). In gastric cancer, E2F1 could activate CDC25B transcription to regulate the MAPK pathway and enhance the proliferation and stemness of gastric cancer cells (24). Additionally, two other members of the CDC25 family, CDC25A and CDC25C also play crucial role in sarcoma. Martinez-Font et al. (25) confirmed that impact of Wnt/β-catenin inhibition on cell proliferation through CDC25A downregulation in soft tissue sarcomas. Inoue et al. (26) reported that AURKA/PLK1/CDC25C axis as a novel therapeutic target in INI1-deficient epithelioid sarcoma. In our study, the GO, KEGG, and GSEA analysis found significant enrichment in DNA replication and cell cycle, and WB analysis further confirmed that cell cycle-related proteins cyclin D1 and CDK4 are decreased after CDC25B inhibition which suggesting that CDC25B expression regulating cell cycle to play function. Certainly, our future studies will further explore the knockdown role of CDC25B in sarcoma.

Conclusions

In brief, our study highlights that CDC25B may serve as an independent prognostic factor in sarcoma, and could be a promising therapeutic target in sarcoma through the regulation of the G2 cell cycle. Our study provides a solid foundation for further investigation into the biological functions of CDC25B in soft tissue sarcoma, paving the way for the development of targeted therapies to improve patient outcomes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the TRIPOD, MDAR and ARRIVE reporting checklists. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2328/rc

Data Sharing Statement: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2328/dss

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2328/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2328/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. All animal experiments were performed under a project license (No. 2020-0013) granted by the Ethics Committee of Fujian Medical University, in compliance with Chinese national guidelines for the care and use of animals.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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