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Role of cell division cycle associated 2 in ovarian cancer: Effects on tumor progression and cisplatin resistance
*Corresponding author: Wei Li, Department of Oncology, Affiliated Hospital of Jining Medical University, Jining, China. 17853795986@139.com
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Received: ,
Accepted: ,
How to cite this article: Jin Y, Xu X, Li W. Role of cell division cycle associated 2 in ovarian cancer: Effects on tumor progression and cisplatin resistance. CytoJournal. 2025;22;81. doi: 10.25259/Cytojournal_59_2025
Abstract
Objective:
Ovarian cancer is a disease that seriously endangers the health and life safety of women. At present, no effective preventive and therapeutic measures are available. This study probed the impact of cell division cycle-associated 2 (CDCA2) on ovarian cancer development and cisplatin sensitivity, which provides a new research direction for the study of ovarian cancer.
Material and Methods:
The protein expression level of CDCA2 was tested by Western blot assay. Cell proliferation was evaluated by cell cloning formation assay and Celigo cell counting. Cell invasion and migration were assessed by Transwell assay. An experiment for nude mouse tumor formation was conducted to analyze the influence of CDCA2 knockdown on tumor growth in vivo. We treated CDCA2 knockdown cells with gradient cisplatin and measured cell viability using the cell counting kit-8 assay. Apoptosis and DNA damage induced by CDCA2 knockdown were investigated by flow cytometry and histone family member X (H2AX) phosphorylated on Ser 139 (γ-H2AX) immunofluorescence, respectively.
Results:
CDCA2 expression was knocked down in A2780 and SKOV3 cells. After CDCA2 knockdown, cell proliferation, migration, and invasion ability decreased significantly, and tumor growth in vivo was also limited (P < 0.01). The phosphorylation levels of protein kinase B (AKT) and mechanistic target of rapamycin (mTOR) were reduced by CDCA2 knockdown (P < 0.01), but the effect was reversed by the AKT activator SC-79 (P < 0.01). Knockdown of CDCA2 increased the cisplatin sensitivity of ovarian cancer cells by enhancing apoptosis and DNA damage (P < 0.01).
Conclusion:
CDCA2 knockdown inhibited the development of ovarian cancer through the AKT/mTOR pathway and enhanced cisplatin sensitivity. CDCA2 is a potential target to reverse cisplatin resistance in ovarian cancer. It can also be used as a new research direction for the development of ovarian cancer therapy.
Keywords
Cell division cycle associated 2
Cell proliferation
Cisplatin resistance
Ovarian cancer
INTRODUCTION
Ovarian cancer, as a malignant tumor with high incidence in the female reproductive system, originates from ovarian tissue or oviduct epithelium. This type of cancer is common among women over 50 years old, but it can also occur in younger women.[1] At present, the treatment principle for ovarian cancer is mainly surgery and chemotherapy, with targeted therapy or immunotherapy as supplementary measures.[2] Although cisplatin-based chemotherapy is highly effective against ovarian cancer, the emergence of drug resistance greatly reduces its efficacy.[3,4] Post-operative recurrence rate of ovarian cancer patients is the main cause of treatment failure and death. The current challenges in ovarian cancer lie in decoding resistance mechanisms and prolonging long-term survival. Therefore, exploring the molecular biomarkers of ovarian cancer and studying the mechanism of chemotherapy resistance can provide theoretical references for developing effective prevention and treatment measures for ovarian cancer.
The close correlation between the proliferation of tumor cells and abnormal cell cycle has encouraged researchers to extensively investigate the cell division cycle-associated (CDCA) genes.[5-7] The expression of most genes in the CDCA family is positively correlated with DNA damage, cell proliferation, cell cycle, and DNA repair, which suggests that CDCA family genes may become novel markers of breast cancer.[8] In colorectal cancer, knockdown of CDCA2 and CDCA3 significantly reduces the proliferation of cancer cells.[9] Liu found that all CDCAs are expressed at high levels in lung cancer, and CDCA4 and CDCA5 can serve as biomarkers for the prognosis and diagnosis of lung cancer.[10] CDCA2 is located on chromosome 8 and has a vital function in the regulation of cell mitosis and DNA repair. CDCA2 is associated with the development, treatment, and prognosis of various tumors.[11,12] Zhang et al.’s research has shown that CDCA2 acts as an oncogene in prostate cancer, and knocking down CDCA2 reduces cancer cell proliferation and induces apoptosis.[13] Silencing CDCA2 inhibits the migration and proliferation ability of melanoma cells, which weakens the malignant progression of melanoma.[14] High expression of CDCA2, CDCA3, CDCA5, and CDCA7 may be associated with poor ovarian cancer survival and poor prognostic accuracy, and patients with elevated CDCA2 expression have poorer progression-free survival and overall survival.[15] Therefore, we focus on the molecular mechanism of CDCA2 in ovarian cancer and have conducted research through relevant experiments.
Here, through in vivo and in vitro cytological experiments, the mechanism of CDCA2 in the proliferation, migration, and invasion of ovarian cancer cells was explored. The influence of CDCA2 on the cisplatin sensitivity was also studied. The aim was to provide a new strategy for treating ovarian cancer by targeting CDCA2.
MATERIAL AND METHODS
Ovarian cancer cells
HOSEpiC (ml096443), A2780 (mlCC-Y1557), SKOV3 (mlCC-Y1473), OV-56 (mlCC1616), and EFO27 (mlCC1958) were purchased from EK-Bioscience (Shanghai, China). Short tandem repeat identification and mycoplasma assay (negative) were performed to ensure cell quality. The cell culture medium was Roswell Park Memorial Institute 1640 (RPMI1640) medium (GNM-31800, GENOM BIO, Hangzhou, China), which contains 10% fetal bovine serum (FBS, GNMFBAC5, GENOM BIO, Hangzhou, China), and penicillin-streptomycin solution (GNM15140-1, GENOM BIO, Hangzhou, China), among others. The cells were cultured under sterile conditions at 37°C and 5% carbon dioxide (CO2).
CDCA2 knockdown
The transfection reagent (Lipofectamine 3000, Invitrogen, USA) was diluted with 250 μL serum-free medium, and small interfering (si)RNAs (si-NC:5’-UUCUCCGAACGUGUCACGUTT-3’; si-CDCA2: 5’-CACCUGCCUUUCUAAAUAUTT-3’, GenePharma, Shanghai, China) were added and incubated at room temperature for 15 min. After 48 h, Western blot was adopted to detect the transfection effect.
Western blot assay
The cells were cleaved by lysate (BL504A, Biosharp, Hefei, China) at 4°C and centrifuged at 12,000 rpm for 20 min. The 40 μg protein was used for sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and then, polyvinylidene fluoride membrane (BS-PVDF-22 and BS-PVDF-45, Biosharp, Hefei, China) transfer was performed. After transfer, diluted primary antibody was added (anti-glyceraldehyde-3-phosphate dehydrogenase: 1:10,000, SQab1878, Arigo; anti-CDCA2: 1:1,000, 17701-1-AP, Proteintech; anti-protein kinase B [AKT]: 1:1,000, ARG56418, Arigo; anti-phosphorylated AKT [p-AKT]: 1:1,000, 9018, cell signaling; anti-mechanistic target of rapamycin [mTOR]: 1:1,000, 2,983, cell signaling; and anti-phosphorylated mTOR [p-mTOR]: 1:1,000, 5,536, cell signaling) for incubation at 4°C overnight. After washing, the second antibody conjugated with horseradish peroxidase (1:10,000, AS063, ABclonal, Wuhan, China) was added and incubated for 2 h. Finally, electro chemiluminescent solution (BL523A, Biosharp, Hefei, China) was added for development, and the protein content was analyzed by ImageJ software (National Institutes of Health, USA).
Cell cloning formation assay
After digestion (ml095241, EK-Bioscience, Shanghai, China) of the logarithmic growth cells, the cells were re-suspended in a complete culture medium (10% FBS). A total of 400–1,000 cells/wells were seeded in a 6-well plate and continued to culture until the cell count was >50 in the vast majority of individual clones. After cloning, 1 mL of 4% paraformaldehyde (abs9179, Absin, Shanghai, China) was added to each well for 30–60 min. A total of 1 mL of crystal violet (abs42015934, Absin, Shanghai, China) was added to each well to stain the cells for 20 min. After washing, the cells were photographed (BX53, Olympus, Japan).
Celigo cell counting
Each group of cells (1.5 × 103 cells/well) was inoculated into 96-well plates. After routine culture, the number of green fluorescent cells was measured once a day by Celigo Image Cytometer (Nexcelom Bioscience, USA) for 5 consecutive days.
Transwell assay
The cells were inoculated into the upper chamber (serum-free medium) of the Transwell facility (3422, YuBo, Shanghai, China). After 2 days of culture at 37°C, the unmigrated cells were removed. The migrating cells were immersed in 4% paraformaldehyde and stained with crystal violet. The test of cell invasion ability involved applying 30 μL of Matrigel (354277, Corning, USA) to the bottom of the upper chamber. The following steps were the same as those of the migration experiment. The cells were photographed and counted under a microscope.
Cell counting kit-8 (CCK-8) assay
A total of 5 × 103 cells/100 μL were added to 96-well plates and cultured for 24 h. Gradient cisplatin solution was added, followed by incubation for 48 h. Each well was incubated with 10% CCK-8 (KTA1020, Abbkine, Wuhan, China) for 60 min. The absorbance was detected at 450 nm by an enzyme-labeled instrument (680, Bio-Rad, USA), and cell viability was calculated.
Flow cytometry
The cells were digested using routine pancreatic enzymes, and cell suspension was inoculated on a 6-well plate. Cells of the logarithmic stage were treated with cisplatin for 48 h. Cell suspension was prepared again and centrifuged to remove the supernatant. Annexin V-fluorescein isothiocyanate (V-FITC) and propidium iodide (Tb4101, Toscience Biotechnology, Shanghai, China) were added, followed by incubation for 15 min at room temperature away from light. Subsequently, the level of apoptosis was detected using a flow cytometer (FACSCalibur™, BD, USA).
Tumor xenograft in nude mice
Twelve female BALB/c nude mice (18–22 g, 4–6 weeks) were purchased from Henan Skobes (Anyang, China). They were kept in a barrier environment without specific pathogens at 26–28°C and 40–60% humidity. They were divided into the si-NC group and the si-CDCA2 group, with six mice in each group. A total of 0.5 mL of cell suspension transfected with si-NC and si-CDCA2 was injected into the subcutaneous armpit of nude mice. The tumor growth was observed every 3 days and measured with vernier calipers when the transplanted tumor was visible. After 5 weeks, the nude mice were killed using the CO2 method, and the tumors were collected. This animal experiment conforms to the principles of animal protection, animal welfare, and ethics as well as the relevant provisions of national experimental animal ethics.
Immunohistochemistry (IHC)
The tumors were embedded in paraffin and cut into 4 μm sections. The slices were dewaxed (R30148, Yuanye, Shanghai, China) and then successively placed into ethanol solutions of different concentrations for hydration. The sections were added with a dewaxed antigen repair solution (DAS-0011, Maixin, Fuzhou, China). Thereafter, the primary antibody (anti-CDCA2: 17701-1-AP, Proteintech; anti-Ki67: 27309-1-AP, Proteintech) was added at 4°C overnight, and the secondary antibody (AS014, ABclonal, Wuhan, China) was added at 37°C for 30 min. Diaminobenzidine (DAB-0031, Maixin, Fuzhou, China) and hematoxylin (CTS-1090, Maixin, Fuzhou, China) were added for dyeing. Subsequently, the resultant was dehydrated, rendered transparent, and neutrally sealed with gum. The staining intensity was determined by ImageJ software (National Institutes of Health, USA).
g-H2AX immunofluorescence
After 48 h of treatment with cisplatin, the cells were reacted with 4% paraformaldehyde and 0.2% Triton X-100 (T8200, Solarbio, Beijing, China). The cells were then blocked with goat serum for 1 h and incubated with primary antibody at 4°C overnight. Then, the cells were incubated with the secondary antibody (C2036s, Beyotime, Shanghai, China). Observation and photography were conducted using a confocal microscope (LSM 900, Zeiss, Germany).
Statistical analysis
The Statistical Package for the Social Sciences 21.0 was used for statistical analysis. Comparison between the two groups was performed by t-test. One-way analysis of variance was adopted for comparison among multiple groups. The data are presented as mean ± standard deviation. P < 0.05 was considered statistically significant.
RESULTS
CDCA2 knockdown blocked cell malignant progression of ovarian cancer cells
According to the GEPIA database, CDCA2 was overexpressed in ovarian cancer tissues (P < 0.05), [Supplemental Figure 1a]. However, abnormal expression of CDCA2 was not related to overall survival [Supplemental Figure 1b] and disease-free survival [Supplemental Figure 1c]. Here, the expression pattern of CDCA2 in ovarian cancer cells (A2780, SKOV3, OV-56, and EFO27) was verified by Western blot experiments. Overall, the elevated expression of CDCA2 was observed in ovarian cancer cell lines [Figure 1a], (P < 0.01). Two cell lines with relatively high expression levels of CDCA2, namely A2780 and SKOV3, were selected for functional experiments. In A2780 and SKOV3 cells, CDCA2 expression was successfully knocked down [Figure 1b], (P < 0.01). After the knockdown of CDCA2 expression, the effect of the alteration in CDCA2 expression on the proliferation was explored by cell cloning formation assay and Celigo cell counting. As shown in Figure 1c and d, the number of clones in the CDCA2 knockdown group was significantly lower than that in the si-NC group. In addition, CDCA2 knockdown hindered cell proliferation [Figure 1e-h], (P < 0.05). Furthermore, the cell invasion ability of the CDCA2 knockdown group was significantly lower than that of the si-NC group [Figure 2a and b], (P < 0.01). Similar results have been confirmed in cell migration experiments [Figure 2c and d], (P < 0.01). Therefore, inhibiting the expression of CDCA2 impeded the development of ovarian cancer.
- CDCA2 knockdown blocked the proliferation of ovarian cancer cells. (a) Relative expression of CDCA2 in ovarian cancer cells. (b) CDCA2 expression was knocked down in A2780 and SKOV3 cells. (c and d) Effect of CDCA2 knockdown on the cell clone formation. (e and f) Celigo cell counting assay displayed that knockdown of CDCA2 hindered the proliferation of A2780 cells (magnification: 400x, scale bar: 50 μm). (g and h) Celigo cell counting assay showed that knockdown of CDCA2 hindered the proliferation of SKOV3 cells (magnification: ×400, scale bar: 50 μm). ✶P < 0.05, ✶✶P < 0.01; n = 3. CDCA2: Cell division cycle associated 2, GAPDH: Glyceraldehyde-3-phosphate dehydrogenase, si-NC: Small interfering negative control.
- CDCA2 knockdown blocked the invasion and migration of ovarian cancer cells. (a and b) Transwell assay showed that knockdown of CDCA2 hindered the cell invasion (magnification: ×200, scale bar: 50 μm). (c and d) Transwell assay showed that knockdown of CDCA2 inhibited the cell migration (magnification: ×200, scale bar: 50 μm). ✶✶P < 0.01; n = 3. CDCA2: Cell division cycle associated 2, NC: Negative control.
CDCA2 knockdown blocked the tumor in vivo
The experiment for nude mouse tumor formation was conducted to analyze the influence of CDCA2 knockdown on tumor growth in vivo. The transplanted tumors of nude mice transfected with CDCA2 knockdown were significantly smaller than those of the si-NC group [Figure 3a], (P < 0.05). After 35 days, the tumors in the CDCA2 knockdown group were significantly smaller [Figure 3b] and lighter [Figure 3c], (P < 0.01) than those in the si-NC group. In addition, IHC showed low expression of Ki67 and CDCA2 [Figure 3d and e], (P < 0.01). Therefore, our data suggested that CDCA2 knockdown blocked tumor growth in vivo.
- CDCA2 knockdown blocked the tumor in vivo. (a) Tumor volume measured at different time points. (b) Representative images of the tumors. (c) Weight of tumors. (d) Representative IHC staining images of CDCA2 and Ki67 in tumor tissues (magnification: ×200, scale bar: 100 μm). (e) Statistics of positive cell rate. ✶P < 0.05, ✶✶P < 0.01; n = 6. CDCA2: Cell division cycle associated 2, IHC: Immunohistochemistry, NC: Negative control.
CDCA2 modulated the AKT/mTOR pathway
The effects of CDCA2 on AKT/mTOR pathway were investigated by Western blot. The levels of p-AKT and p-mTOR were reduced by CDCA2 knockdown, but they were neutralized by the AKT activator SC-79 [Figure 4a-d], (P < 0.01). Next, we discovered that the decrease in cell proliferation induced by CDCA2 knockdown was reversed by SC-79 [Figure 4e and f], (P < 0.05). Similarly, the decrease in cell invasion and migration induced by CDCA2 knockdown was also reversed by SC-79 [Figure 4g-j], (P < 0.05). Therefore, we speculated that CDCA2 may affect the development of ovarian cancer through the AKT/mTOR pathway.
- CDCA2 modulated the AKT/mTOR pathway. (a and b) The expression of p-AKT and p-mTOR in A2780 cells was detected by Western blot. (c and d) The expression of p-AKT and p-mTOR in SKOV3 cells was detected by Western blot. (e and f) Cell cloning formation assay. (g-j) Transwell assay (magnification: ×200, scale bar: 50 μm). ✶P < 0.05, ✶✶P < 0.01, compared with si-NC; &P < 0.05, &&P < 0.01, compared with si-CDCA2; n = 3. CDCA2: Cell division cycle associated 2, AKT: Protein kinase B, p-AKT: Phosphorylated AKT, mTOR: Mechanistic target of rapamycin, p-mTOR: Phosphorylated mTOR.
CDCA2 knockdown sensitized ovarian cancer cells to cisplatin
To further probe the effect of CDCA2 knockdown on cisplatin resistance, CDCA2 knockdown cells were treated with gradient cisplatin, and the cell viability was measured using CCK-8 after 24 h. CDCA2 knockdown decreased the IC50 of cisplatin from 13.28 μM to 6.26 μM in A2780 cells [Figure 5a], (P < 0.01) and from 24.28 μM to 14.46 μM in SKOV3 cells. [Figure 5b], (P < 0.01). Thereafter, we treated A2780 and SKOV3 cells with 10 and 20 μM cisplatin for 48 h, respectively. The results showed that the cloning ability of cells transfected with CDCA2 knockdown was reduced [Figure 5c-e], (A2780: P < 0.05; SKOV3: P < 0.01). Moreover, the apoptosis rate of cells transfected with CDCA2 knockdown was clearly increased [Figure 6a and b], (P < 0.01). Furthermore, higher levels of g-H2AX were observed in cells transfected with CDCA2 knockdown [Figure 6c-e], (P < 0.01). Here, we concluded that ovarian cancer cells with CDCA2 knockout exhibited enhanced sensitivity to cisplatin.
- CDCA2 knockdown sensitized ovarian cancer cells to cisplatin. (a and b) After 48 h treatment with different doses of cisplatin, CCK-8 was used to detect cell viability. (c-e) After cisplatin treatment, the cell growth was measured by cell cloning formation assay. ✶P < 0.05, ✶✶P < 0.01, compared with control; &P < 0.05, &&P < 0.01, compared with cisplatin; n = 3. CDCA2: Cell division cycle associated 2, CCK-8: Cell counting kit-8.
- CDCA2 knockout enhanced the sensitivity of ovarian cancer cells to cisplatin by regulating cell apoptosis and DNA damage. (a and b) After cisplatin treatment, the cell apoptosis was measured by flow cytometry. (c-e) After cisplatin treatment, the level of g-H2AX was detected by IF (magnification: ×400, scale bar: 100 μm). ✶✶P < 0.01, compared with control; &&P < 0.01, compared with cisplatin; n = 3. CDCA2: Cell division cycle associated 2, IF: Immunofluorescence.
DISCUSSION
Ovarian cancer, as a common malignant tumor of the female reproductive system, has high incidence. Owing to the unclear early symptoms and the lack of diagnostic markers, approximately 70% of ovarian cancer patients are already in the advanced stage when they are first diagnosed, which loses the best opportunity for surgery.[16] The occurrence of drug resistance stage in ovarian cancer is a key factor leading to low survival time. Accordingly, exploring new therapeutic targets for ovarian cancer is particularly important. Here, we studied the function of CDCA2 on cell progression and explored how it affects the cisplatin sensitivity of ovarian cancer cells.
CDCA2 is a cell cycle-related protein, and its abnormal expression can lead to the development of various tumors. In renal papillary cell carcinoma, CDCA2 expression was discovered to be closely related to the expression of immunostimulatory molecules, lymphocytes, chemokines, and immunosuppressive molecules.[17] In this study, we knocked down CDCA2 in A2780 and SKOV3 cells. The function of CDCA2 knockout on the proliferation behavior of ovarian cancer cells was verified by cell cloning formation assay and Celigo cell counting experiment. Meanwhile, the effect of CDCA2 knockdown on the metastasis behavior was preliminarily verified by Transwell results. Notably, the knockdown of CDCA2 exerted inhibitory effects on cell viability, invasion, and migration of ovarian cancer cells. Moreover, CDCA2 knockdown hindered the growth of transplanted tumors in vivo. Therefore, our results suggest that CDCA2 accelerates the malignant progression of ovarian cancer. Yu et al.’s study concluded that CDCA2 knockdown blocked the migration, proliferation, and invasion of glioma cells, which was similar to the conclusion of our study.[18] A similar study found that CDCA2 was clearly upregulated in gastric cancer and exerted a carcinogenic effect by reducing radiosensitivity and promoting cell proliferation.[19] CDCA2 is mainly enriched in mitosis, cell cycle, and DNA replication; it serves as a new biomarker for pan-cancer prognosis and diagnosis.[20] Overall, we concluded that CDCA2 also plays a catalytic role in ovarian cancer.
The AKT/mTOR pathway, as an important signaling pathway, regulates cell proliferation, migration, apoptosis, differentiation, and other cancer behaviors. CDCA2 knockdown decreased the phosphorylation levels of AKT and mTOR, but the effect was reversed by AKT activator SC-79. Subsequently, SC-79 also neutralized the inhibitory effect of CDCA2 silencing on the malignant cell progression. In liver cancer, the knockdown of CDCA2 also led to a reduction in the level p-AKT.[21] Furthermore, CDCA2 promoted the proliferation and reduced the radiosensitivity of gastric cancer cells by regulating the PI3K/AKT pathway.[19] Therefore, we speculated that CDCA2 knockdown impeded ovarian cancer progression by inhibiting AKT/mTOR pathway activation.
Cisplatin, as a first-line chemotherapy drug for ovarian cancer, mainly induces cell apoptosis by inducing DNA damage; it also involves DNA repair and inflammatory response.[22,23] Here, we treated cells with cisplatin and found that the apoptosis rate of cells transfected with CDCA2 knockdown was significantly increased, and g-H2AX showed higher levels. This result suggests that CDCA2 knockdown enhances the sensitivity of ovarian cancer cells through DNA damage. In oral squamous cell carcinoma, cisplatin sensitivity was improved in the CDCA2 knockdown group.[24] Wang’s research also yielded similar results: Knockdown of CDCA2 enhanced the chemosensitivity of hepatoma cells to cisplatin.[25] Therefore, CDCA2 has a certain value in studying the cisplatin resistance that occurs during the treatment of ovarian cancer.
Our research still has some shortcomings. First, this study is an in vitro cell experiment and does not involve clinical data. Second, the specific downstream signaling pathway of CDCA2 and its interaction with other carcinogenic factors still need to be further explored.
SUMMARY
CDCA2 knockdown in ovarian cancer inhibits tumor progression by regulating cell proliferation and metastasis. It also enhances cisplatin sensitivity. The potential of CDCA2 as a prognostic marker and therapeutic target warrants further investigation. Additional clinical validation is also needed to advance translational applications.
AVAILABILITY OF DATA AND MATERIALS
The data that support the findings of this study are available from the corresponding author upon reasonable request.
ABBREVIATIONS
AKT: Protein kinase B
CCK-8: Cell counting kit-8
CDCA2: Cell division cycle associated 2
FBS: Fetal bovine serum
IHC: Immunohistochemistry
mTOR: Mechanistic target of rapamycin
AUTHOR CONTRIBUTIONS
YYJ and XYX: Conducted the research and analyzed the data; WL: Provided assistance and suggestions for the experiments. All authors participated in the drafting and critical revision of the manuscript. All authors were fully involved in the work, able to take public responsibility for relevant portions of the content and agreed to be accountable for all aspects of the work, ensuring that any questions related to its accuracy or integrity are addressed. All authors have read and approved the final manuscript. All authors meet the ICMJE authorship requirements.
ACKNOWLEDGMENT
Not applicable.
ETHICS APPROVAL AND CONSENT TO PARTICIPATE
The animal experiments in this study were approved by the Medical Science Research Ethics Committee of the Affiliated Hospital of Jining Medical University (2025-02-B003). Consent to participate is not required as there are no human subjects in this study.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
EDITORIAL/PEER REVIEW
To ensure the integrity and highest quality of CytoJournal publications, the review process of this manuscript was conducted under a double-blind model (authors are blinded for reviewers and vice versa) through an automatic online system.
FUNDING: This study was supported by Jining Key Research and Development Project (Medical Research and Clinical Medicine) (No. 2023YXNS212).
References
- Epigenetic regulation in ovarian cancer. Int Rev Cell Mol Biol. 2024;387:77-98.
- [CrossRef] [PubMed] [Google Scholar]
- Heterogeneous treatment effect of dose-dense paclitaxel plus carboplatin therapy for advanced ovarian cancer. Int J Cancer. 2024;155:1068-77.
- [CrossRef] [PubMed] [Google Scholar]
- Therapeutic strategies to overcome cisplatin resistance in ovarian cancer. Eur J Med Chem. 2022;232:114205.
- [CrossRef] [PubMed] [Google Scholar]
- Molecular mechanisms of platinum-based chemotherapy resistance in ovarian cancer (Review) Oncol Rep. 2022;47
- [CrossRef] [PubMed] [Google Scholar]
- Role of cell division cycle-associated proteins in regulating cell cycle and promoting tumor progression. Biochim Biophys Acta Rev Cancer. 2024;1879:189147.
- [CrossRef] [PubMed] [Google Scholar]
- Mechanistic insights into CDCA gene family-mediated glioblastoma progression: Implications for diagnosis, prognosis, and therapeutic targeting. Hereditas. 2025;162:43.
- [CrossRef] [PubMed] [Google Scholar]
- Decoding the role of CDCA genes in breast cancer progression: Insights from in silico and functional assay. Asia Pac J Clin Oncol. 2025;0:1-12.
- [Google Scholar]
- Roles of the CDCA gene family in breast carcinoma. Sci Prog. 2025;108:368504241312305.
- [CrossRef] [PubMed] [Google Scholar]
- CDCA genes as prognostic and therapeutic targets in Colon adenocarcinoma. Hereditas. 2025;162:19.
- [CrossRef] [PubMed] [Google Scholar]
- CDCA gene family promotes progression and prognosis in lung adenocarcinoma. Medicine (Baltimore). 2024;103:e38581.
- [CrossRef] [PubMed] [Google Scholar]
- CDCA2 promotes tumorigenesis and induces radioresistance in oesophageal squamous cell carcinoma cells. Mol Med Rep. 2021;24:530.
- [CrossRef] [PubMed] [Google Scholar]
- Increased CDCA2 level was related to poor prognosis in hepatocellular carcinoma and associated with Up-Regulation of immune checkpoints. Front Med (Lausanne). 2022;8:773724.
- [CrossRef] [PubMed] [Google Scholar]
- CDCA2 inhibits apoptosis and promotes cell proliferation in prostate cancer and is directly regulated by HIF-1a pathway. Front Oncol. 2020;10:725.
- [CrossRef] [PubMed] [Google Scholar]
- CDCA2 promotes proliferation and migration of melanoma by upregulating CCAD1. Eur Rev Med Pharmacol Sci. 2020;24:6858-63.
- [Google Scholar]
- CDCA The role of the gene family in ovarian cancer. Ann Transl Med. 2020;8:190.
- [CrossRef] [PubMed] [Google Scholar]
- Nano biosensor unlocks tumor derived immune signals for the early detection of ovarian cancer. Biosens Bioelectron. 2025;278:117368.
- [CrossRef] [PubMed] [Google Scholar]
- Comprehensive molecular analyses and experimental validation of CDCAs with potential implications in kidney renal papillary cell carcinoma prognosis. Heliyon. 2024;10:e33045.
- [CrossRef] [PubMed] [Google Scholar]
- Integration analysis of cell division cycle-associated family genes revealed potential mechanisms of gliomagenesis and constructed an artificial intelligence-driven prognostic signature. Cell Signal. 2024;119:111168.
- [CrossRef] [PubMed] [Google Scholar]
- E2F3/CDCA2 reduces radiosensitivity in gastric adenocarcinoma by activating PI3K/ AKT pathway. Br J Radiol. 2023;96:20230477.
- [CrossRef] [PubMed] [Google Scholar]
- A pan-cancer analysis reveals the diagnostic and prognostic role of CDCA2 in low-grade glioma. PLoS One. 2023;18:e0291024.
- [CrossRef] [PubMed] [Google Scholar]
- CDCA2 triggers in vivo and in vitro proliferation of hepatocellular carcinoma by activating the AKT/CCND1 signaling. J BUON. 2021;26:882-8.
- [Google Scholar]
- Hypoxia-induced PRPF19 modulates TPT1 alternative splicing to facilitate cisplatin resistance in high-grade serous ovarian cancer. Biochim Biophys Acta Mol Basis Dis. 2025;1871:167721.
- [CrossRef] [PubMed] [Google Scholar]
- Novel factors of cisplatin resistance in epithelial ovarian tumours. Adv Med Sci. 2025;70:94-102.
- [CrossRef] [PubMed] [Google Scholar]
- Overexpression of CDCA2 in human squamous cell carcinoma: correlation with prevention of G1 phase arrest and apoptosis. PLoS One. 2013;8:e56381.
- [CrossRef] [PubMed] [Google Scholar]
- Cell division cycle associated 2 (CDCA2) upregulation promotes the progression of hepatocellular carcinoma in a p53-dependant manner. PeerJ. 2022;10:e13535.
- [CrossRef] [PubMed] [Google Scholar]