CEP192 overexpression is correlated with poor prognosis of gastric cancer and promotes gastric cancer cell proliferation by regulating PLK1/CDK1/Cyclin B1 signaling

doi:10.12122/j.issn.1673-4254.2024.11.10

Abstract

Abstract:

Objective To investigate the correlation of CEP192 expression with prognosis of gastric cancer and biological behaviors of gastric cancer cells. Methods Public databases and clinical tissue samples were used to examine CEP192 expression level in gastric cancer. Kaplan-Meier survival curves, univariate and multivariate Cox regression analyses, ROC curves and bioinformatics analyses were used to explore the risk factors affecting the 5-year postoperative survival, the correlation of CEP192 expression level with the patients' survival, and its biological role in gastric cancer development. In gastric cancer MGC-803 cells with lentivirus-mediated CEP192 interference or overexpression, cell proliferation and expressions of PLK1, CDK1 and Cyclin B1 were examined with CCK-8 assay and Western blotting. The effects of CEP192 knockdown or overexpression on tumorigenesis of MGC-803 cells was observed in nude mice, and the expressions of PLK1, CDK1 and Cyclin B1 in the xenografts were detected. Results CEP192 was highly expressed in gastric cancer and associated with poor prognosis of the patients (P<0.05). High expression of CEP192, CEA ≥5 ng/mL, CA199 ≥37 IU/mL, T3-4 stage, and N2-3 stage were independent risk factors affecting the patients' 5-year postoperative survival (P<0.05). Bioinformatics analyses suggested that CEP192 was involved in several vital biological processes and positively regulated cell cycle progression. In MGC-803 cells, CEP192 knockdown significantly inhibited cell proliferation and lowered the expression levels of PLK1, CDK1, and Cyclin B1, while its overexpression produced the opposite effects. In the nude mouse models, CEP192 knockdown resulted in lowered tumorigenic potential of MGC-803 cells and decreased protein levels of PLK1, CDK1, and Cyclin B1 in the xenografts, while CEP192 overexpression in MGC-803 cells caused the opposite changes. Conclusion CEP192 overexpression is correlated with unfavorable outcomes of gastric cancer patients and promotes gastric cell proliferation by regulating the key proteins during G2/M phase transition.

Key words: gastric cancer, CEP192, poor prognosis, proliferation, cell cycle

Zhen ZHANG, Hui LU, Xiaohua CHEN, Lian WANG, Ziliang WANG, Yueyue WANG, Sitang GE, Lugen ZUO. CEP192 overexpression is correlated with poor prognosis of gastric cancer and promotes gastric cancer cell proliferation by regulating PLK1/CDK1/Cyclin B1 signaling[J]. Journal of Southern Medical University, 2024, 44(11): 2137-2145.

Figures/Tables 10

Fig. 1 CEP192 is highly expressed in multiple cancers. A: Expression of CEP192 in common human cancers. B, C: Expression of CEP192 in gastric cancer. *P<0.05, **P<0.01, ***P<0.001 vs normal group.

Fig.2 Immunohistochemical detection of CEP192 expression and cellular localization in gastric cancer and adjacent tissues (A) and quantitative analysis of its expression levels (B). *P<0.05 vs adjacent tissues.

Tab.1 Relationship between CEP192 expression and clinicopathological parameters of gastric cancer patients

Factors	n	CEP192 expression		χ²	P
Factors	n	Low (n=54)	High (n=55)	χ²	P
Gender
Male	58	30 (51.7%)	28 (48.3%)	0.236	0.627
Female	51	24 (47.1%)	27 (52.9%)
Age (year)
<60	47	26 (55.3%)	21 (44.7%)	1.103	0.294
≥60	62	28 (45.2%)	34 (54.8%)
CEA (ng/mL)
<5	55	35 (63.6%)	20 (36.4%)	8.823	0.003
≥5	54	19 (35.2%)	35 (64.8%)
CA199 (IU/mL)
<37	63	41 (65.1%)	22 (34.9%)	14.418	<0.001
≥37	46	13 (28.3%)	33 (71.7%)
Cancer cell type
Adenocarcinoma	83	43 (51.8%)	40 (48.2%)	0.715	0.398
Others	26	11 (42.3%)	15 (57.7%)
Tumor size (cm)
<5	49	26 (53.1%)	23 (46.9%)	0.441	0.507
≥5	60	28 (46.7%)	32 (53.3%)
T stage
T1-T2	52	33 (63.5%)	19 (36.5%)	7.708	0.005
T3-T4	57	21 (36.8%)	36 (63.2%)
N stage
N0-N1	54	35 (64.8%)	19 (35.2%)	9.987	0.002
N2-N3	55	19 (34.5%)	36 (65.5%)

Fig.3 Impact of CEP192 expression on 5-year survival rate of gastric cancer patients after surgery.

Fig. 4 Analysis of risk factors affecting the 5-year postoperative survival rate of gastric cancer patients. A: Impact of preoperative serum CEA level on the 5-year survival rate of the patients. B: Impact of preoperative serum CA199 level on the patients' survival. C: Impact of tumor T stage on the patients' survival. D: Impact of tumor N stage on the patients' survival. E: Cox regression analysis of independent risk factors affecting the 5-year postoperative survival rate of gastric cancer patients.

Fig.5 Predictive value of CEP192 expression for 5-year survival rate of gastric cancer patients after radical surgery.

Fig.6 Gene functional enrichment analysis of CEP192. A: GO enrichment analysis of CEP192 and its co-expressed genes. B: REACTOME enrichment analysis of CEP192 and co-expressed genes. C-H: CEP192 and GSEA enrichment of co-expressed genes.

Fig.7 CEP192 overexpression promotes proliferation of MGC-803 cells. A: Proliferation of MGC-803 cells with CEP192 knockdown. B: Proliferation of MGC-803 cells with CEP192 overexpression. *P<0.05 vs sh-NC group.

Fig.8 CEP192 overexpression promote expressions of cell cycle proteins. A: Western blotting for detecting expressions of PLK1, CDK1 and Cyclin B1 proteins. B, C: Expression levels PLK1, CDK1 and Cyclin B1 proteins. *P<0.05 vs sh-NC or LV-NC group.

Fig.9 CEP192 overexpression promotes proliferation of gastric cancer cells in nude mice. A: Tumor xenografts in different groups. B, C: Tumor weight of the nude mice. D, E: The tumor volume of the nude mice. F-H: Western blotting for detecting the expression levels of PLK1, CDK1 and Cyclin B1 proteins in the xenografts. *P<0.05 vs sh-NC or LV-NC group.

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