High expression of ATP5A1 in gastric carcinoma is correlated with a poor prognosis and enhanced glucose metabolism in tumor cells

doi:10.12122/j.issn.1673-4254.2024.05.20

Abstract

Abstract:

Objective To analyze the expression level of ATP5A1 in gastric carcinoma and its influence on the prognosis of the patients and glucose metabolism in the tumor cells. Methods We retrospectively analyzed the data of 115 patients undergoing radical resection of gastric carcinoma in our hospital from February, 2013 to November, 2016. ATP5A1 expression in the surgical specimens were detected using immunohistochemistry, and the long-term prognosis of the patients with high (n=58) and low ATP5A1 expression (n=57) were analyzed. In gastric carcinoma MGC803 cells, the effects of lentivirus-mediated ATP5A1 knockdown or overexpression on glucose metabolism were investigated. We also observed the growth and glucose metabolism of xenografts derived from MGC803 cells with ATP5A1 knockdown or overexpression in nude mice. Results ATP5A1 was significantly overexpressed in gastric carcinoma tissues in close correlation with blood CEA and CA19-9 levels, pathological grade, T stage and N stage (P<0.05). ATP5A1 overexpression was an independent risk factor for a significantly lowered 5-year survival rate of patients with gastric carcinoma (P<0.05). ROC curve analysis demonstrated the predictive value of high ATP5A1 expression for the patients' prognosis (P<0.001). In MGC803 cells, ATP5A1 overexpression significantly up-regulated cellular glucose uptake and lactate production and increased the protein levels of HK2, PFK1, and LDHA (P<0.05), while ATP5A1 knockdown produced the opposite changes (P<0.05). In the tumor-bearing mice, overexpression of ATP5A1 increased glucose metabolism of the tumor cells and promoted tumor growth (P<0.05). Overexpression of ATP5A1 promoted the expressions of p-JNK and p-JUN in MGC803 cells (P<0.05), and the JNK inhibitor SP600125 significantly inhibited the enhancement of cellular glucose metabolism induced by ATP5A1 overexpression (P<0.05). Conclusion High ATP5A1 expression in gastric cancer is associated a poor long-term prognosis of the patients, and its effect is mediated at least partly by promoting glucose metabolism of the cells through the JNK/JUN pathway.

Key words: ATP5A1, gastric carcinoma, glucose metabolism, prognosis, JNK/JUN pathway

Jingjing YANG, Lixia YIN, Ting DUAN, Minzhu NIU, Zhendong HE, Xinrui CHEN, Xiaofeng ZHANG, Jing LI, Zhijun GENG, Lugen ZUO. High expression of ATP5A1 in gastric carcinoma is correlated with a poor prognosis and enhanced glucose metabolism in tumor cells[J]. Journal of Southern Medical University, 2024, 44(5): 974-980.

Figures/Tables 8

Fig.1 ATP5A1 is overexpressed in gastric carcinoma tissues. A: Immunohistochemistry of ATP5A1 in gastric carcinoma and adjacent tissues. B: IOD values of ATP5A1 expression in gastric carcinoma and adjacent tissues. *P<0.05 vs adjacent tissue.

Tab.1 Clinical data of 115 patients with gastric carcinoma

Factors		n	ATP5A1 expression (n, %)		χ²	P
Factors		n	Low (n=57)	High (n=58)	χ²	P
Gender	Male	85	42 (49.41%)	43 (50.59%)	0.003	0.956
Gender	Female	30	15 (50.00%)	15 (50.00%)	0.003	0.956
Age (year)	<60	40	20 (50.00%)	20 (50.00%)	0.005	0.946
Age (year)	≥60	75	37 (49.33%)	38 (50.67%)	0.005	0.946
CEA (μg/L)	<5	54	35 (64.81%)	19 (35.19%)	9.470	0.002
CEA (μg/L)	≥5	61	22 (36.07%)	39 (63.93%)	9.470	0.002
CA19-9 (kU/L)	<37	55	38 (69.09%)	17 (30.91%)	16.077	<0.001
CA19-9 (kU/L)	≥37	60	19 (31.67%)	41 (68.33%)	16.077	<0.001
Tumor size (cm)	<5	53	30 (56.60%)	23 (43.40%)	1.948	0.163
Tumor size (cm)	≥5	62	27 (43.55%)	35 (56.45%)	1.948	0.163
Pathological grading	G1-2	60	36 (60.00%)	24 (40.00%)	5.464	0.019
Pathological grading	G3-4	55	21 (38.18%)	34 (61.82%)	5.464	0.019
Cancer cell type	Adenocarcinoma	90	47 (52.22%)	43 (47.78%)	1.169	0.280
Cancer cell type	Other	25	10 (40.00%)	15 (60.00%)	1.169	0.280
T stage	T1-T2	60	38 (63.33%)	22 (36.67%)	9.513	0.002
T stage	T3-T4	55	19 (34.55%)	36 (65.45%)	9.513	0.002
N stage	N0-N1	66	43 (65.15%)	23 (34.85%)	15.053	<0.001
N stage	N2-N3	49	14 (28.57%)	35 (71.43%)	15.053	<0.001

Fig.2 Relationship between ATP5A1 expression and prognosis in patients with gastric carcinoma.

Tab.2 Factors affecting postoperative survival of patients with gastric carcinoma

Factors	Univariate analysis		Multivariate analysis
Factors	Log-rank χ ²	P	HR	95% CI	P
Gender (female vs male)	1.436	0.231
Age (≥60 year vs <60 year)	0.745	0.388
ATP5A1 expression (high vs low)	30.968	<0.001	2.771	1.458-5.267	0.002
CEA (≥5 μg/L vs <5 μg/L)	16.152	<0.001	2.003	1.097-3.658	0.024
CA19-9 (≥37 kU/L vs <37kU/L)	35.142	<0.001	3.348	1.666-6.728	0.001
Tumor size (≥5 cm vs <5 cm)	0.077	0.782
Pathological grading (G3-G4 vs G1-G2)	32.142	<0.001	2.759	1.484-5.128	0.001
Cancer cell type (adenocarcinoma vs other)	1.251	0.263
T stage (T3-T4 vs T1-T2)	27.798	<0.001	2.056	1.122-3.768	0.020
N stage (N2-N3 vs N0-N1)	28.006	<0.001	2.251	1.211-4.187	0.010

Fig.3 Sensitivity and specificity of ATP5A1 expression for predicting postoperative survival of patients with gastric carcinoma.

Fig.4 Overexpression of ATP5A1 accelerates glucose metabolism in gastric carcinoma cells. A, B: Western blotting for detecting ATP5A1 protein after lentivirus transfection. C, D: Glucose uptake and lactate production of the gastric cancer cells. E, F: Western blotting for the proteins related to glucose metabolism. *P<0.05 vs Control.

Fig.5 ATP5A1 promotes glucose metabolism by activating the JNK/JUN signaling pathway. A, B: Phosphorylation levels of JNK and JUN detected by Western blotting. C, D: Glucose uptake and lactate production in gastric cancer cells. E, F: Western blotting for detecting glucose metabolism-related protein expressions. *P<0.05 vs Control. #P<0.05 vs LV-ATP5A1.

Fig.6 Overexpression of ATP5A1 accelerates tumor growth and glucose metabolism in nude mice. A: Tumor xenografts in the 3 groups. B: Weight of the transplanted tumors. C: Volume of the transplanted tumors. D, E: Protein expressions of HK2, PFK1 and LDHA in xenografts detected by Western blotting. *P<0.05 vs Control.

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