The prognostic value of high expression of FKBP1A in gastric cancer and the regulatory effect of targeted PI3K/AKT on glucose metabolism

doi:10.19401/j.cnki.1007-3639.2023.08.002

Abstract

Abstract:

Background and purpose: Gastric cancer is one of the common gastrointestinal malignancies. FKBP1A has been reported to be involved in the occurrence and development of various tumors, but the biological role and mechanism of it in gastric cancer remain unclear. This study aimed to investigate the expression level and prognostic value of FKBP1A in gastric cancer tissues, and to analyze the possible pathways and mechanisms of its regulation of gastric cancer progression. Methods: The expression of FKBP1A in gastric cancer was observed by immunohistochemistry, and its correlation with poor prognosis was analyzed by combining bioinformatics and clinicopathological parameters. Kaplan-Meier survival curve was used to analyze the effect of FKBP1A on the 5-year survival rate of patients with gastric cancer after surgery, and COX multivariate regression analysis was used to explore the independent prognostic factors affecting the 5-year survival rate of patients with gastric cancer after surgery. The diagnostic value of FKBP1A expression in patients with gastric cancer was analyzed using receiver operating characteristic (ROC) curve. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to enrich and analyze the biological function of FKBP1A and the possible signal pathways involved. We constructed the MGC803 cell model transfected with lentivirus in vitro, explored the influence of FKBP1A on the glucose metabolism and malignant biological behavior of MGC803 cells, and the possible molecular mechanism involved, and established a nude mouse transplantation tumor model in vitro to verify it. Results: Immunohistochemical results showed that FKBP1A was highly expressed in gastric cancer (P<0.01), and bioinformatics and clinical parameter analysis showed that FKBP1A was associated with poor prognosis. Kaplan-Meier survival analysis and COX regression analysis showed that the expression level of FKBP1A was negatively correlated with 5-year survival. And carcinoembryonic antigen (CEA)≥5 μg/L, carbohydrate antigen (CA) 19-9≥37 kU/L, T stage (T₃-T₄) and N stage (N₂-N₃) were independent prognostic factors affecting the 5-year survival rate of gastric cancer patients after surgery (P<0.05). ROC analysis showed that high expression of FKBP1A had good prognostic value (P<0.01). Enrichment of GO and KEGG suggested that FKBP1A was involved in regulating glucose metabolism in gastric cancer cells. In vitro experiments showed that overexpression of FKBP1A promoted glucose metabolism and proliferation, invasion and migration of MGC803 cells, while silencing of FKBP1A did the opposite (P<0.05). In vivo experiments showed that overexpression of FKBP1A in gastric cancer cells promoted the growth of transplanted tumor in nude mice, while silencing FKBP1A inhibited it (P<0.05). Mechanism analysis showed that overexpression of FKBP1A upregulated the expressions of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) in gastric cancer cells, while silencing FKBP1A downregulated the expressions (P<0.05). Conclusion: FKBP1A is highly expressed in gastric cancer tissues, and is associated with poor prognosis, which may be due to the promotion of glucose metabolism and malignant biological behavior of gastric cancer cells by activating PI3K/AKT.

Key words: Gastric cancer, FKBP prolyl isomerase 1A, Prognosis, Glucose metabolism, Phosphatidylinositol3-kinase/protein kinase B

CLC Number:

R735.2

SUN Yang, WANG Lian, ZHAO Meng, ZHANG Xiaofeng, GENG Zhijun, WANG Yueyue, SONG Xue, ZUO Lugen, LI Jing, HU Jianguo. The prognostic value of high expression of FKBP1A in gastric cancer and the regulatory effect of targeted PI3K/AKT on glucose metabolism[J]. China Oncology, 2023, 33(8): 726-739.

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Characteristic	Case n	FKBP1A n(%)		χ²	P value
Characteristic	Case n	Low expression (n=54)	High expression (n=53)	χ²	P value
Gender
Male	82	39 (47.6)	43 (52.4)	1.186	0.276
Female	25	15 (60.0)	10 (40.0)
Age/year
<60	35	17 (48.6)	18 (51.4)	0.075	0.784
≥60	72	37 (51.4)	35 (48.6)
CEA/(μg·L^-1)
<5	48	31 (64.6)	17 (35.4)	6.939	0.008
≥5	59	23 (39.0)	36 (61.0)
CA19-9/(kU·L^-1)
<37	51	38 (74.5)	13 (25.5)	22.533	<0.001
≥37	56	16 (28.6)	40 (71.4)
Tumor size D/cm
<5	48	28 (58.3)	20 (41.7)	2.155	0.142
≥5	59	26 (44.1)	33 (55.9)
Histological type
Adenocarcinoma	80	42 (52.5)	38 (47.5)	0.524	0.469
Other	27	12 (44.4)	15 (55.6)
Pathological grading
G₁-G₂	54	27 (50.0)	27 (50.0)	0.010	0.922
G₃-G₄	53	27 (50.9)	26 (49.1)
T stage
T₁-T₂	54	36 (66.7)	18 (33.3)	11.444	<0.001
T₃-T₄	53	18 (34.0)	35 (66.0)
N stage
N₀-N₁	62	41 (66.1)	21 (33.9)	14.466	<0.001
N₂-N₃	45	13 (28.9)	32 (71.1)

Characteristic	Univariate analysis		Multivariabale analysis
Characteristic	Log-rank χ²	P value	HR	95% CI	P value
Gender (male vs female)	0.017	0.898	-	-	-
Age (<60 years vs ≥60 years)	0.468	0.494	-	-	-
FKBP1A expression (high vs low)	44.469	<0.001	3.342	1.617-6.909	0.001
CEA (<5 μg/L vs ≥5 μg/L)	17.172	<0.001	1.958	1.007-3.806	0.048
CA19-9 (<37 kU/L vs ≥37 kU/L)	25.458	<0.001	2.728	1.439-5.170	0.002
Tumor size (<5 cm vs ≥5 cm)	0.005	0.944	-	-	-
Histological type (STAD vs other)	1.764	0.184	-	-	-
Pathological grading (G1-G2 vs G3-G4)	0.466	0.495	-	-	-
T stage (T₁-T₂ vs T₃-T₄)	20.419	<0.001	1.889	1.019-3.503	0.043
N stage (N₀-N₁ vs N₂-N₃)	29.513	<0.001	2.119	1.116-4.023	0.022