胃癌中FKBP1A高表达的预后价值及其靶向PI3K/AKT对糖代谢的调控作用

doi:10.19401/j.cnki.1007-3639.2023.08.002

摘要/Abstract

摘要：

背景与目的：胃癌是常见的消化道恶性肿瘤之一，FKBP脯氨酸异构酶1A（FKBP prolyl isomerase 1A，FKBP1A）参与多种肿瘤的发生、发展，但在胃癌中的生物学作用及机制尚未明确。本研究旨在探讨FKBP1A在胃癌组织中的表达水平及预后价值，分析其调控胃癌进展的可能途径和机制。方法：免疫组织化学观察FKBP1A在胃癌中的表达情况并结合生物信息学与临床病理学参数分析其与预后不良的相关性；采用Kaplan-Meier生存曲线描述FKBP1A对胃癌患者术后5年生存率的影响，采用COX多因素回归分析探讨影响胃癌患者术后生存率的独立预后因素；通过受试者工作特征（receiver operating characteristic，ROC）曲线分析FKBP1A表达在胃癌患者中的诊断价值；基因本体（Gene Ontology，GO）和京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes，KEGG）富集分析FKBP1A的生物学功能及可能参与的信号转导通路，体外构建慢病毒转染的MGC803细胞模型，探究FKBP1A对MGC803细胞糖代谢和恶性生物学行为的影响以及可能的分子机制，并构建裸鼠移植瘤模型加以验证。结果：免疫组织化学检测结果显示，FKBP1A在胃癌中呈高表达（P<0.01），生物信息学与临床参数分析结果显示，其与患者预后不良相关；Kaplan-Meier生存分析和COX回归分析显示，FKBP1A表达量与患者5年生存率呈负相关，且其与外周血癌胚抗原（carcinoembryonic antigen，CEA）≥5 μg/L、糖类抗原19-9（carbohydrate antigen 19-9，CA19-9）≥37 kU/L、T分期（T₃ ~ T₄期）和N分期（N₂ ~ N₃期）是影响胃癌患者术后5年生存率的独立预后因素（P<0.05）；ROC曲线分析表明，FKBP1A高表达具有较好的预后诊断价值（P<0.01）；GO和KEGG富集分析推测FKBP1A可能参与调节胃癌细胞糖代谢。体外实验显示，过表达FKBP1A促进MGC803细胞糖代谢、增殖、侵袭和迁移，沉默FKBP1A则相反（P<0.05）。在体实验显示，胃癌细胞过表达FKBP1A促进裸鼠移植瘤的生长，而沉默则抑制之（P <0.05）。机制分析表明，过表达FKBP1A上调胃癌细胞中磷酸化的磷脂酰肌醇3激酶（phosphatidylinositol 3-kinase，PI3K）和磷酸化的蛋白激酶B（protein kinase B，AKT）的表达，而沉默则下调之（P<0.05）。 结论：FKBP1A在胃癌组织中高表达且与患者预后不良相关，可能是通过激活PI3K/AKT促进胃癌细胞的糖代谢和恶性生物学行为。

关键词: 胃癌, FKBP脯氨酸异构酶1A, 预后, 糖代谢, 磷酰脂肌醇3激酶/蛋白激酶B

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

中图分类号:

R735.2

孙洋, 王炼, 赵萌, 张小凤, 耿志军, 王月月, 宋雪, 左芦根, 李静, 胡建国. 胃癌中FKBP1A高表达的预后价值及其靶向PI3K/AKT对糖代谢的调控作用[J]. 中国癌症杂志, 2023, 33(8): 726-739.

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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参考文献 23

[1]	RIZZO A, RACCA M, GARROU F, et al. Diagnostic performance of positron emission tomography with fibroblast-activating protein inhibitors in gastric cancer: a systematic review and meta-analysis[J]. Int J Mol Sci, 2023, 24(12): 10136. doi: 10.3390/ijms241210136
[2]	YU H, ZHAO K, ZENG H, et al. N6-methyladenosine (m6A) methyltransferase WTAP accelerates the Warburg effect of gastric cancer through regulating HK2 stability[J]. Biomed Pharmacother, 2021, 133: 111075. doi: 10.1016/j.biopha.2020.111075
[3]	ZHAO M Y, WEI F, SUN G W, et al. Natural compounds targeting glycolysis as promising therapeutics for gastric cancer: a review[J]. Front Pharmacol, 2022, 13: 1004383. doi: 10.3389/fphar.2022.1004383
[4]	ZHONG X Y, HE X F, WANG Y X, et al. Warburg effect in colorectal cancer: the emerging roles in tumor microenvironment and therapeutic implications[J]. J Hematol Oncol, 2022, 15(1): 160. doi: 10.1186/s13045-022-01358-5
[5]	HOU H, LYU Y L, JIANG J, et al. Peripheral blood transcriptome identifies high-risk benign and malignant breast lesions[J]. PLoS One, 2020, 15(6): e0233713.
[6]	LIU Z, ZHANG K, ZHAO Z, et al. Prognosis-related autophagy genes in female lung adenocarcinoma[J]. Medicine (Baltimore), 2022, 101(1): e28500.
[7]	ZHANG Y, ZHANG D, LV J, et al. LncRNA SNHG15 acts as an oncogene in prostate cancer by regulating miR-338-3p/FKBP1A axis[J]. Gene, 2019, 705: 44-50. doi: S0378-1119(19)30386-5 pmid: 30981837
[8]	WANG G, ZHAO H, DUAN X, et al. CircRNA pappalysin 1 facilitates prostate cancer development through miR-515-5p/FKBP1A axis[J]. Andrologia, 2021, 53(11): e14227.
[9]	FU L S, WANG X Y, YANG Y, et al. Septin11 promotes hepatocellular carcinoma cell motility by activating RhoA to regulate cytoskeleton and cell adhesion[J]. Cell Death Dis, 2023, 14(4): 280. doi: 10.1038/s41419-023-05726-y pmid: 37080972
[10]	BIE Q L, SUN C X, GONG A H, et al. Non-tumor tissue derived interleukin-17B activates IL-17RB/AKT/β-catenin pathway to enhance the stemness of gastric cancer[J]. Sci Rep, 2016, 6: 25447. doi: 10.1038/srep25447 pmid: 27146881
[11]	HOXHAJ G, MANNING B D. The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism[J]. Nat Rev Cancer, 2020, 20(2): 74-88. doi: 10.1038/s41568-019-0216-7 pmid: 31686003
[12]	LI Z G, CUI Y, DUAN Q C, et al. The prognostic significance of FKBP1A and its related immune infiltration in liver hepatocellular carcinoma[J]. Int J Mol Sci, 2022, 23(21): 12797. doi: 10.3390/ijms232112797
[13]	LENG W, LIU Q, ZHANG S, et al. LncRNA AFAP1-AS1 modulates the sensitivity of paclitaxel-resistant prostate cancer cells to paclitaxel via miR-195-5p/FKBP1A axis[J]. Cancer Biol Ther, 2020, 21(11): 1072-1080. doi: 10.1080/15384047.2020.1829266 pmid: 33138677
[14]	PATEL D, DABHI A M, DMELLO C, et al. FKBP1A upregulation correlates with poor prognosis and increased metastatic potential of HNSCC[J]. Cell Biol Int, 2022, 46(3): 443-453. doi: 10.1002/cbin.v46.3
[15]	DARANG E, PEZESHKIAN Z, MIRHOSEINI S Z, et al. Bioinformatics and pathway enrichment analysis identified hub genes and potential biomarker for gastric cancer prognosis[J]. Front Oncol, 2023, 13: 1187521. doi: 10.3389/fonc.2023.1187521
[16]	TANG J, ZHANG C, LIN J, et al. ALOX5-5-HETE promotes gastric cancer growth and alleviates chemotherapy toxicity via MEK/ERK activation[J]. Cancer Med, 2021, 10(15): 5246-5255. doi: 10.1002/cam4.v10.15
[17]	XU T P, YU T, XIE M Y, et al. LOC101929709 promotes gastric cancer progression by aiding LIN28B to stabilize c-MYC mRNA[J]. Gastric Cancer, 2023, 26(2): 169-186. doi: 10.1007/s10120-022-01348-z
[18]	ZHOU Y, GU H J, SHAO B F, et al. Glycolysis-related gene dihydrolipoamide acetyltransferase promotes poor prognosis in hepatocellular carcinoma through the Wnt/β-catenin and PI3K/Akt signaling pathways[J]. Ann Transl Med, 2022, 10(22): 1240. doi: 10.21037/atm-22-5272 pmid: 36544660
[19]	CHENG J, HUANG Y, ZHANG X H, et al. TRIM21 and PHLDA3 negatively regulate the crosstalk between the PI3K/AKT pathway and PPP metabolism[J]. Nat Commun, 2020, 11(1): 1880. doi: 10.1038/s41467-020-15819-3 pmid: 32312982
[20]	LI Z, JIANG Y, LIU J, et al. Exosomes from PYCR1 knockdown bone marrow mesenchymal stem inhibits aerobic glycolysis and the growth of bladder cancer cells via regulation of the EGFR/PI3K/AKT pathway[J]. Int J Oncol, 2023, 63(1): 84. doi: 10.3892/ijo
[21]	WANG Y Y, ZHOU Y Q, XIE J X, et al. MAOA suppresses the growth of gastric cancer by interacting with NDRG1 and regulating the Warburg effect through the PI3K/AKT/mTOR pathway[J]. Cell Oncol (Dordr), 2023. Online ahead of print.
[22]	YE W, SHI Z H, ZHOU Y L, et al. Autophagy-related signatures as prognostic indicators for hepatocellular carcinoma[J]. Front Oncol, 2022, 12: 654449. doi: 10.3389/fonc.2022.654449
[23]	JIN G, LV J, YANG M, et al. Genetic risk, incident gastric cancer, and healthy lifestyle: a meta-analysis of genome-wide association studies and prospective cohort study[J]. Lancet Oncol, 2020, 21(10): 1378-1386. doi: S1470-2045(20)30460-5 pmid: 33002439

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