Expression of serpin family E member 1 in gastric cancer and its mechanisms in promoting gastric cancer

doi:10.3969/j.issn.1674-8115.2025.02.003

Abstract

Abstract:

Objective ·To investigate the expression of serpin family E member 1 (SERPINE1) in gastric cancer and its potential mechanisms in promoting gastric cancer. Methods ·Pan-cancer analysis of SERPINE1 was performed by using the TIMER2.0 online website, and the differences in the expression of SERPINE1 in samples with different tumor stages of gastric cancer were analysed by the clinical data of gastric cancer from The Cancer Genome Atlas (TCGA) database. Survival curves were plotted. Quantitative real-time PCR (qRT-PCR) was used to detect mRNA expression in paired samples of clinical gastric cancer tissues. The small interfering RNA (siRNA) transfection technique was used to knock down the expression of SERPINE1 in MGC-803 and SGC-7901 gastric cancer cell lines, and the migration and invasive abilities of gastric cancer cells were investigated by Transwell and invasion chamber experiments. The effects of SERPINE1 knockdown on the angiogenesis of gastric cancer cells were further explored by the migration assay of human umbilical vein endothelial cells (HUVEC) and tubule formation assay of HUVECs. The Gene Expression Omnibus (GEO) dataset was used for differential gene analysis in high and low expression groups based on the median value of SERPINE1 expression. The differentially expressed genes were further analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and Gene Set Enrichment Analysis (GSEA). qRT-PCR was performed to verify the expression levels of key genes related to epithelial-mesenchymal transition (EMT) and angiogenesis. Results ·Bioinformatics analysis showed that SERPINE1 was highly overexpressed in a variety of primary tumour tissues, including gastric cancer. SERPINE1 gene expression increased with increasing tumour stage (P<0.001), and increased expression of SERPINE1 was associated with poor prognosis of gastric cancer (P<0.001). qRT-PCR results showed that SERPINE1 was significantly highly expressed in gastric cancer tissues (P=0.038). After knocking down SERPINE1, gastric cancer cell lines MGC-803 and SGC-7901 cells had decreased migration and invasion (P<0.05). Gastric cancer culture supernatants from the SERPINE1-knockdown gastric cancer cell line reduced angiogenesis in HUVECs (P<0.05). Differential genes in gastric cancer patients in the SERPINE1 high-expression group in the GEO database were enriched in cancer-related pathways such as focal adhesion, extracellular matrix receptor interaction, and angiogenesis-related pathways like angiogenesis and the vascular endothelial growth factor (VEGF) signalling pathway. The expression of SERPINE1 was negatively correlated with cadherin 1 (CDH1), and positively correlated with other key genes related to EMT and angiogenesis. Moreover, the expression levels of key genes related to EMT and angiogenesis detected by qRT-PCR in SERPINE1 knockdown gastric cancer cell lines (P<0.05), were consistent with the correlation analysis results mentioned above. Conclusion ·SERPINE1 expression is elevated in gastric cancer tissues, which could regulate the expression levels of key genes related to EMT and angiogenesis to promote the migration, invasion and angiogenesis of gastric cancer cells.

Key words: serpin family E member 1 (SERPINE1), gastric cancer, epithelial-mesenchymal transition, angiogenesis

CLC Number:

R735.2

CHEN Yongyu, HUANG Yiren, CHEN Zheyi, ZHOU Bingqian, CHEN Shiyu, ZHENG Yingxia. Expression of serpin family E member 1 in gastric cancer and its mechanisms in promoting gastric cancer[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(2): 150-160.

Figures/Tables 6

TrendMD

References 19

1	BRAY F, LAVERSANNE M, SUNG H, et al. Global cancer statistics 2022: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2024, 74(3): 229-263.
2	LÓPEZ M J, CARBAJAL J, ALFARO A L, et al. Characteristics of gastric cancer around the world[J]. Crit Rev Oncol Hematol, 2023, 181: 103841.
3	SMYTH E C, NILSSON M, GRABSCH H I, et al. Gastric cancer[J]. Lancet, 2020, 396(10251): 635-648.
4	GUAN W L, HE Y, XU R H. Gastric cancer treatment: recent progress and future perspectives[J]. J Hematol Oncol, 2023, 16(1): 57.
5	KÖRFER J, LORDICK F, HACKER U T. Molecular targets for gastric cancer treatment and future perspectives from a clinical and translational point of view[J]. Cancers (Basel), 2021, 13(20): 5216.
6	DELLAS C, LOSKUTOFF D J. Historical analysis of PAI-1 from its discovery to its potential role in cell motility and disease[J]. Thromb Haemost, 2005, 93(4): 631-640.
7	LI S J, WEI X H, HE J Y, et al. Plasminogen activator inhibitor-1 in cancer research[J]. Biomed Pharmacother, 2018, 105: 83-94.
8	SAKAKIBARA T, HIBI K, KOIKE M, et al. Plasminogen activator inhibitor-1 as a potential marker for the malignancy of gastric cancer[J]. Cancer Sci, 2006, 97(5): 395-399.
9	ZHANG Y, ZHANG Y L, CHEN H M, et al. Expression of Bmi-1 and PAI-1 in esophageal squamous cell carcinoma[J]. World J Gastroenterol, 2014, 20(18): 5533-5539.
10	ZHANG W W, XU J, FANG H H, et al. Endothelial cells promote triple-negative breast cancer cell metastasis via PAI-1 and CCL5 signaling[J]. FASEB J, 2018, 32(1): 276-288.
11	HONG C L, YU I S, PAI C H, et al. CD248 regulates Wnt signaling in pericytes to promote angiogenesis and tumor growth in lung cancer[J]. Cancer Res, 2022, 82(20): 3734-3750.
12	ZUBAC D P, WENTZEL-LARSEN T, SEIDAL T, et al. Type 1 plasminogen activator inhibitor (PAI-1) in clear cell renal cell carcinoma (CCRCC) and its impact on angiogenesis, progression and patient survival after radical nephrectomy[J]. BMC Urol, 2010, 10: 20.
13	OFFERSEN B V, PFEIFFER P, ANDREASEN P, et al. Urokinase plasminogen activator and plasminogen activator inhibitor type-1 in nonsmall-cell lung cancer: relation to prognosis and angiogenesis[J]. Lung Cancer, 2007, 56(1): 43-50.
14	LIN X, LIN B W, CHEN X L, et al. PAI-1/PIAS3/Stat3/miR-34a forms a positive feedback loop to promote EMT-mediated metastasis through Stat3 signaling in non-small cell lung cancer[J]. Biochem Biophys Res Commun, 2017, 493(4): 1464-1470.
15	PAVÓN M A, ARROYO-SOLERA I, TÉLLEZ-GABRIEL M, et al. Enhanced cell migration and apoptosis resistance may underlie the association between high SERPINE1 expression and poor outcome in head and neck carcinoma patients[J]. Oncotarget, 2015, 6(30): 29016-29033.
16	CONWAY E M, COLLEN D, CARMELIET P. Molecular mechanisms of blood vessel growth[J]. Cardiovasc Res, 2001, 49(3): 507-521.
17	GOMES-GIACOIA E, MIYAKE M, GOODISON S, et al. Targeting plasminogen activator inhibitor-1 inhibits angiogenesis and tumor growth in a human cancer xenograft model[J]. Mol Cancer Ther, 2013, 12(12): 2697-2708.
18	GEIS T, DÖRING C, POPP R, et al. HIF-2α-dependent PAI-1 induction contributes to angiogenesis in hepatocellular carcinoma[J]. Exp Cell Res, 2015, 331(1): 46-57.
19	CHEN S J, LI Y Q, ZHU Y H, et al. SERPINE1 overexpression promotes malignant progression and poor prognosis of gastric cancer[J].J Oncol, 2022, 2022: 2647825.

siRNA	Forward (5'→3')	Reverse (5'→3')
SERPINE1-siRNA1	GAUUCAAGAUUGAUGACAATT	UUGUCAUCAAUCUUGAAUCTT
SERPINE1-siRNA2	GAGCCAGAUUCAUCAUCAATT	UUGAUGAUGAAUCUGGCUCTT
SERPINE1-siRNA3	CAAAAGGUAUGAUCAGCAATT	UUGCUGAUCAUACCUUUUGTT

siRNA	Forward (5'→3')	Reverse (5'→3')
SERPINE1-siRNA1	GAUUCAAGAUUGAUGACAATT	UUGUCAUCAAUCUUGAAUCTT
SERPINE1-siRNA2	GAGCCAGAUUCAUCAUCAATT	UUGAUGAUGAAUCUGGCUCTT
SERPINE1-siRNA3	CAAAAGGUAUGAUCAGCAATT	UUGCUGAUCAUACCUUUUGTT

Primer	Forward (5'→3')	Reverse (5'→3')
SERPINE1	ACCGCAACGTGGTTTTCTCA	TTGAATCCCATAGCTGCTTGAAT
β-actin	CATGTACGTTGCTATCCAGGC	CTCCTTAATGTCACGCACGAT
CDH1	CGAGAGCTACACGTTCACGG	GGGTGTCGAGGGAAAAATAGG
CDH2	TGCGGTACAGTGTAACTGGG	GAAACCGGGCTATCTGCTCG
VIM	GACGCCATCAACACCGAGTT	CTTTGTCGTTGGTTAGCTGGT
SNAI1	ACTGCAACAAGGAATACCTCAG	GCACTGGTACTTCTTGACATCTG
HIF1A	GAACGTCGAAAAGAAAAGTCTCG	CCTTATCAAGATGCGAACTCACA
VEGFA	AGGGCAGAATCATCACGAAGT	AGGGTCTCGATTGGATGGCA
FGF2	AGAAGAGCGACCCTCACATCA	CGGTTAGCACACACTCCTTTG
PGF	GAACGGCTCGTCAGAGGTG	ACAGTGCAGATTCTCATCGCC

Primer	Forward (5'→3')	Reverse (5'→3')
SERPINE1	ACCGCAACGTGGTTTTCTCA	TTGAATCCCATAGCTGCTTGAAT
β-actin	CATGTACGTTGCTATCCAGGC	CTCCTTAATGTCACGCACGAT
CDH1	CGAGAGCTACACGTTCACGG	GGGTGTCGAGGGAAAAATAGG
CDH2	TGCGGTACAGTGTAACTGGG	GAAACCGGGCTATCTGCTCG
VIM	GACGCCATCAACACCGAGTT	CTTTGTCGTTGGTTAGCTGGT
SNAI1	ACTGCAACAAGGAATACCTCAG	GCACTGGTACTTCTTGACATCTG
HIF1A	GAACGTCGAAAAGAAAAGTCTCG	CCTTATCAAGATGCGAACTCACA
VEGFA	AGGGCAGAATCATCACGAAGT	AGGGTCTCGATTGGATGGCA
FGF2	AGAAGAGCGACCCTCACATCA	CGGTTAGCACACACTCCTTTG
PGF	GAACGGCTCGTCAGAGGTG	ACAGTGCAGATTCTCATCGCC

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