Overexpression of Lewis y antigen promotes human epididymis protein 4-mediated invasion and metastasis of ovarian cancer cells

Zhuang, Huiyu; Hu, Zhenhua; Tan, Mingzi; Zhu, Liping; Liu, Juanjuan; Liu, Dawo; Yan, Limei; Lin, Bei

doi:10.1016/j.biochi.2014.06.022

Cited by 33 publications

(28 citation statements)

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“…In our previous studies, we demonstrated that HE4 enhanced the proliferation, invasion and metastasis of ovarian cancer (20) partially via the interaction of Annexin A2 (23), and fuco-glycosylation may increase this effect (24,31). A similar phenomenon was also noted in others studies (18,19,21), even in endometrial (32,33) and pancreatic cancer (33).…”

Section: He4 Hcii ---------------------------------------------------supporting

confidence: 78%

“…recent years, several studies have reported that HE4 acts as an oncogene implicated in various cancer behaviors, such as cell adhesion (18), proliferation, migration, metastasis (19)(20)(21) and chemoresistance (19,22). The molecular mechanisms may be attributed to the activation of epidermal growth factor (EGF) (18), vascular endothelial growth factor (VEGF) (19), HIF1α (19) or the interaction with Annexin A2 (23), and Lewis y glycosylation (24). Nevertheless, investigation of the role of HE4 in the malignant biological behaviors of ovarian cancer is limited.…”

Section: Analysis Of the Gene Expression Profile In Response To Humanmentioning

confidence: 99%

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Analysis of the gene expression profile in response to human epididymis protein 4 in epithelial ovarian cancer cells

et al. 2016

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Currently, there are emerging multiple studies on human epididymis protein 4 (HE4) in ovarian cancer. HE4 possesses higher sensitivity and specificity than CA125 in the confirmative early diagnosis for ovarian cancer. Although much attention has been given to explore its clinical application, research of the basic mechanisms of HE4 in ovarian cancer are still unclear. In the present study, we provide fundamental data to identify full-scale differentially expressed genes (DEGs) in response to HE4 by use of human whole-genome microarrays in human epithelial ovarian cancer cell line ES-2 following overexpression and silencing of HE4. We found that a total of 717 genes were upregulated and 898 genes were downregulated in the HE4-overexpressing cells vs. the HE4-Mock cells, and 166 genes were upregulated and 285 were downregulated in the HE4-silenced cells vs. the HE4-Mock cells. An overlap of 16 genes consistently upregulated and 8 genes downregulated in response to HE4 were noted. These DEGs were involved in MAPK, steroid biosynthesis, cell cycle, the p53 hypoxia pathway, and focal adhesion pathways. Interaction network analysis predicted that the genes participated in the regulatory connection. Highly differential expression of the FOXA2, SERPIND1, BDKRD1 and IL1A genes was verified by quantitative real-time PCR in 4 cell line samples. Finally, SERPIND1 (HCII) was validated at the protein level by immunohistochemistry in 107 paraffin-embedded ovarian tissues. We found that SERPIND1 may act as a potential oncogene in the development of ovarian cancer. The present study displayed the most fundamental and full-scale data to show DEGs in response to HE4. These identified genes may provide a theoretical basis for investigations of the underlying molecular mechanism of HE4 in ovarian cancer.

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Section: He4 Hcii ---------------------------------------------------supporting

confidence: 78%

Section: Analysis Of the Gene Expression Profile In Response To Humanmentioning

confidence: 99%

Analysis of the gene expression profile in response to human epididymis protein 4 in epithelial ovarian cancer cells

et al. 2016

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“…Negative controls were performed with 1% BSA instead of the mAbs. The optical density of each well was determined within 30 min using a microplate reader at 450 nm [ 21 ].…”

Section: Methodsmentioning

confidence: 99%

Human epididymis protein 4 in association with Annexin II promotes invasion and metastasis of ovarian cancer cells

et al. 2014

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BackgroundThe objective of the present study was to identify human epididymis protein 4 (HE4) interacting proteins and explore the mechanisms underlying their effect on ovarian cancer cell invasion and metastasis.MethodsHE4 interacting proteins were identified by mass spectrometry and validated by co-immunoprecipitation and pull-down assays. The scratch test, the Transwell assay and animal experiments were used to assess the invasive and metastatic abilities of ovarian cancer cells before and after transfection and HE4 protein treatment. HE4 and annexin II protein expression in epithelial ovarian tissues was detected by immunohistochemistry, and the relation between their expression levels was examined.ResultsAnnexin II was identified as an HE4 interacting protein. HE4 and annexin II binding interaction promoted ovarian cancer cell invasion and metastasis. HE4 and annexin II expression levels were significantly higher in malignant epithelial ovarian tissues than in benign and normal epithelial ovarian tissues, and they were higher in tissues with lymph node metastases than in those without. HE4 gene interference downregulated the expression of MAPK and the FOCAL adhesion signaling pathway-associated molecules MKNK2 and LAMB2, and HE4 protein supplementation reversed this effect.ConclusionThe binding interaction between HE4 and annexin II activates the MAPK and FOCAL adhesion signaling pathways, promoting ovarian cancer cell invasion and metastasis.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-13-243) contains supplementary material, which is available to authorized users.

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“…On the contrary, other researchers noted that HE4 high expression promotes cell migration, adhesion, proliferation, and spreading, which can be associated with its effects on the EGFR-MAPK signaling pathway [18,36]. What is more, HE4 contains fucosylated modi cation (Lewis y antigen) [37], Lewis y overexpression can promote HE4-mediated invasion and metastasis in ovarian cancer cells [38]. Impressively, overexpression of Lewis y antigen enhanced tyrosine phosphorylation of EGFR and HER/neu, which improved cell proliferation by the PI3K/Akt and Raf/MEK/MAPK pathways [39]; hence, Lewis y antigen and HE4 may affect alike signaling pathways that promote tumor growth and malignancy [40].…”

Section: Discussionmentioning

confidence: 96%

Gene Expression Profile of Active HE4 Stimulation in Epithelial Ovarian Cancer Cells: Microarray Study and Comprehensive Bioinformatics Analysis

Zhu

Tan

et al. 2020

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Background.Human Epididymis Protein 4 (HE4) is a novel serum biomarker for diagnosis of epithelial ovarian cancer (EOC) with high specificity and sensitivity compared with CA125, and the increasing researches have been carried out on its roles in promoting carcinogenesis and chemoresistance in EOC in recent years, however, its underlying molecular mechanisms remain poorly understood. The aim of this study was to elucidate the molecular mechanisms of HE4 stimulation and to identify the key genes and pathways mediating carcinogenesis in EOC using microarray and bioinformatics analysis.Methods. We established a stable HE4-silence ES-2 ovarian cancer cell line labeled as “S”, and its active HE4 protein stimulated cells labeled as “S4”. Human whole genome microarray analysis was used to identify deferentially expressed genes (DEGs) from triplicate samples of S4 and S cells. “clusterProfiler” package in R, DAVID, Metascape, and Gene Set Enrichment Analysis (GSEA) were used to perform gene ontology (GO) and pathway enrichment analysis, and cBioPortal for WFDC2 coexpression analysis. GEO dataset (GSE51088) and quantitative real-time polymerase chain reaction (qRT-PCR) was applied for validation. The protein–protein interaction (PPI) network and modular analyses were performed using Metascape and Cytoscape. Results.In total, 713 DEGs were found (164 up regulated and 549 down regulated) and further analyzed by GO, pathway enrichment and PPI analyses. We found that MAPK pathway accounted for a significant portion of the enriched terms. WFDC2 coexpression analysis revealed ten WFDC2 coexpressed genes (TMEM220A, SEC23A, FRMD6, PMP22, APBB2, DNAJB4, ERLIN1, ZEB1, RAB6B, and PLEKHF1) that were also dramatically changed in S4 cells and validated by dataset GSE51088. Kaplan–Meier survival statistics revealed clinical significance for all of the 10 target genes. Finally, PPI was constructed, sixteen hub genes and eight molecular complex detections (MCODEs) were identified, the seeds of five most significant MCODEs were subjected to GO and KEGG enrichment analysis and their clinical significance was evaluated.Conclusions.By applying microarray and bioinformatics analyses, we identified DEGs and determined a comprehensive gene network of active HE4 stimulation in EOC cells. We offered several possible mechanisms and identified therapeutic and prognostic targets of HE4 in EOC.

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Overexpression of Lewis y antigen promotes human epididymis protein 4-mediated invasion and metastasis of ovarian cancer cells

Cited by 33 publications

References 20 publications

Analysis of the gene expression profile in response to human epididymis protein 4 in epithelial ovarian cancer cells

Analysis of the gene expression profile in response to human epididymis protein 4 in epithelial ovarian cancer cells

Human epididymis protein 4 in association with Annexin II promotes invasion and metastasis of ovarian cancer cells

Gene Expression Profile of Active HE4 Stimulation in Epithelial Ovarian Cancer Cells: Microarray Study and Comprehensive Bioinformatics Analysis

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