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

Zhuang, Huiyu; Tan, Mingzi; Liu, Juanjuan; Hu, Zhenhua; Liu, Dawo; Gao, Jian; Zhu, Liping; Lin, Bei

doi:10.1186/1476-4598-13-243

Cited by 49 publications

(49 citation statements)

References 19 publications

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“…Inclusion of preoperative serum HE4 levels into the diagnostic Risk of Ovarian Malignancy Algorithm (ROMA) results in demonstrably improved specificity and sensitivity in detection and monitoring of the disease over Cancer Antigen 125 (CA 125), pelvic sonography, and menopausal status alone [5]. Research has also shown its ability to support EOC pathogenesis, including the promotion of proliferation, chemoresistance, antiestrogen resistance, adhesion, invasion, and migration [6][7][8][9][10][11][12][13][14][15][16][17]. One oncogenic pathway that has consistently been shown to interact with HE4 in several studies is the extracellular signal regulated kinase (ERK) pathway.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of DUSP6 sensitizes ovarian cancer cells to chemotherapeutic agents via regulation of ERK signaling response genes

et al. 2019

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Dual specificity phosphatase 6 (DUSP6) is a protein phosphatase that deactivates extracellular-signal-regulated kinase (ERK). Since the ovarian cancer biomarker human epididymis protein 4 (HE4) interacts with the ERK pathway, we sought to determine the relationship between DUSP6 and HE4 and elucidate DUSP6's role in epithelial ovarian cancer (EOC). Viability assays revealed a significant decrease in cell viability with pharmacological inhibition of DUSP6 using (E/Z)-BCI hydrochloride in ovarian cancer cells treated with carboplatin or paclitaxel, compared to treatment with either agent alone. Quantitative PCR was used to evaluate levels of ERK pathway response genes to BCI in combination with recombinant HE4 (rHE4), carboplatin, and paclitaxel. Expression of EGR1, a promoter of apoptosis, was higher in cells co-treated with BCI and paclitaxel or carboplatin than in cells treated with chemotherapeutic agents alone, while expression of the proto-oncogene c-JUN was decreased with co-treatment. The effect of BCI on the expression of these two genes opposed that of rHE4. Pathway focused quantitative PCR also revealed suppression of ERBB3 in cells co-treated with BCI plus carboplatin or paclitaxel. Finally, expression levels of DUSP6 in EOC tissue were evaluated by immunohistochemistry, revealing significantly increased levels of DUSP6 in serous EOC tissue compared to adjacent normal tissue. A positive correlation between HE4 and DUSP6 levels was determined by Spearman Rank correlation. In conclusion, DUSP6 inhibition sensitizes ovarian cancer cells to chemotherapeutic agents and alters gene expression of ERK response genes, suggesting that DUSP6 could plausibly function as a novel therapeutic target to reduce chemoresistance in EOC.

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Section: Introductionmentioning

confidence: 99%

Inhibition of DUSP6 sensitizes ovarian cancer cells to chemotherapeutic agents via regulation of ERK signaling response genes

et al. 2019

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“…In our study using recombinant mouse WFDC2, we were unable to identify any proteinase inhibitory activity nor were we able to show robust antimicrobial activity against a number of bacteria. Other studies, largely from the cancer field, have shown that WFDC2 has the capacity to promote cell growth [43][44][45][46][47][48].…”

Section: Discussionmentioning

confidence: 99%

Expression and function of murine WFDC2 in the respiratory tract

Bingle

Armes

Williams

et al. 2020

Preprint

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WFDC2/HE4 encodes a poorly characterised secretory protein that shares structural similarity with multifunctional host defence proteins through possession of two conserved Whey Acidic Protein/four disulphide-core (WFDC) domains. WFDC2 is expressed in multiple epithelia and although its' function remains unresolved, it is also overexpressed in a number of human cancers and has an established role as a cancer marker. Currently, little is known about the distribution of WFDC2 in the mouse and thus we have systematically analysed the mouse wfdc2 gene, its' expression and distribution. We have used recombinant WFDC2 for functional studies. Wfdc2 is the most highly expressed family member in the lung and is enriched in the nasopharynx. Wfdc2 is the most highly expressed family member in differentiated epithelial cells isolated from the trachea, nasal passages and middle ear. Wfdc2 consists of 5 exons with exon 3 encoding an unstructured linker region that separates the two WFDC domains. This genomic organisation appears to be restricted to the Muridae and Cricetidae families of rodents.Similar to the situation in man, mouse wfdc2 can be alternatively spliced to yield a number of distinct transcripts that have the potential to generate a repertoire of distinct protein isoforms.We used immunohistochemistry to localise the proteins to tissues of the respiratory tract and head and neck regions. Although the protein was limited to epithelial cells of the respiratory tract and nasal and oral cavities, it was expressed in different cells in different regions suggesting expression is governed by a unique regulatory mechanism. Recombinant WFDC2 did not possess antiproteinase activity against trypsin or elastase and had no clear antimicrobial activity.

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“…was identi ed as a robust interacting partner of HE4 by mass spectrometry and co-immunoprecipitation, the HE4-ANXA2 complex can promote ovarian cancer cell invasion and migration in vitro and tumor distant metastasis of lung in vivo, downregulation of HE4 decreases expression of MKNK2 and LAMB2, which were associated with signaling pathways of MAPK and focal adhesion [5].…”

Section: Discussionmentioning

confidence: 99%

“…In physiological conditions, HE4 is secreted into the blood to act as a protease inhibitor and is involved in the maturation of sperm cells [2]. Several types of cancers are associated with HE4 overexpression both in serum and tissues, and it is a relatively promising and useful biomarker for the diagnosis of ovarian cancer [3][4][5], primary fallopian tube carcinoma [6], endometrial cancer(combined with CA125) [7], lung cancer [8], breast cancer(combined with miR-127) [9], gastric cancer [1], colorectal cancer [10] and pancreatic adenocarcinomas [11]. In 2008, HE4 was cleared as a serum marker to monitor disease recurrence or progression in patients with epithelial ovarian cancer (EOC) by Food and Drug Administration of USA.…”

Section: Introductionmentioning

confidence: 99%

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

Zhu

Tan

et al. 2020

Preprint

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

Cited by 49 publications

References 19 publications

Inhibition of DUSP6 sensitizes ovarian cancer cells to chemotherapeutic agents via regulation of ERK signaling response genes

Inhibition of DUSP6 sensitizes ovarian cancer cells to chemotherapeutic agents via regulation of ERK signaling response genes

Expression and function of murine WFDC2 in the respiratory tract

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

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