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Human Epididymis Protein 4 and Lewis y Enhance Chemotherapeutic Resistance in Epithelial Ovarian Cancer Through the p38 MAPK Pathway

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Abstract

Introduction

Ovarian cancer has a high mortality rate due to difficulties in early detection and chemotherapy resistance. Human epididymal protein 4 (HE4) has been adopted as a novel serum biomarker for early ovarian cancer diagnosis, and the presence of Lewis y antigen modifications on HE4 in ovarian cancer cell lines has been detected in previous studies. The aim of this study was to analyze the expression of HE4 and Lewis y antigen in human ovarian cancer in order to find a correlation between them, as well as with the clinical pathological parameters of patients with ovarian cancer.

Methods

Immunohistochemistry was used to detect the respective expression of these compounds in two patient groups (chemotherapy-resistant and chemotherapy-sensitive) containing a total of 95 patients. Then, a bioinformatic approach was adopted and online large sample databases (TCGA, CCLE, and GTEx; Metascape, Cytoscape) were used to explore the potential mechanisms of action of these compounds.

Results

The results of this study demonstrate that high HE4 and Lewis y expression could be used as markers for chemotherapy resistance and poor prognosis in patients with ovarian cancer. These two expression events were widely correlated in various cancer tissues and are thought to act by activating the p38 mitogen-activated protein kinases (MAPK) pathway and inducing Vascular Endothelial Growth Factor A (VEGFA), Prostaglandin-Endoperoxide Synthase 2 (PTGS2), Early Growth Response 1 (EGR1), and Hypoxia-Inducible Factor 1-Alpha (HIFI1A), thereby promoting malignant biological behavior and resistance in ovarian cancer.

Conclusions

These findings not only reveal the possible mechanism by which HE4 and Lewis y antigen affect ovarian cancer but also identify a four-gene signature that could be very useful in ovarian cancer detection and/or the development of new targeted therapies.

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Acknowledgements

Funding

The present study was supported by the National Natural Science Foundation of China (grant nos. 81472437 and 81672590), National Natural Science Foundation of China Youth Science Foundation (No. 81602438), Doctoral start-up fund of Liaoning Province (Grant No. 201601133) and 345 Talent Project of Shengjing Hospital. The journal’s Rapid Service Fee was funded by the authors.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Author Contributions

Jian Gao and Liancheng Zhu contributed equally to this work. Jian Gao and Liancheng Zhu conceived, designed the study, wrote and drafted the manuscript. Jian Gao and Huiyu Zhuang performed the immunohistochemical staining experiment and data analysis. Liancheng Zhu performed the bioinformatics analysis. Bei Lin provided fund support and reviewed the manuscript. All authors read and approved the final version of the manuscript and agree to be accountable for all aspects of the research in ensuring that the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Compliance with Ethics Guidelines

The present study was approved by the Ethical Committee of Shengjing Hospital affiliated to China Medical University (number of approval 2021PS561K).

Disclosures

Jian Gao, Liancheng Zhu, Huiyu Zhuang and Bei Lin all confirm that they have no conflicts of interest to disclose.

Data Availability

The datasets used during the present study are available from the corresponding author upon reasonable request.

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Author notes

  1. Jian Gao and Liancheng Zhu contributed equally to this work.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, China

    Jian Gao, Liancheng Zhu & Bei Lin

  2. Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Benxi, Liaoning, China

    Jian Gao, Liancheng Zhu & Bei Lin

  3. Department of Obstetrics and Gynecology, Beijing Chaoyang Hospital Affiliated To Capital Medical University, Beijing, 100043, China

    Huiyu Zhuang

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  1. Jian Gao
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Correspondence to Bei Lin.

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Gao, J., Zhu, L., Zhuang, H. et al. Human Epididymis Protein 4 and Lewis y Enhance Chemotherapeutic Resistance in Epithelial Ovarian Cancer Through the p38 MAPK Pathway. Adv Ther 39, 360–378 (2022). https://doi.org/10.1007/s12325-021-01941-1

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