Tight junction disruption via claudin-6 overexpression promotes invasion and recurrence in high-grade endometrial tumors

doi:10.5306/wjco.v16.i11.110257

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Nov 24, 2025 (publication date) through Nov 21, 2025

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World Journal of Clinical Oncology

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2218-4333

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

Basic Study

World J Clin Oncol. Nov 24, 2025; 16(11): 110257
Published online Nov 24, 2025. doi: 10.5306/wjco.v16.i11.110257

Tight junction disruption via claudin-6 overexpression promotes invasion and recurrence in high-grade endometrial tumors

Noura A A Ebrahim, Tamer S Eissa, Mustafa A Hussein, Omnia Mohamed Korany, Nancy H Amin

Noura A A Ebrahim, Mustafa A Hussein, Nancy H Amin, Department of Oncologic Pathology, National Cancer Institute, Cairo University, Cairo 11796, Al Qāhirah, Egypt

Tamer S Eissa, Department of Obstetrics and Gynecology, Kasr Alainy Faculty of Medicine, Cairo University, Cairo 11562, Al Qāhirah, Egypt

Omnia Mohamed Korany, Department of Medical Oncology, National Cancer Institute, Cairo University, Cairo 11796, Al Qāhirah, Egypt

Author contributions: Ebrahim NAA was responsible for the overall design, coordination, and execution of the study. She carried out the histopathological and immunohistochemical analyses, performed the tumor subtype classification, conducted the statistical data evaluation, prepared the figures, and was deeply involved in drafting the manuscript; Eissa TS contributed significantly to the study’s conceptual development, provided expert clinical input in gynecologic oncology, assisted with the selection and clinical profiling of cases, and supported the interpretation of pathological and clinical correlations; Hussein MA contributed to the validation and interpretation of the histological data, provided expertise in tumor classification protocols, and critically reviewed the manuscript to enhance its scientific rigor; Korany OM participated in writing the manuscript, facilitated the acquisition of clinical data and patient identification, and offered thoughtful revisions and conceptual insights throughout the writing process; Amin NH contributed to the pathological evaluation of tissue samples, ensured the accuracy and consistency of diagnostic findings, and was involved in quality control for both histological and immunohistochemical assessments. All the authors reviewed and approved the final manuscript and collectively assume responsibility for the validity, integrity, and originality of the work.

Institutional review board statement: This study was conducted following the ethical standards outlined in the Declaration of Helsinki. Ethical clearance was obtained from the Institutional Review Board (IRB) of the National Cancer Institute, Cairo University (Approval No. PA2502-501-094-197). Patient confidentiality was rigorously preserved through data anonymization. Owing to the retrospective nature of the research, the IRB waived the requirement for informed consent.

Institutional animal care and use committee statement: No animals or animal-derived procedures were used in this study. As such, approval from the Institutional Animal Care and Use Committee (IACUC) was not applicable. All experimental work was conducted in full compliance with institutional and ethical regulations governing research involving human tissue specimens.

Conflict-of-interest statement: The authors declare that they have no competing interests. All stages of the study, including data analysis and interpretation, were performed independently and were free from any external financial, professional, or institutional influence.

Data sharing statement: The data supporting the findings of this study are available from the corresponding author upon reasonable request.

Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

Corresponding author: Noura A A Ebrahim, MD, PhD, Assistant Professor, Consultant, Post Doctoral Researcher, Postdoc, Department of Oncologic Pathology, National Cancer Institute, Cairo University, 1^st Kasr Alainy Street, Cairo 11796, Al Qāhirah, Egypt. npathologist@gmail.com

Received: June 3, 2025
Revised: June 20, 2025
Accepted: October 25, 2025
Published online: November 24, 2025
Processing time: 171 Days and 18.7 Hours

Abstract

BACKGROUND

Claudin-6 (CLDN6), a tight junction protein typically restricted to embryonic tissues, is re-expressed in various cancers. However, its prognostic significance in high-grade endometrial carcinoma (HGEC) remains unclear.

AIM

To investigate the expression pattern of CLDN6 in HGEC and assess its correlation with clinicopathological parameters and patient survival.

METHODS

Immunohistochemical analysis of CLDN6 expression was performed on formalin-fixed, paraffin-embedded tissues from 80 patients diagnosed with HGEC. Associations between CLDN6 expression and histological subtype, the International Federation of Gynecology and Obstetrics (FIGO) stage, depth of myometrial invasion, lymphovascular space invasion, recurrence, and survival outcomes were statistically analysed. Univariate and multivariate Cox regression models were used to identify independent prognostic factors.

RESULTS

High CLDN6 expression was detected in a subset of HGEC patients and was significantly associated with nonendometrioid histology (P = 0.026), advanced FIGO stage (P = 0.015), deep myometrial invasion (P = 0.038), and recurrence (P = 0.002). While Kaplan-Meier analysis did not reveal a statistically significant difference in disease-free survival or overall survival between the high CLDN6 expression group and the low CLDN6 expression group, multivariate Cox regression revealed that CLDN6 overexpression was an independent predictor of shorter disease-free survival [hazard ratio (HR) = 68.98, P = 0.022] and overall survival (HR = 24.023, P = 0.038).

CONCLUSION

CLDN6 overexpression is associated with aggressive tumor features and poor clinical outcomes in HGEC, suggesting its utility as a prognostic biomarker and potential therapeutic target.

Keywords: Claudin-6; High-grade endometrial carcinoma; Prognostic biomarker; Immunohistochemistry; Survival analysis; Tumor aggressiveness

Core Tip: This investigation elucidates the tumor-promoting function of claudin-6 (CLDN6) in high-grade endometrial carcinoma. Immunohistochemical analysis of 80 clinical samples revealed a strong correlation between elevated CLDN6 expression and adverse pathological features, such as the nonendometrioid histologic subtype, extensive myometrial infiltration, lymphovascular space involvement, and regional lymph node dissemination. Multivariate statistical evaluation revealed that CLDN6 expression was an independent prognostic indicator for both disease-free survival and overall survival. Collectively, these results suggest that CLDN6 may serve as a valuable prognostic marker and a viable therapeutic target in the management of aggressive forms of endometrial cancer.