Observational Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Apr 15, 2024; 16(4): 1344-1360
Published online Apr 15, 2024. doi: 10.4251/wjgo.v16.i4.1344
Establishment of a cholangiocarcinoma risk evaluation model based on mucin expression levels
Chun-Yuan Yang, Li-Mei Guo, Yang Li, Guang-Xi Wang, Xiao-Wei Tang, Qiu-Lu Zhang, Ling-Fu Zhang, Jian-Yuan Luo
Chun-Yuan Yang, Li-Mei Guo, Yang Li, Guang-Xi Wang, Xiao-Wei Tang, Qiu-Lu Zhang, Department of Pathology, Institute of Systems Biomedicine, School of Basic Medical Sciences Peking University, Peking University Third Hospital, Peking University Health Science Center, Beijing 100191, China
Ling-Fu Zhang, Department of General Surgery, Peking University Third Hospital, Beijing 100191, China
Jian-Yuan Luo, Department of Medical Genetics, Department of Biochemistry and Biophysics, School of Basic Medical Sciences Peking University, Peking University Health Science Center, Beijing 100191, China
Co-first authors: Chun-Yuan Yang and Li-Mei Guo.
Author contributions: Yang CY and Guo LM provided study concept, design, and methodology of the paper; Yang CY, Guo LM, and Luo JY performed writing, review and revision of the paper; Yang CY, Li Y, Wang GX, Tang XW, Zhang QL, and Zhang LF performed acquisition, analysis and interpretation of data, and statistical analysis; Guo LM provided technical and material support. All authors read and approved the final paper. Yang CY and Guo LM contributed equally to this work and are designated as co-first authors for two main reasons. Firstly, our study was a result of collaborative efforts, with the design and conceptualization evolving through extensive discussions between Yang CY and Guo LM. Continuous communications ensured improvement of our manuscript at both pre-submission and post-submission stages. Secondly, the overall research team encompassed authors with diverse skills from various fields. Yang CY performed bioinformatic analyses, and Guo LM was responsible for clinical validation. The co-first authorship signature respected the collaboration of different expertise, ultimately enhancing the paper’s quality and reliability. In summary, we believe that designating Yang CY and Guo LM as co-first authors of our manuscript as it accurately reflects our team’s collaborative spirit and equal contributions.
Institutional review board statement: The study was reviewed and approved by the Science and Research Office of Peking University Third Hospital.
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: There are no conflicts of interest to report.
Data sharing statement: No additional data are available.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
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: Li-Mei Guo, MD, Doctor, Professor, Department of Pathology, Institute of Systems Biomedicine, School of Basic Medical Sciences Peking University, Peking University Third Hospital, Peking University Health Science Center, No. 38 Xueyuan Road, Haidian District, Beijing 100191, China. guolimei@bjmu.edu.cn
Received: December 20, 2023
Peer-review started: December 20, 2023
First decision: December 27, 2023
Revised: January 9, 2024
Accepted: February 25, 2024
Article in press: February 25, 2024
Published online: April 15, 2024
Processing time: 112 Days and 19 Hours
Abstract
BACKGROUND

Cholangiocarcinoma (CCA) is a highly malignant cancer, characterized by frequent mucin overexpression. MUC1 has been identified as a critical oncogene in the progression of CCA. However, the comprehensive understanding of how the mucin family influences CCA progression and prognosis is still incomplete.

AIM

To investigate the functions of mucins on the progression of CCA and to establish a risk evaluation formula for stratifying CCA patients.

METHODS

Single-cell RNA sequencing data from 14 CCA samples were employed for elucidating the roles of mucins, complemented by bioinformatic analyses. Subsequent validations were conducted through spatial transcriptomics and immunohistochemistry. The construction of a risk evaluation model utilized the least absolute shrinkage and selection operator regression algorithm, which was further confirmed by independent cohorts and diverse data types.

RESULTS

CCA tumor cells with elevated levels of MUC1 and MUC4 showed activated nucleotide metabolic pathways and increased invasiveness. MUC5AC-high cells were found to promote CCA progression through WNT signaling. MUC5B-high cells exhibited robust cellular oxidation activities, leading to resistance against antitumoral treatments. MUC13-high cells were observed to secret chemokines, recruiting and transforming macrophages into the M2-polarized state, thereby suppressing antitumor immunity. MUC16-high cells were found to promote tumor progression through interleukin-1/nuclear factor kappa-light-chain-enhancer of activated B cells signaling upon interaction with neutrophils. Utilizing the expression levels of these mucins, a risk factor evaluation formula for CCA was developed and validated across multiple cohorts. CCA samples with higher risk factors exhibited stronger metastatic potential, chemotherapy resistance, and poorer prognosis.

CONCLUSION

Our study elucidates the functional mechanisms through which mucins contribute to CCA development, and provides tools for risk stratification in CCA.

Keywords: Mucin; Cholangiocarcinoma; Single-cell RNA sequencing; Spatial transcriptomics; Prognosis

Core Tip: In this study, we have conducted a comprehensive investigation of mucins in cholangiocarcinoma (CCA) using a combination of bioinformatics analysis, including single-cell RNA sequencing and spatial transcriptomics, along with experimental validations. Our findings highlight the significant roles of MUC1, MUC4, and MUC5B in CCA metabolism, contributing to tumor progression and therapy resistance. Additionally, MUC5AC has been identified as a regulator of CCA invasiveness through the WNT signaling. MUC13 and MUC16 are found to play critical roles in tumor-immune interactions, regulating antitumoral immune defense. The collect impact of these mucins enables the development of a CCA prognosis evaluation model that effectively predicts tumor malignancy, treatment effectiveness, and prognosis in CCA cases.