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
ARTICLE HIGHLIGHTS
Research background

Cholangiocarcinoma (CCA) is the second most common type of liver cancer and exhibits a high mortality rate. Mucins are a family of protein that are elevated in various tumor types, including CCA. However, the comprehensive functional mechanisms and prognosis evaluation significance of mucins in CCA progression remain largely unknown.

Research motivation

MUC1 has been identified as an oncogene that induce CCA progression through multiple signaling pathways. Nevertheless, how the mucin family regulate CCA is still elusive.

Research objectives

To investigate the functional mechanisms of mucins in CCA and to conduct a CCA risk evaluation model based on mucin expression levels.

Research methods

For the detection of mucin functions in CCA, single-cell RNA sequencing data from 14 CCA samples were employed, supported by comprehensive bioinformatic analyses. Validations were pursued through spatial transcriptomics and immunohistochemistry. The establishment of a CCA risk evaluation model based on mucin expression levels employed the least absolute shrinkage and selection operator regression algorithm. The risk evaluation model was constructed using RNA level of mucins, and subsequently validated by both RNA and protein levels of mucins, as well as multiple independent cohorts.

Research results

Elevated levels of MUC1 and MUC4 in CCA tumor cells were associated with activated nucleotide metabolic pathways and higher invasiveness. CCA tumor cells with heightened MUC5AC expression were found to induce tumor progression through the WNT signaling pathway. Robust cellular oxidation activities in MUC5B-high CCA tumor cells facilitated antitumoral treatment resistance. MUC13-high cells transformed macrophage into M2-polarization state through the PROS signaling and chemokines, including CCL2, CCL4, and CXCR12. Neutrophils induced the activation of nuclear factor kappa-light-chain-enhancer of activated B cells signaling in MUC16-high cells through the IL1B signaling, thereby promoting CCA development. Utilizing the expression levels of these mucins, a CCA prognosis evaluation model was developed and validated across multiple cohorts, which simultaneously exhibited predictive functions on the evaluation of CCA malignancy, metastasis potential, and chemotherapy sensitivity.

Research conclusions

Our study unveils the functional mechanisms by which mucins contribute to CCA progression, and offers a potential tool for CCA risk stratification.

Research perspectives

The discovery of mucin functions in CCA development and prognosis prediction indicate that mucins may be promising treatment targets for CCA.