Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Jun 15, 2024; 16(6): 2646-2662
Published online Jun 15, 2024. doi: 10.4251/wjgo.v16.i6.2646
Complement factor I knockdown inhibits colon cancer development by affecting Wnt/β-catenin/c-Myc signaling pathway and glycolysis
Yong-Jun Du, Yue Jiang, Yan-Mei Hou, Yong-Bo Shi
Yong-Jun Du, Yan-Mei Hou, Department of Proctology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan Province, China
Yue Jiang, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
Yong-Bo Shi, Department of Proctology, Zigong Hospital of Traditional Chinese Medicine, Zigong 643000, Sichuan Province, China
Author contributions: Du YJ contributed to the conceptualization of this study; Jiang Y was involved in the methodology; Shi YB took part in the investigation, resources, and writing - review & editing; Hou YM participated in the formal analysis; Du YJ, Jiang Y, and Hou YM contributed to the writing - original draft; and all authors had full access to the data in and take responsibility for the integrity of the data and the accuracy of the data analysis.
Institutional animal care and use committee statement: All animal experiments conducted in this study were approved by the Experimental Animal Ethics Committee of Hospital of Chengdu University of Traditional Chinese Medicine (Approval No. 2023DL-39).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. The relevant data in the GSE33113 and GSE44861 datasets can be accessed by entering numbers GSE33113 and GSE44861 in the Gene Expression Omnibus database (https://www.ncbi.nlm.nih.gov/).
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
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: Yong-Bo Shi, MM, Associate Chief Physician, Department of Proctology, Zigong Hospital of Traditional Chinese Medicine, No. 59 Machongkou Street, Da’an District, Zigong 643000, Sichuan Province, China. syb821004@163.com
Received: October 27, 2023
Peer-review started: October 27, 2023
First decision: January 6, 2024
Revised: January 24, 2024
Accepted: March 27, 2024
Article in press: March 27, 2024
Published online: June 15, 2024
Processing time: 231 Days and 19.7 Hours
Abstract
BACKGROUND

Colon cancer (CC) occurrence and progression are considerably influenced by the tumor microenvironment. However, the exact underlying regulatory mechanisms remain unclear.

AIM

To investigate immune infiltration-related differentially expressed genes (DEGs) in CC and specifically explored the role and potential molecular mechanisms of complement factor I (CFI).

METHODS

Immune infiltration-associated DEGs were screened for CC using bioinformatics. Quantitative reverse transcription polymerase chain reaction was used to examine hub DEGs expression in the CC cell lines. Stable CFI-knockdown HT29 and HCT116 cell lines were constructed, and the diverse roles of CFI in vitro were assessed using CCK-8, 5-ethynyl-2’-deoxyuridine, wound healing, and transwell assays. Hematoxylin and eosin staining and immunohistochemistry staining were employed to evaluate the influence of CFI on the tumorigenesis of CC xenograft models constructed using BALB/c male nude mice. Key proteins associated with glycolysis and the Wnt pathway were measured using western blotting.

RESULTS

Six key immune infiltration-related DEGs were screened, among which the expression of CFI, complement factor B, lymphoid enhancer binding factor 1, and SRY-related high-mobility-group box 4 was upregulated, whereas that of fatty acid-binding protein 1, and bone morphogenic protein-2 was downregulated. Furthermore, CFI could be used as a diagnostic biomarker for CC. Functionally, CFI silencing inhibited CC cell proliferation, migration, invasion, and tumor growth. Mechanistically, CFI knockdown downregulated the expression of key glycolysis-related proteins (glucose transporter type 1, hexokinase 2, lactate dehydrogenase A, and pyruvate kinase M2) and the Wnt pathway-related proteins (β-catenin and c-Myc). Further investigation indicated that CFI knockdown inhibited glycolysis in CC by blocking the Wnt/β-catenin/c-Myc pathway.

CONCLUSION

The findings of the present study demonstrate that CFI plays a crucial role in CC development by influencing glycolysis and the Wnt/β-catenin/c-Myc pathway, indicating that it could serve as a promising target for therapeutic intervention in CC.

Keywords: Colon cancer, Immune infiltration, Complement factor I, Glycolysis, Wnt/β-catenin/c-Myc pathway

Core Tip: We identified six hub immune infiltration-related differentially expressed genes, of which the expression of complement factor I (CFI), complement factor B, lymphoid enhancer binding factor 1, and SRY-related high-mobility-group box 4 were upregulated, whereas that of fatty acid-binding protein 1 and bone morphogenic protein-2 were downregulated. CFI knockdown inhibited HT29 and HCT116 cell proliferation, migration, invasion, and tumor growth in a colon cancer (CC) mouse model constructed from HT29 cells. CFI knockdown suppressed the expression of glycolysis-related proteins (glucose transporter type 1, hexokinase 2, lactate dehydrogenase A, and pyruvate kinase M2) and Wnt/β-catenin/c-Myc-related protein-expression levels (β-catenin and c-Myc). CFI knockdown suppressed glycolysis by inhibiting the Wnt/β-catenin/c-Myc signaling pathway. These findings delineate a potential therapeutic strategy for the clinical management of CC.