Tumor necrosis factor promotes doublecortin-like kinase 1 expression and cellular reprogramming in intestinal epithelial cells leading to neoplastic transformation

Background Tumor necrosis factor (TNF) is a critical mediator in chronic inflammation and colorectal cancer (CRC) progression. However, whether and how prolonged TNF exposure triggers CRC is not fully understood. Methods TNF-induced expression of Dclk1 , a cancer stem cell (CSC) marker, was assessed...

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Published in:Cell communication and signaling Vol. 23; no. 1; pp. 415 - 19
Main Authors: Huang, Lin, Li, Tianqi, Huang, Xu, Chen, Xiaoxi, Ju, Yuanyuan, Xu, Lili, Ma, Chunhua, Tao, Yumei, Yang, Yonghong, Bian, Xiaoyun, Huycke, Mark M., Wang, Xingmin
Format: Journal Article
Language:English
Published: London BioMed Central 02.10.2025
BioMed Central Ltd
Springer Nature B.V
BMC
Subjects:
Analysis
Animal models
Antimitotic agents
Antineoplastic agents
Biomedical and Life Sciences
c-Myc protein
Cancer
Cancer therapies
Cell activation
Cell Biology
Cell culture
Cell State and Fate in Health and Disease
Colitis
Colorectal cancer
Colorectal cancer stem cells
Colorectal carcinoma
Complications and side effects
Cytokines
Cytokines and Growth Factors
Development and progression
Doublecortin protein
Doublecortin-like kinase 1
EMT
Epithelial cells
Gene expression
Genetic aspects
Genetic engineering
Genetic transformation
Health aspects
Immunodeficiency
Inflammation
Inflammatory bowel disease
Intestine
Kinases
Life Sciences
Medical prognosis
Myc protein
Necrosis
NF-κB protein
Oncology, Experimental
Organoid
Organoids
Penicillin G
Protein-Ligand Interactions
Receptors
Reprogramming
RNA
RNA sequencing
Stem cells
Therapeutic targets
TNF-humanized mice
Transcription factors
Transgenic animals
Transgenic mice
Tumor necrosis factor
Tumor necrosis factor-TNF
Tumorigenesis
Tumors
Xenografts
China
Shanghai China
TNF-humanized mice
Organoid
Reprogramming
Doublecortin-like kinase 1
EMT
Colorectal cancer stem cells
ISSN:1478-811X, 1478-811X
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Summary:Background Tumor necrosis factor (TNF) is a critical mediator in chronic inflammation and colorectal cancer (CRC) progression. However, whether and how prolonged TNF exposure triggers CRC is not fully understood. Methods TNF-induced expression of Dclk1 , a cancer stem cell (CSC) marker, was assessed in IEC-6 intestinal epithelial cells, murine models, and colon organoids. TNF-induced reprogramming of intestinal epithelial cells was investigated through single-cell RNA sequencing and cellular transformation assayed by xenograft tumor model. Results We observed a significant increase in Dclk1 in the intestines of TNF -transgenic mice and TNF-treated IEC-6 cells. Notably, DCLK1 expression correlated positively with inflammation, TNF levels, and TNFRSF1a in human subjects. Silencing of Tnfrsf1a markedly reduced Dclk1 expression, underscoring the role of TNF-Tnfrsf1a axis in the regulation of Dclk1 expression. Furthermore, Dclk1-positive cells were significantly elevated in the intestines of TNF-treated wild-type mice, but not in Tnfrsf1a −/− mice, compared to controls. Inhibition of NFκB and c-Myc also led to a marked reduction in Dclk1 expression. Intriguingly, colonic organoids derived from TNF -transgenic mice exhibited increased numbers and sizes, whereas those from Tnfrsf1a −/− mice showed the opposite trend. Single-cell RNA sequencing revealed that prolonged TNF exposure induced CSC emergence through the reprogramming of Dclk1-positive tuft cells and activation of CRC-related pathways. Critically, prolonged TNF treatment resulted in neoplastic transformation of intestinal epithelial cells, leading to xenograft tumor formation in immunodeficient mice. Conclusions These findings provide novel insights into how chronic inflammation drives the genesis of intestinal CSCs and fosters CRC development, highlighting potential therapeutic targets for combating colitis-associated colorectal cancer.
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ISSN:1478-811X
1478-811X
DOI:10.1186/s12964-025-02400-y