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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Vydáno v:	Cell communication and signaling Ročník 23; číslo 1; s. 415 - 19
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London BioMed Central 02.10.2025 BioMed Central Ltd Springer Nature B.V BMC
Témata:	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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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1478-811X 1478-811X
DOI:	10.1186/s12964-025-02400-y