Academic Journal
Tumor necrosis factor promotes doublecortin-like kinase 1 expression and cellular reprogramming in intestinal epithelial cells leading to neoplastic transformation.
| Τίτλος: | Tumor necrosis factor promotes doublecortin-like kinase 1 expression and cellular reprogramming in intestinal epithelial cells leading to neoplastic transformation. |
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| Συγγραφείς: | Huang L; Department of Gastroenterology, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, 226018, Jiangsu, China.; Nantong Institute of Genetics and Reproductive Medicine, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, 226018, Jiangsu, China.; Nantong Key Laboratory of Genetics and Reproductive Medicine, Nantong, 226018, Jiangsu, China., Li T; Nantong Institute of Genetics and Reproductive Medicine, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, 226018, Jiangsu, China.; Nantong Key Laboratory of Genetics and Reproductive Medicine, Nantong, 226018, Jiangsu, China., Huang X; Nantong Institute of Genetics and Reproductive Medicine, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, 226018, Jiangsu, China.; Nantong Key Laboratory of Genetics and Reproductive Medicine, Nantong, 226018, Jiangsu, China., Chen X; Department of Gastroenterology, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, 226018, Jiangsu, China., Ju Y; Nantong Institute of Genetics and Reproductive Medicine, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, 226018, Jiangsu, China.; Nantong Key Laboratory of Genetics and Reproductive Medicine, Nantong, 226018, Jiangsu, China., Xu L; Nantong Institute of Genetics and Reproductive Medicine, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, 226018, Jiangsu, China.; Nantong Key Laboratory of Genetics and Reproductive Medicine, Nantong, 226018, Jiangsu, China., Ma C; Nantong Institute of Genetics and Reproductive Medicine, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, 226018, Jiangsu, China.; Nantong Key Laboratory of Genetics and Reproductive Medicine, Nantong, 226018, Jiangsu, China., Tao Y; Department of Pathology, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, 226018, Jiangsu, China., Yang Y; Department of Nephrology, Rheumatology, and Immunology, Nantong Children's Hospital, Nantong, 226018, Jiangsu, China., Bian X; Department of Gastroenterology, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, 226018, Jiangsu, China., Huycke MM; Department of Radiation Oncology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA., Wang X; Nantong Institute of Genetics and Reproductive Medicine, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, 226018, Jiangsu, China. xingmin-wang@ntu.edu.cn.; Nantong Key Laboratory of Genetics and Reproductive Medicine, Nantong, 226018, Jiangsu, China. xingmin-wang@ntu.edu.cn.; Nantong Maternity and Child Healthcare Hospital, 399 Century Ave, Nantong, 226018, Jiangsu, China. xingmin-wang@ntu.edu.cn. |
| Πηγή: | Cell communication and signaling : CCS [Cell Commun Signal] 2025 Oct 02; Vol. 23 (1), pp. 415. Date of Electronic Publication: 2025 Oct 02. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: BioMed Central Country of Publication: England NLM ID: 101170464 Publication Model: Electronic Cited Medium: Internet ISSN: 1478-811X (Electronic) Linking ISSN: 1478811X NLM ISO Abbreviation: Cell Commun Signal Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [London] : BioMed Central, c2003- |
| Ιατρικοί όροι (MeSH): | Cell Transformation, Neoplastic*/pathology , Cell Transformation, Neoplastic*/metabolism , Cell Transformation, Neoplastic*/genetics , Cell Transformation, Neoplastic*/drug effects , Protein Serine-Threonine Kinases*/metabolism , Protein Serine-Threonine Kinases*/genetics , Tumor Necrosis Factor-alpha*/metabolism , Tumor Necrosis Factor-alpha*/pharmacology , Epithelial Cells*/metabolism , Epithelial Cells*/pathology , Epithelial Cells*/drug effects , Cellular Reprogramming*/drug effects , Intracellular Signaling Peptides and Proteins*/metabolism , Intracellular Signaling Peptides and Proteins*/genetics , Intestinal Mucosa*/pathology, Receptors, Tumor Necrosis Factor, Type I/metabolism ; Receptors, Tumor Necrosis Factor, Type I/genetics ; Intestines/pathology ; Animals ; Doublecortin-Like Kinases ; Humans ; Mice ; Mice, Transgenic ; Mice, Inbred C57BL |
| Περίληψη: | 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. |
| Competing Interests: | Declarations. Ethics approval and consent to participate: The animal studies were approved by the Institutional Animal Care and Use Committee at Nantong University (Approval number: S20210512-004). No human subjects were involved in this study. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests. |
| References: | Mol Biol Cell. 2003 May;14(5):1790-800. (PMID: 12802055) EMBO Rep. 2014 Mar;15(3):244-53. (PMID: 24531722) Oncotarget. 2017 Nov 1;8(60):102176-102190. (PMID: 29254234) J Cell Biol. 1979 Feb;80(2):248-65. (PMID: 88453) J Intern Med. 1997 Nov;242(5):413-9. (PMID: 9408072) Mol Biol Rep. 2019 Jun;46(3):3149-3156. (PMID: 30989559) Gastroenterology. 2014 Jan;146(1):245-56. (PMID: 24096005) Int J Mol Sci. 2023 Nov 16;24(22):. (PMID: 38003596) Carcinogenesis. 2020 May 14;41(3):303-312. (PMID: 31562741) Genes Immun. 2019 Nov;20(8):609-626. (PMID: 30686825) Oncogene. 2016 Nov 3;35(44):5795-5806. (PMID: 27065323) Theranostics. 2022 Jul 4;12(12):5258-5271. (PMID: 35910805) Lab Invest. 2017 Oct;97(10):1245-1261. (PMID: 28414327) Nat Genet. 2019 Dec;51(12):1723-1731. (PMID: 31784729) Int J Biol Sci. 2021 Jun 26;17(11):2683-2702. (PMID: 34345201) Cancer Res. 2011 Jul 1;71(13):4707-19. (PMID: 21555371) EMBO J. 2021 Sep 15;40(18):e108647. (PMID: 34459003) EMBO J. 1991 Dec;10(13):4025-31. (PMID: 1721867) Oncotarget. 2015 Oct 13;6(31):30876-86. (PMID: 26362399) Cancer Res. 2011 Mar 15;71(6):2328-38. (PMID: 21285251) Transl Oncol. 2022 Mar;17:101317. (PMID: 34998236) J Immunol. 2017 Sep 1;199(5):1886-1897. (PMID: 28747340) Cancer Res. 2006 Dec 15;66(24):11565-70. (PMID: 17178846) Lancet Gastroenterol Hepatol. 2017 Apr;2(4):269-276. (PMID: 28404156) Sci Rep. 2020 Feb 4;10(1):1804. (PMID: 32019974) Nature. 2007 Jan 4;445(7123):111-5. (PMID: 17122771) Cell Mol Gastroenterol Hepatol. 2022;13(1):219-232. (PMID: 34418586) Nat Med. 2017 Oct 6;23(10):1124-1134. (PMID: 28985214) Nature. 2009 Jan 29;457(7229):608-11. (PMID: 19092804) Nat Genet. 2013 Jan;45(1):98-103. (PMID: 23202126) Nat Commun. 2024 Aug 22;15(1):7204. (PMID: 39169060) Gastroenterology. 2022 Mar;162(3):715-730.e3. (PMID: 34757143) Cancer Res. 2012 Oct 15;72(20):5219-29. (PMID: 22915753) Cell Death Differ. 2023 May;30(5):1184-1197. (PMID: 36914767) Sci Rep. 2015 Oct 08;5:14983. (PMID: 26447334) J Clin Invest. 2008 Feb;118(2):560-70. (PMID: 18219394) EMBO Mol Med. 2023 May 8;15(5):e17198. (PMID: 36896602) Nature. 2019 Mar;567(7746):49-55. (PMID: 30814735) World J Gastroenterol. 2022 Feb 7;28(5):502-516. (PMID: 35316962) Nucleic Acids Res. 2022 Jan 7;50(D1):D1334-D1339. (PMID: 34718715) FEBS J. 2011 Apr;278(6):888-98. (PMID: 21232019) J Clin Invest. 2014 Mar;124(3):1283-95. (PMID: 24487592) Dis Model Mech. 2021 May 1;14(5):. (PMID: 33969420) Am J Physiol Cell Physiol. 2021 Jun 1;320(6):C1042-C1054. (PMID: 33788631) JAMA. 2023 Sep 12;330(10):951-965. (PMID: 37698559) Gastroenterology. 2023 Apr;164(4):593-609.e13. (PMID: 36634827) Cell Mol Gastroenterol Hepatol. 2022;13(1):195-197. (PMID: 34644539) Nature. 2013 Nov 14;503(7475):218-23. (PMID: 24196716) Exp Cell Res. 2016 Nov 15;349(1):119-127. (PMID: 27742576) Nat Cancer. 2021 Nov;2(11):1185-1203. (PMID: 35122059) Nature. 2007 Jan 4;445(7123):106-10. (PMID: 17122772) Nature. 2017 Nov 16;551(7680):333-339. (PMID: 29144463) Cell. 2013 Jan 17;152(1-2):25-38. (PMID: 23273993) Semin Cancer Biol. 2020 Aug;64:51-60. (PMID: 31112753) Gastroenterology. 2009 Dec;137(6):2179-80; author reply 2180-1. (PMID: 19879217) Gut. 2015 Mar;64(3):459-68. (PMID: 24906974) |
| Grant Information: | MS2022072 Nantong Commission of Health; CX2023002 Seed grant of Jiangsu Health Innovation Team Program; 81972783 National Natural Science Foundation of China; 2019 Jiangsu Distinguished Medical Expert Program; 2020 Jiangsu Health Innovation Team Program; YYR202001 Nantong Maternity and Child Healthcare Hospital |
| Contributed Indexing: | Keywords: Colorectal cancer stem cells; Doublecortin-like kinase 1; EMT; Organoid; Reprogramming; TNF-humanized mice |
| Substance Nomenclature: | EC 2.7.1.11 (Doublecortin-Like Kinases) EC 2.7.11.1 (Protein Serine-Threonine Kinases) 0 (Tumor Necrosis Factor-alpha) 0 (Receptors, Tumor Necrosis Factor, Type I) 0 (Intracellular Signaling Peptides and Proteins) EC 2.7.1.11 (DCLK1 protein, human) EC 2.7.11.1 (Dclk1 protein, mouse) |
| Entry Date(s): | Date Created: 20251002 Date Completed: 20260626 Latest Revision: 20260626 |
| Update Code: | 20260627 |
| PubMed Central ID: | PMC12492607 |
| DOI: | 10.1186/s12964-025-02400-y |
| PMID: | 41039610 |
| Βάση Δεδομένων: | MEDLINE |
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