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Tumor Necrosis Factor Ligand-Related Molecule 1A Regulates the Occurrence of Colitis-Associated Colorectal Cancer

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Abstract

Background

Tumor necrosis factor ligand-related molecule 1 A (TLlA) is closely related to the occurrence and development of inflammatory bowel disease.

Aims

We aimed to explore whether TLlA was involved in the occurrence of colitis-associated colorectal cancer (CAC).

Methods

Firstly, azoxymethane (AOM) and dextran sulfate sodium (DSS) were used to construct the CAC mice model in wild-type (WT) and TL1A transgenic (Tg) mice with TL1A high expression. The histopathological analysis was used for the evaluation of inflammation level, and the immunohistochemistry staining analysis was used to test the expression and location of proliferating cell nuclear antigen (PCNA) and β-catenin. Secondly, the HCT116 and HT29 cell lines were used for knockdown of TL1A gene for further assay including cell viability, cell clone, cell apoptosis and matrigel invasion. Western blot were used for quantitative protein expression of β-catenin and downstream oncogenes including c-myc and Cyclin D1 after knockdown of TL1A gene.

Results

The evaluation of inflammation level showed that the disease activity index score and tumor formation rate were significantly higher in AOM + DSS/Tg group than that in AOM + DSS/WT group. The expression of PCNA, β-catenin, c-myc, and Cyclin D1 in AOM + DSS/Tg group was significantly higher than that in AOM + DSS/WT group. The cell experiment showed that TL1A knockdown inhibited the cell proliferation, invasion, and migration. Moreover, the expression of c-myc and Cyclin D1 was significantly decreased after TL1A knockdown.

Conclusions

TL1A can induce tumor cell proliferation and promote the occurrence of CAC by activating Wnt/β-catenin pathway.

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References

  1. Targan SR. Introductory words about TL1A/DR3. Adv Exp Med Biol. 2011;691:271–274.

    Article  PubMed  CAS  Google Scholar 

  2. Lan X, Lan X, Chang Y, et al. Identification of two additional susceptibility loci for inflammatory bowel disease in a Chinese population. Cell Physiol Biochem. 2017;41:2077–2090.

    Article  PubMed  CAS  Google Scholar 

  3. Slebioda TJ, Bojarska-Junak A, Stanislawowski M, et al. TL1A as a potential local inducer of IL17A expression in colon mucosa of inflammatory bowel disease patients. Scand J Immunol. 2015;82:352–360.

    Article  PubMed  CAS  Google Scholar 

  4. Tremelling M, Berzuini C, Massey D, et al. Contribution of TNFSF15 gene variants to Crohn’s disease susceptibility confirmed in UK population. Inflamm Bowel Dis. 2008;14:733–737.

    Article  PubMed  Google Scholar 

  5. Siakavellas SI, Bamias G. Tumor necrosis factor-like cytokine TL1A and its receptors DR3 and DcR3: important new factors in mucosal homeostasis and inflammation. Inflamm Bowel Dis. 2015;21:2441–2452.

    PubMed  Google Scholar 

  6. Yoshihiro A, Minoru N. The role of TL1A and DR3 in autoimmune and inflammatory diseases. Mediators Inflamm. 2013;2013:258164.

    Google Scholar 

  7. Takedatsu H, Michelsen KS, Wei B, et al. TL1A (TNFSF15) regulates the development of chronic colitis by modulating both T-helper 1 and T-helper 17 activation. Gastroenterology. 2008;135:552–567.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Zaki MH, Vogel P, Malireddi RK, et al. The NOD-like receptor NLRP12 attenuates colon inflammation and tumorigenesis. Cancer Cell. 2011;20:649–660.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Tenesa A, Dunlop MG. New insights into the aetiology of colorectal cancer from genome-wide association studies. Nat Rev Genet. 2009;10:353–358.

    Article  PubMed  CAS  Google Scholar 

  10. Rubin DC, Shaker A, Levin MS. Chronic intestinal inflammation: inflammatory bowel disease and colitis-associated colon cancer. Front Immunol. 2012;3:107.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Farraye FA, Odze RD, Eaden J, et al. AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology. 2010;138:738–745.

    Article  PubMed  Google Scholar 

  12. Gemoll T, Kollbeck SL, Karstens KF, et al. EB1 protein alteration characterizes sporadic but not ulcerative colitis associated colorectal cancer. Oncotarget.. 2017;8:54939–54950.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Pikoulis E, Margonis GA, Angelou A, et al. Statins in the chemoprevention of colorectal cancer in established animal models of sporadic and colitis-associated cancer. Eur J Cancer Prev. 2016;25:102–108.

    Article  PubMed  CAS  Google Scholar 

  14. Yaeger R, Shah MA, Miller VA, et al. Genomic alterations observed in colitis-associated cancers are distinct from those found in sporadic colorectal cancers and vary by type of inflammatory bowel disease. Gastroenterology. 2016;151(278.e276):287.e276.

    Google Scholar 

  15. Lu T, Dang S, Zhu R, et al. Adamts18 deficiency promotes colon carcinogenesis by enhancing β-catenin and p38MAPK/ERK1/2 signaling in the mouse model of AOM/DSS-induced colitis-associated colorectal cancer. Oncotarget. 2017;8:18979–18990.

    PubMed  PubMed Central  Google Scholar 

  16. Shih DQ, Barrett R, Zhang X, et al. Constitutive TL1A (TNFSF15) expression on lymphoid or myeloid cells leads to mild intestinal inflammation and fibrosis. PLoS ONE. 2011;6:e16090.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Sethi G, Sung B, Aggarwal BB. Therapeutic potential of VEGI/TL1A in autoimmunity and cancer. Adv Exp Med Biol. 2009;647:207–215.

    Article  PubMed  CAS  Google Scholar 

  18. Wang X, Mandal AK, Saito H, et al. Arsenic and chromium in drinking water promote tumorigenesis in a mouse colitis-associated colorectal cancer model and the potential mechanism is ROS-mediated Wnt/beta-catenin signaling pathway. Toxicol Appl Pharmacol. 2012;262:11–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Lee G, Goretsky T, Managlia E, et al. Phosphoinositide 3-kinase signaling mediates beta-catenin activation in intestinal epithelial stem and progenitor cells in colitis. Gastroenterology. 2010;139(869.e9):881.e9.

    Google Scholar 

  20. Claessen MMH, Schipper MEI, Bas O, Siersema PD, Offerhaus GJA, Vleggaar FP. WNT-pathway activation in IBD-associated colorectal carcinogenesis: potential biomarkers for colonic surveillance. Cell Oncol. 2010;32:303–310.

    PubMed  PubMed Central  CAS  Google Scholar 

  21. Brown JB, Lee G, Managlia E, et al. Mesalamine inhibits epithelial beta-catenin activation in chronic ulcerative colitis. Gastroenterology. 2010;138:595.

    Article  PubMed  CAS  Google Scholar 

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Funding

This research is supported by funding from an innovative project for provincial graduate students in Hebei Province (CXZZBS2017116).

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Authors and Affiliations

  1. Department of Gastroenterology, The Second Hospital of Hebei Medical University, No. 215, West Heping Road, Shijiazhuang City, Hebei Province, People’s Republic of China

    Weiwei Niu, Zhe Wu, Jing Wang, Hong Zhang, Wenxiu Jia, Mingyue Yang, Yuxin Luo & Xiaolan Zhang

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  1. Weiwei Niu
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  2. Zhe Wu
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  3. Jing Wang
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  4. Hong Zhang
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  5. Wenxiu Jia
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  6. Mingyue Yang
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  7. Yuxin Luo
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  8. Xiaolan Zhang
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Author’s contribution

All named authors have agreed to the publication of this manuscript, and it does not infringe on any copyright or property rights.

Corresponding author

Correspondence to Xiaolan Zhang.

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The authors have no conflict of interest to disclose.

Ethics standard

A statement of nonretrospective ethical approval obtained for the animal experiments was conducted in the study. In addition, I confirm that tumor burden did not exceed the recommended dimensions, see University of Pennsylvania Guidelines and that animals were anesthetized and killed using acceptable techniques.

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Niu, W., Wu, Z., Wang, J. et al. Tumor Necrosis Factor Ligand-Related Molecule 1A Regulates the Occurrence of Colitis-Associated Colorectal Cancer. Dig Dis Sci 63, 2341–2350 (2018). https://doi.org/10.1007/s10620-018-5126-0

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  • DOI: https://doi.org/10.1007/s10620-018-5126-0

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