NDST4 deficiency enhances acute colitis and colitis-associated tumorigenesis in mice
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1
National Taiwan University, Taiwan
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2
Cardinal Tien Hospital, Taiwan
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3
Fu-Jen Catholic University, Taiwan
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4
National Taiwan University Hospital, Taiwan
NDST4 is one member of N-deacetylase/N-sulfotransferase (heparan glucosaminyl) (NDST) family, which are responsible for heparan sulfate (HS) biosynthesis on a core protein to form heparan sulfate proteoglycans (HSPGs). The HS chains of HSPGs bind to and regulate their functions of various growth factors, cytokines and chemokines. HSPGs ubiquitously reside on cell surface, inside the cell, and in the extracellular matrix. Importantly, the content and distribution of HSPGs are altered during tumorigenesis. Here we show that 30 (57.7%) out of 52 human colorectal carcinomas exhibited a dramatic reduction in NDST4 RNA transcripts, and that genetic loss of NDST4 was significantly associated with poor survival of patients with colorectal cancer. In addition, we generated an NDST4-knockout mouse strain, which developed and reproduced normally, while showed a marked increase in the thickness of the colonic crypts and the number of goblet cells of the colonic mucosa. Using the dextran sodium sulfate model of acute colitis, homozygous NDST4 mutants showed a significantly higher disease activity index and obviously hyperemic appearance in the cecum. In a colitis-associated cancer model, the size of colonic tumors induced by azoxymethane/dextran sodium sulfate was significantly increased in NDST4-deficient mice compared with wild-type mice. These results suggest that NDST4 might limit tumor-promoting inflammation and tumorigenesis by regulating the modification of HS chains of specific HSPGs in colon.
Acknowledgements
This work was supported by grants from the National Health Research Institutes (NHRI-EX101-10136BI) and the Cardinal Tien Hospital (CTH-100-1-2A01).
Keywords:
colorectal cancer,
NDST4-knockout mouse,
Colitis,
colitis-associated cancer,
tumor-promoting inflammation
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Immune-mediated disease pathogenesis
Citation:
Huang
C,
Tsai
M,
Jao
T,
Tzeng
S,
Lee
J,
Lo
W,
Chang
C,
Li
Y and
Yang
Y
(2013). NDST4 deficiency enhances acute colitis and colitis-associated tumorigenesis in mice.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00288
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Received:
12 Mar 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Prof. Ya-Chien Yang, National Taiwan University, Taipei, Taiwan, ycyangntu@ntu.edu.tw