N-deacetylase/N-sulfotransferase (heparan glucosaminyl) 4, a novel tumor suppressor, suppresses tumorigenesis and liver metastasis of colorectal cancer cells in mice
Resource
Cancer Res., 75,
Journal
Cancer Res.
Journal Issue
75
Pages
-
Date Issued
2015
Date
2015
Author(s)
Jao, Tzu-Ming
Tsai, Ming-Hong
Tzeng, Sheng-Tai
Yang, Ya-Chien
Abstract
Abstract Colorectal cancer (CRC) is one of the most common causes of cancer deaths in the world, and most of CRC arise sporadically by the emergence of multiple chromosomal aberrations. Allelic losses in the long arm of chromosome 4 are commonly encountered in many human malignancies, but few tumor suppressor genes (TSGs) are identified. By loss of heterozygosity study at chromosome 4 in 114 colorectal carcinomas, we identified N-deacetylase/N-sulfotransferase (heparan glucosaminyl) 4 (NDST4) as a novel TSG that had been published recently. We demonstrated for the first time that the genetic loss of NDST4 was significantly associated with advanced pathological stage and poorer overall survival of patients. Meanwhile, gene expression of NDST4 was obviously decreased in 30 (57.7%) of 52 CRC tumors when compared with their matched normal mucosae. In the present study, tumor suppressor activity of NDST4 was identified by in vitro cell models and mouse xenograft tumor models. Ectopic expression of NDST4 in the human CRC cells induced a significant suppression in cell proliferation, anchorage-independent growth and invasion in vitro. Subcutaneous injection of NDST4-inducible CRC cells in nude mice showed alleviated tumor growth in doxycycline treated mice when compared with doxycycline untreated mice. More importantly, via intrasplenic implantation, re-expression of NDST4 in silenced cells restrained liver metastasis, and also improved survival in nude mice. Taken together, these results indicate that NDST4 is a tumor suppressor gene associated with CRC, and its downregulation might promote tumor progression and distant metastasis. In addition, allelic loss of NDST4 gene could serve as a molecular predictor of metastasis and poor prognosis in patients with CRC. Citation Format: Tzu-Ming Jao, Ming-Hong Tsai, Sheng-Tai Tzeng, Ya-Chien Yang. N-deacetylase/N-sulfotransferase (heparan glucosaminyl) 4, a novel tumor suppressor, suppresses tumorigenesis and liver metastasis of colorectal cancer cells in mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2149. doi:10.1158/1538-7445.AM2015-2149