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Heparin/Heparan Sulfate Interacting Protein Gene Expression Is Up-regulated in Human Colorectal Carcinoma and Correlated with Differentiation Status and Metastasis¹

Department of Physiology, Faculty of Medicine, National University of Singapore, Singapore 119260 [Y. W., S. C. H.]; Department of Surgery, Tan Tock Seng Hospital, Singapore 308433 [D. C.]; and Department of Surgery, National University Hospital, Singapore 119074 [S. C.], Republic of Singapore

We applied a subtractive hybridization strategy to obtain genes that are differentially expressed in colorectal carcinoma. Heparin/heparan sulfate interacting protein (HIP) was shown to be up-regulated in colorectal carcinoma. A study of 53 patients with documented colorectal carcinoma showed that 70% of the tumors had HIP tumor-to-normal ratios (expression in tumor tissue compared to expression in normal mucosa) of >2. In six patients with concomitant polyps, HIP expression in the polyps was similar to the carcinoma, showing that up-regulation of HIP may be an early event in tumorigenesis. A significant inverse correlation between HIP levels and the presence of distant metastasis (Duke’s stage D) was noted. Similarly, HIP expression was also related to differentiation status in human colorectal carcinoma cell lines. HIP expression was lower in the poorly differentiated COLO 205 cell line compared to the well-differentiated HT-29 cell line. The correlation was further strengthened by studies in COLO 205 cells that were induced to differentiate with herbimycin A treatment. HIP expression was significantly higher when the cells were induced to differentiate. Withdrawal of herbimycin A resulted in a reversal of morphological changes associated with differentiation and an associated decrease in HIP expression. These studies indicate that HIP is an important molecule for cell-cell and cell-extracellular matrix adhesion. The up-regulation of HIP may be an early event in tumorigenesis, and its increased expression may facilitate growth and local invasion. A lower expression of HIP in tumors results in decreased cell adhesion, favoring metastasis. HIP is a candidate marker of abnormal cell growth in the colon and a prognostic marker for colorectal carcinoma.

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