Basic research and clinical application of SAP-1, a protein tyrosine phosphatase expressed in gastrointestinal cancers.

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Since the level of tyrosine phosphorylation is determined by the balance between the actions of both protein tyrosine kinases and protein tyrosine phosphatases (PTPases), not only the unregulated activation of PTKs but also the inactivation of PTPases may be involved in the malignant transformation of gastrointestinal cells. SAP-1 is a human transmembrane-type PTPase that has recently been molecularly cloned. This enzyme contains a single PTPase domain in the cytoplasmic region and eight fibronectin type III-like domains with multiple potential N-glycosylation sites in the extracellular region. SAP-1 is abundant in human colorectal cancer cell lines and pancreatic cancer cell lines but not in the corresponding normal tissues. In this study, we investigated the physiological roles of SAP-1 and clinical applications of SAP-1. (1) Overexpression of SAP-1 inhibited growth of cultured cells. SAP-1 binds to EGF receptors. (2) Genomic DNA of SAP-1 promoter region was cloned and several transcription factor binding elements were observed. (3) With the use of immunohistochemistry, we have now examined the expression of SAP-1 in surgically or endoscopically excised colorectal cancers, adenoma and normal colon mucosa. Normal colon tissue or adenomas with mild dysplasia showed no detectable expression of SAP-1. In contrast, 19 of 48 (40%) adenocarcinomas expressed SAP-1. Sequencing of the K-RAS gene revealed that 10 of 15 (67%) SAP-1-positive cancers contained a mutation in codon 12. These results suggest that SAP-1 is frequently overexpressed in human colorectal cancers and that such overexpression may occur relatively late in the adenoma-carcinoma sequence. We will further investigate the existance of soluble form of SAP-1 in serm of patients with cob-rectal or pancreatic cancers.