Prognostic significance of metallothionein in human gastrointestinal cancer

Purpose: Metallothionein (MT) is a small protein with a high affinity for divalent heavy metal ions. This metalloprotein is involved in many (patho) physiological processes, like metal homeostasis and detoxification, cell proliferation, apoptosis, therapy resistance, and protection against oxidative damage. Alterations in the immunohistochemical expression of NIT have been reported for various human tumors, and a high expression has been found to be associated with a poor clinical outcome. We showed previously that gastrointestinal cancer is accompanied by a decrease in NIT expression, but the most malignant phenotypes had the highest NIT levels. The purpose of the present study was to assess the clinical relevance of NIT in gastrointestinal cancer. Experimental Design: In this study, we determined the MT levels, by radioimmunoassay, in intestinal tissue of 251 patients with colorectal cancer and 81 patients with gastric cancer and assessed the relation with the overall survival of these patients. Results: More than 74% of the carcinomas were found to have a lower NIT level than their corresponding normal mucosa. In colorectal cancer patients, but not in gastric cancer patients, a high NIT level in both the carcinomas and normal mucosa was, however, significantly associated with a poor overall survival, independently from clinicopathological features. Conclusions: Overexpression of NIT in intestinal tissue of colorectal cancer patients is a prognostic marker for a poor overall survival. In gastric cancer, however, NIT expression in the gastric mucosa is not of prognostic significance. This observation emphasizes the clinical relevance of this multifunctional metalloprotein in colorectal carcinogenesis and therapy.