Distribution of carbonic anhydrase IX, MN/CA IX, in normal and neoplastic gastrointestinal and hepatobiliary tissues : its potential value as a new biomarker and comparison of its expression with that of isoenzymes I, II, IV, V, and VI

Abstract

<div lang="en" class="abs"><p class="abs_header">Abstract</p><p>The carbonic anhydrase (CA) gene family contains eleven active members, the basic physiological functions of which are linked to the interconversion of carbon dioxide and bicarbonate (CO₂ + H₂O ⇔ H⁺ + HCO₃⇔ H₂CO₃^-). They participate in a variety of physiological processes that involve pH regulation, CO₂ and HCO₃^- transport and water and electrolyte balance, and some new functions have also been suggested recently. A novel tumour-associated antigen, MN, containing a CA-domain and named MN/CA IX, has been found to promote cell proliferation when transfected into NIH3T3 cells and has also been shown to be a potential biomarker for neoplasia in the uterine cervix.</p><p>The present study examines the expression of MN/CA IX in the normal alimentary tract by immunohistochemistry and compares it with the expression of cytoplasmic CA I, CA II, apical plasma membrane associated CA IV and secretory CA VI. The distribution of mitochondrial CA V is examined by immunohistochemistry and Western blotting. The value of MN/CA IX as a potential biomarker of gastrointestinal tumours is assessed in a series of colorectal and hepatobiliary neoplasms.</p><p>A positive immunoreaction for MN/CA IX was detected in the basolateral plasma membrane of the gastric, intestinal and biliary epithelium, but was confined to the proliferating cryptal enterocytes in the human gut, suggesting a role in cellular proliferation. In colorectal tumours, MN/CA IX immunoreaction was also located in the proliferative zone, indicating that it could be a useful marker of cellular proliferation. In the case of hepatobiliary tumours a positive signal was mainly associated with tumours of biliary epithelial parentage.</p><p>These results demonstrate that MN/CA IX has a unique expression pattern in the alimentary tract relative to other CAs. Its localization and enzymatic properties suggest that it may have a dual function in the gastrointestinal epithelium. Through its CA activity it could participate in the regulation of carbon dioxide/bicarbonate homeostasis, while its localization to the basolateral surfaces of proliferating cryptal enterocytes suggests that it may serve as a ligand or receptor for one or more other proteins that regulate intercellular communication and/or cell proliferation. MN/CA IX may also serve as a new biomarker of gastrointestinal tumours.</p></div>