Increased expression of N-myristoyltransferase in gallbladder carcinomas

Abstract

Activated Src, which has intrinsic protein tyrosine kinase activity, has been found in human solid tumors such as colorectal and breast carcinomas. The Src gene encodes a cytoplasmic tyrosine kinase p60src, which attaches to the inner surface of the membrane after N-terminal myristoylation and is implicated in transduction of signals to the nucleus. N-myristoyltransferase (NMT) catalyzes the biochemical modification process called N-myristoylation. To investigate whether, through Src, NMT contributes to the pathogenesis of gallbladder carcinoma, the authors investigated expression of NMT and p53 in in situ and invasive carcinomas. One hundred cases of documented gallbladder carcinoma were reviewed, and 30 cases were selected randomly to evaluate expression of NMT and p53 by immunohistochemistry in both in situ and in invasive tumor components. Eighteen cases (60%) of gallbladder carcinoma showed moderate to strong cytoplasmic positivity for NMT with increased intensity in the invasive component, and 12 cases (40%) were negative. The in situ component revealed mild to moderate cytoplasmic staining in 20 cases (67%), whereas the normal gallbladder mucosa showed weak to negative cytoplasmic staining. Moderate to strong p53 staining was observed in 17 in situ cases (63%) and 24 invasive cases (80%). The in situ staining patterns of p53 were unrelated to the clinical outcome of the tumor. However, moderate to strong staining of the invasive component as observed in 15 cases (50%) was associated with a mean survival of 8.8 months. Amplification of intron-8 in normal gallbladder mucosa and invasive carcinoma were similar in intensity, suggesting the absence of NMT gene amplification in these tumors. The increased expression of NMT in these tumors could be due to transcriptional activation. Tumors with increased expression of NMT and p53 were associated with poor clinical outcomes as evidenced by their mean survival times. NMT is likely to play a pathogenic role in gallbladder carcinoma.