Thioredoxin, a putative oncogene product, is overexpressed in gastric carcinoma and associated with increased proliferation and increased cell survival

Human thioredoxin is a putative oncogene that may confer both a growth and survival advantage to tumor cells. Overexpressed thioredoxin mRNA has been found in both primary human lung and colorectal cancers. To determine the i ntratumor distribution and amount of thioredoxin protein in human primary c arcinomas, we developed an immunohistochemical assay for thioredoxin in par affin-embedded tissue. We then studied 10 patients with primary high-risk g astric carcinoma. To further relate thioredoxin protein overexpression to c ell death and survival, we used a paraffin-based in situ end-labeling (ISEL ) assay. To delineate proliferation, we used the nuclear proliferation anti gen detected by Ki-67. In this survey, we found that thioredoxin was locali zed to tumor cells and overexpressed compared with normal gastric mucosa in 8 of 10 gastric carcinomas. The thioredoxin was found at high levels in 5 of the 8 overexpressing carcinomas. The overexpression of thioredoxin was t ypically found in both a nuclear and cytoplasmic location in the neoplastic cells. There was a significant positive correlation (P = .0061) with cance r cell proliferation measured by Ki-67. There was a significant negative co rrelation (P = .0001) with DNA damage measured by the ISEL assay, suggestin g decreased apoptosis and increased carcinoma cell survival. Thus, human pr imary gastric tumors that are highly expressive of thioredoxin have both a higher proliferative rate and a higher survival rate than tumors that do no t express thioredoxin. With these newly developed assays in hand, it is now feasible to question whether this: thioredoxin-related combined growth and survival advantage translates into poor clinical outcome. HUM PATHOL 31:47 5-481, 2000. Copyright (C) 2000 by W.B. Saunders Company.