EXPRESSION OF BCL-X-L, AN ANTIAPOPTOTIC MEMBER OF THE BCL-2 FAMILY, IN ESOPHAGEAL SQUAMOUS-CELL CARCINOMA

Bcl-X, a Bcl-2-related protein, is a potent antagonist of apoptosis in its long splice variant (Bcl-X-L), The present study was performed to determine its expression in preneoplastic and neoplastic lesions of t he esophagus, its correlation with other members of the Bcl-2 family, and its impact on the outcome of surgically treated esophageal cancer patients, Samples of normal esophageal squamous epithelium (n = 10), s evere squamous cell dysplasias (n = 19), carcinomas in situ (n = 14), invasive squamous cell carcinomas (n = 172), and lymph node metastases (n = 21) were immunohistochemically analyzed for Bcl-X-L expression u sing a polyclonal anti-Bcl-X-L antibody, The immunostaining was evalua ted according to a score system (0 - 12 points) based on the percentag e of positive tumor cells and the relative immunostaining intensity, C ytoplasmic staining for Bcl-X-L protein was invariably found in all ce ll layers of the normal esophageal squamous epithelium. In contrast, a considerable portion of preneoplastic and neoplastic lesions display a decreased Bcl-X-L expression as compared with that in the normal eso phageal epithelium. On comparison of the amount of Bcl-X-L expression between the different types of lesions, however, no significant differ ences were found between severe squamous cell dysplasias (mean immunor eactive score +/- SD, 5.2 +/- 1.8), carcinomas in situ (5.2 +/- 2.2), invasive carcinomas (4.5 +/- 2.8), and lymph node metastases (4.2 +/- 2.6), In invasive carcinomas, Bcl-X-L expression decreased continuousl y with decreasing tumor differentiation (P = 0.0001) and was also dire ctly correlated with bcl-2-associated X protein expression (P = 0.0001 ), On the contrary, an inverse correlation was found between Bcl-X-L e xpression and Bcl-2 protein expression (P = 0.0001), No correlation wa s found between Bcl-X-L expression and the parameters pT category, pN category, and tumor size, In the univariate survival analysis, patient s with low immunoreactive scores (less than or equal to 4) of Bcl-X-L expression in the tumor tissue showed lower 2-year and 5-year survival rates than patients with high immunoreactive scores (>4; P = 0.0485), In multivariate survival analysis, however, only the parameters pN ca tegory and pT category, but not Bcl-X-L expression, could be verified as independent prognostic factors, This tendency of decreasing levels of an antiapoptotic protein toward unfavorable outcome is supported by an increasing number of studies on the role of Bcl-2, another antiapo ptotic protein, and must be interpreted against the backdrop of apopto sis as a result of the interaction of many cell death-promoting and pr otecting proteins.