Elevated expression of Bcl-X and reduced bak in primary colorectal adenocarcinomas

• Published in: Cancer research (Chicago, Ill.) Ill.), 1996-05, Vol.56 (10), p.2422-2427
• Main Authors: KRAJEWSKA, M, MOSS, S. F, KRAJEWSKI, S, SONG, K, HOLT, P. R, REED, J. C
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenoma - genetics; Adenoma - metabolism; Amino Acid Sequence; Apoptosis - genetics; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein; bcl-X Protein; Biological and medical sciences; Cell Transformation, Neoplastic - genetics; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Disease Progression; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic; Humans; Medical sciences; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Molecular Sequence Data; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Proto-Oncogene Proteins - biosynthesis; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins c-bcl-2; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors
• ISSN: 0008-5472; 1538-7445

Expression of several members of the BCL-2 family of genes was investigated by immunohistochemical methods in 30 primary colorectal adenocarcinomas and 24 adenomatous polyps. When compared to the intensity observed in adjacent normal mucosal epithelial cells, the intensity of Bcl-X immunostaining was elevated in 18 of 30 (60%) carcinomas (P = 0.0001) and 12 of 24 (50%) adenomatous polyps (P = 0.0001). Immunoblot analysis of five pairs of tumors and adjacent normal colonic tissue indicated marked elevations in the relative levels of the anti-apoptotic Bcl-XL, protein in all cases. In contrast to the increased Bcl-X expression, the intensity of Bcl-2 immunostaining was greater than that of normal colonic mucosa in only 3 of 30 (10%) carcinomas and, in fact, was lower than that of adjacent normal epithelia] cells in 25 (83%) cases (P = 0.0001). Furthermore, the percentage of Bcl-2 immunopositive cells was generally lower in carcinomas than in adenomas (mean +/- SE, 44 +/- 6% versus 73 +/- 5%, respectively; P = 0.001) and in moderately or poorly differentiated tumors than in well-differentiated tumors (39 +/- 6% versus 70 +/- 11%, respectively; P = 0.045). In addition, the proportion of tumors in which the Bcl-2 immunointensity was more than or equal to that of normal colonic mucosa was significantly lower in carcinomas than adenomas (5 of 30 versus 15 of 24, respectively; P < 0.001), suggesting that decreases in Bcl-2 expression represent a later event associated with the progression of colorectal cancers. When compared to that of normal adjacent colonic epithelium, the intensity of Mcl-1 immunostaining was reduced in 20 of 30 (67%) of carcinomas (P = 0.0001) compared to only 1 of 24 adenomas, suggesting that decreases in Mcl-1 expression represent a later event associated with progression from a benign to a malignant phenotype or with transition to a less-differentiated state, because most of the carcinomas evaluated here (25 of 30; 83%) were not well differentiated. The intensity of immunostaining for the pro-apoptotic protein Bak was reduced compared to that of normal mucosal epithelial cells in 27 of 30 (90%) carcinomas and 22 of 24 (92%) adenomas, suggesting that reductions in Bak expression occur early in colorectal tumor progression (P = 0.0001). In contrast, the intensity of immunostaining for the pro-apoptotic protein Bax was not significantly altered in carcinomas; compared to that of normal colonic mucosa, Bax immunointensity was reduced in only 7