Elevated expression of Bcl-X and reduced Bak in primary colorectal adenocarcinomas.
Elevated expression of Bcl-X and reduced Bak in primary colorectal adenocarcinomas.
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发表时间：
1996-05
期刊：
影响因子：
11.2
通讯作者：
M. Krajewska;S. Moss;S. Krajewski;K. Song;P. Holt;John Calvin Reed
中科院分区：
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作者：
M. Krajewska;S. Moss;S. Krajewski;K. Song;P. Holt;John Calvin Reed
用免疫组化方法检测了30例原发性结直肠腺癌和24例腺瘤性息肉中BCL-2家族基因的表达。当与邻近正常粘膜上皮细胞中观察到的强度相比时，Bcl-X免疫染色强度在30例癌中的18例（60%）（P = 0.0001）和24例腺瘤性息肉中的12例（50%）（P = 0.0001）中升高。五对肿瘤和邻近正常结肠组织的免疫印迹分析表明，在所有情况下，抗凋亡Bcl-XL蛋白的相对水平显着升高。与Bcl-X表达增强相反，Bcl-2免疫染色强度在30例癌中仅3例（10%）高于正常结肠粘膜，而在25例（83%）中低于癌旁正常上皮细胞（P = 0.0001）。此外，癌中Bcl-2免疫阳性细胞的百分比通常低于腺瘤（平均值+/- SE，分别为44 +/- 6%和73 +/-5%; P = 0.001），中度或低分化肿瘤中的Bcl-2免疫阳性细胞百分比低于高分化肿瘤（分别为39 +/- 6%和70 +/-11%; P = 0.045）。此外，Bcl-2免疫强度大于或等于正常结肠粘膜的肿瘤比例在癌中显著低于腺瘤（分别为30例中的5例与24例中的15例; P < 0.001），表明Bcl-2表达的降低代表了与结直肠癌进展相关的晚期事件。与癌旁正常结肠上皮相比，30例结肠癌中有20例（67%）Mcl-1免疫染色强度降低（P = 0.0001），而24个腺瘤中只有1个，表明Mcl-1表达的降低代表了与从良性到恶性表型的进展或与向低分化状态的转变相关的后期事件，因为这里评估的大多数癌（30例中的25例; 83%）没有很好地分化。与正常粘膜上皮细胞相比，在30例癌中的27例（90%）和24例腺瘤中的22例（92%）中促凋亡蛋白巴克的免疫染色强度降低，表明巴克表达的降低发生在结直肠肿瘤进展的早期（P = 0.0001）。与此相反，促凋亡蛋白Bax的免疫染色强度没有显着改变癌相比，正常结肠粘膜，Bax免疫强度降低，只有7 30（23%）癌和3 24（13%）腺瘤，Bax免疫阳性细胞的百分比也没有显着不同的任何组织学亚组。综上所述，这些结果表明，Bcl-XL的表达在未分化的原发性结肠直肠癌中增加，通常伴随着抗凋亡蛋白Bcl-2和Mcl-1以及促凋亡蛋白巴克的相互减少，而Bax的表达相对恒定。因此，在结直肠肿瘤的进展过程中，可能发生从抗凋亡蛋白Bcl-2和Mcl-1到Bcl-XL蛋白的表达的转变。
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 of 30 (23%) carcinomas and 3 of 24 (13%) adenomas, and the percentage of Bax immunopositive cells was also not significantly different in any of the histological subgroups. Taken together, these results suggest that expression of Bcl-XL is increased in undifferentiated primary colorectal cancers, often with accompanying reciprocal decreases in the anti-apoptotic proteins Bcl-2 and Mcl-1 and the pro-apoptotic protein Bak, whereas Bax expression is relatively constant. Thus, a shift from expression of the anti-apoptotic proteins Bcl-2 and Mcl-1 to the Bcl-XL protein may occur during progression of colorectal tumors.