Roy Hemant K, Olusola Bola F, Clemens Dahn L, Karolski William J, Ratashak Anne, Lynch Henry T, Smyrk Thomas C
Department of Internal Medicine, University of Nebraska Medical Center/Eppley Cancer Institute, 982000 Nebraska Medical Center, Omaha, NE 68198-2000, USA.
Carcinogenesis. 2002 Jan;23(1):201-5. doi: 10.1093/carcin/23.1.201.
The inhibition of apoptosis is a critical event in the development of colorectal malignancies, although the mechanism(s) remain incompletely understood. The anti-apoptotic proto-oncogene, AKT, has been implicated in the molecular pathogenesis of a variety of human malignancies; however, no data exist on the role of AKT in colon carcinogenesis. We therefore evaluated the presence of AKT in human and experimental colon neoplasms by immunohistochemistry. Normal colonic mucosa and hyperplastic polyps exhibited no significant AKT expression, in marked contrast to the dramatic AKT immunoreactivity seen in colorectal cancers (57% positive) and in both human colorectal cancer cell lines examined. Importantly, AKT was also detected in 57% of the adenomas examined, implicating overexpression of this proto-oncogene as an early event during colon carcinogenesis. Moreover, in the rodent-carcinogen model, azoxymethane (AOM)-treatment induced AKT expression in premalignant rat colonocytes. Tumors that evolve via different genetic pathways displayed a lower incidence of AKT overexpression. Indeed, only 22% of mismatch repair defective tumors and 42% of AOM-induced rodent tumors upregulated AKT. Staining with an antibody specific for AKT 2 duplicated findings with the AKT 1&2 antibody, suggesting that AKT 2 was the predominant isoform involved in colon carcinogenesis. Furthermore, utilizing an antibody that specifically recognizes the serine-473 phosphorylated form of AKT, we observed that activated AKT was detectable in the neoplastic but not normal epithelium. In summary, our immunohistochemical analysis indicates AKT overexpression occurs frequently during human colon carcinogenesis, but is less common in colon cancers with microsatellite instability. The early inhibition of apoptosis during sporadic colon carcinogenesis may be related, at least partly, to the overexpression of AKT.
细胞凋亡的抑制是结直肠癌发生发展中的一个关键事件，尽管其机制仍未完全明确。抗凋亡原癌基因AKT已被证实与多种人类恶性肿瘤的分子发病机制有关；然而，关于AKT在结肠癌发生中的作用尚无相关数据。因此，我们通过免疫组织化学评估了AKT在人类和实验性结肠肿瘤中的存在情况。正常结肠黏膜和增生性息肉未表现出明显的AKT表达，这与在结直肠癌（57%呈阳性）以及所检测的两个人类结肠癌细胞系中观察到的显著AKT免疫反应性形成鲜明对比。重要的是，在所检测的腺瘤中也有57%检测到AKT，这表明该原癌基因的过表达是结肠癌发生过程中的早期事件。此外，在啮齿动物致癌物模型中，用偶氮甲烷（AOM）处理可诱导癌前大鼠结肠细胞中AKT表达。通过不同遗传途径发展而来的肿瘤中AKT过表达的发生率较低。事实上，错配修复缺陷肿瘤中只有22%以及AOM诱导的啮齿动物肿瘤中只有42%上调了AKT。用针对AKT 2的特异性抗体染色得到的结果与用AKT 1&2抗体得到的结果一致，这表明AKT 2是参与结肠癌发生的主要亚型。此外，利用一种特异性识别AKT丝氨酸-473磷酸化形式的抗体，我们观察到活化的AKT在肿瘤上皮而非正常上皮中可检测到。总之，我们的免疫组织化学分析表明，AKT过表达在人类结肠癌发生过程中频繁出现，但在具有微卫星不稳定性的结肠癌中较少见。散发性结肠癌发生过程中细胞凋亡的早期抑制可能至少部分与AKT的过表达有关。
